NCBI Conserved Domain Search

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-gamma; This family ...

311-458

1.61e-111

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-gamma; This family corresponds to the catalytic domain present in metazoan phosphoinositide-specific phospholipase C (PI-PLC, EC 3.1.4.11)-gamma isozymes. PI-PLC is a signaling enzyme that hydrolyzes the membrane phospholipids phosphatidylinositol-4,5-bisphosphate (PIP2) to generate two important second messengers in eukaryotic signal transduction cascades, inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG). InsP3 triggers inflow of calcium from intracellular stores, while DAG, together with calcium, activates protein kinase C, which goes on to phosphorylate other molecules, leading to altered cellular activity. Calcium is required for the catalysis. PI-PLC-gamma represents a class of mammalian PI-PLC that has an N-terminal pleckstrin homology (PH) domain, an array of EF hands, a PLC catalytic core domain, and a C2 domain.The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. Unique to PI-PLC-gamma, a second PH domain, two SH2 (Src homology 2) regions, and one SH3 (Src homology 3) region is present within this linker region. There are two PI-PLC-gamma isozymes (1-2). They are activated by receptor and non-receptor tyrosine kinases due to the presence of two SH2 and a single SH3 domain within the linker region. Aside from the two PI-PLC-gamma isozymes identified in mammals, some eukaryotic PI-PLC-gamma homologs have been classified with this subfamily.

Pssm-ID: 176534 [Multi-domain] Cd Length: 229 Bit Score: 348.65 E-value: 1.61e-111

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    311 MQDMNNPLSHYWISSSHNTYLTGDQLRSESSPEAYIRCLRMGCRCIELDCWDGPDGKPVIYHGWTRTTKIKFDDVVQAIK 390
Cdd:cd08592    1 PQDMNNPLSHYWIASSHNTYLTGDQLSSESSLEAYARCLRMGCRCIELDCWDGPDGMPIIYHGHTLTSKIKFMDVLKTIK 80

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 190036    391 DHAFVTSSFPVILSIEEHCSVEQQRHMAKAFKEVFGDLLLTKPTEASADQLPSPSQLREKIIIKHKKL 458
Cdd:cd08592   81 EHAFVTSEYPVILSIENHCSLPQQRNMAQAFKEVFGDMLLTQPVDRNADQLPSPNQLKRKIIIKHKKL 148

EFh_PI-PLCgamma2

cd16215

1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2; PI-PLC-gamma2, also termed ...

145-298

3.05e-99

1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2; PI-PLC-gamma2, also termed 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2, or phospholipase C-IV (PLC-IV), or phospholipase C-gamma-2 (PLC-gamma-2), is highly expressed in cells of hematopoietic origin. It has been implicated in cell motility important to invasion and dissemination of tumor cells. As an important component of the B cell receptor (BCR) signaling pathway, PI-PLC-gamma2 is required for efficient formation of germinal center (GC) and memory B cells. It works as a critical effector stimulating the increase of intracellular Ca2+ and activates various signaling pathways downstream of the BCR. Moreover, PI-PLC-gamma2 has been implicated in Fc receptor-mediated degranulation of mast cells, integrin signaling in platelets, as well as integrin and Fc receptor-mediated neutrophil functions. It also acts as a crucial signaling mediator modifying DC gene expression program to activate DC responses to beta-glucan-containing pathogens. PI-PLC-gamma2 contains an N-terminal pleckstrin homology (PH) domain, an array of EF hands, a PLC catalytic core domain, and a C2 domain. The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. Besides, PI-PLC-gamma2 has a second PH domain, two SH2 (Src homology 2) regions, and one SH3 (Src homology 3) region, which are present within this linker. PI-PLC-gamma2 is activated by receptor and non-receptor tyrosine kinases via its two SH2 and a single SH3 domain. Unlike PI-PLC-gamma1, the activation of PI-PLC-gamma2 may require concurrent stimulation of PI 3-kinase.

Pssm-ID: 320045 Cd Length: 154 Bit Score: 312.17 E-value: 3.05e-99

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    145 WLRKQIYSVDQTRRNSISLRELKTILPLINFKVSSAKFLKDKFVEIGAHKDELSFEQFHLFYKKLMFEQQKSILDEFKKD 224
Cdd:cd16215    1 WLRKQIYSVDQTRRNSISVRELKTILPQVNFKVPSAKFLKDKFQEIGAKKDELTFEQFHLFYKKLMFEQQKSILDEFKKD 80

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 190036    225 SSVFILGNTDRPDASAVYLHDFQRFLIHEQQEHWAQDLNKVRERMTKFIDDTMRETAEPFLFVDEFLTYLFSRE 298
Cdd:cd16215   81 SSVFILGNTDRPDASAVHLHDFQRFLVHEQKESWAQDLNKVRERMTKFIDDTMRETAEPFLFVDEFLTYLFSKE 154

PI-PLCc_GDPD_SF super family

cl14615

Catalytic domain of phosphoinositide-specific phospholipase C-like phosphodiesterases ...

926-1031

1.78e-69

Catalytic domain of phosphoinositide-specific phospholipase C-like phosphodiesterases superfamily; The PI-PLC-like phosphodiesterases superfamily represents the catalytic domains of bacterial phosphatidylinositol-specific phospholipase C (PI-PLC, EC 4.6.1.13), eukaryotic phosphoinositide-specific phospholipase C (PI-PLC, EC 3.1.4.11), glycerophosphodiester phosphodiesterases (GP-GDE, EC 3.1.4.46), sphingomyelinases D (SMases D) (sphingomyelin phosphodiesterase D, EC 3.1.4.41) from spider venom, SMases D-like proteins, and phospholipase D (PLD) from several pathogenic bacteria, as well as their uncharacterized homologs found in organisms ranging from bacteria and archaea to metazoans, plants, and fungi. PI-PLCs are ubiquitous enzymes hydrolyzing the membrane lipid phosphoinositides to yield two important second messengers, inositol phosphates and diacylglycerol (DAG). GP-GDEs play essential roles in glycerol metabolism and catalyze the hydrolysis of glycerophosphodiesters to sn-glycerol-3-phosphate (G3P) and the corresponding alcohols that are major sources of carbon and phosphate. Both, PI-PLCs and GP-GDEs, can hydrolyze the 3'-5' phosphodiester bonds in different substrates, and utilize a similar mechanism of general base and acid catalysis with conserved histidine residues, which consists of two steps, a phosphotransfer and a phosphodiesterase reaction. This superfamily also includes Neurospora crassa ankyrin repeat protein NUC-2 and its Saccharomyces cerevisiae counterpart, Phosphate system positive regulatory protein PHO81, glycerophosphodiester phosphodiesterase (GP-GDE)-like protein SHV3 and SHV3-like proteins (SVLs). The residues essential for enzyme activities and metal binding are not conserved in these sequence homologs, which might suggest that the function of catalytic domains in these proteins might be distinct from those in typical PLC-like phosphodiesterases.

The actual alignment was detected with superfamily member cd08628:

Pssm-ID: 472694 [Multi-domain] Cd Length: 254 Bit Score: 233.79 E-value: 1.78e-69

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    926 IAIELSDLVVYCKPTSKTKDNLENPDFREIRSFVETKADSIIRQKPVDLLKYNQKGLTRVYPKGQRVDSSNYDPFRLWLC 1005
Cdd:cd08628  149 IAIELSDLVVYCKPTSKTKDNLENPDFKEIRSFVETKAPSIIRQKPVQLLKYNRKGLTRVYPKGQRVDSSNYDPFRLWLC 228

                         90       100
                 ....*....|....*....|....*.
gi 190036   1006 GSQMVALNFQTADKYMQMNHALFSLN 1031
Cdd:cd08628  229 GSQMVALNFQTADKYMQLNHALFSLN 254

PH_PLC_gamma

cd13362

Phospholipase C-gamma (PLC-gamma) pleckstrin homology (PH) domain; PLC-gamma (PLCgamma) is ...

22-140

4.82e-61

Phospholipase C-gamma (PLC-gamma) pleckstrin homology (PH) domain; PLC-gamma (PLCgamma) is activated by receptor and non-receptor tyrosine kinases due to the presence of its SH2 and SH3 domains. There are two main isoforms of PLC-gamma expressed in human specimens, PLC-gamma1 and PLC-gamma2. PLC-gamma consists of an N-terminal PH domain, a EF hand domain, a catalytic domain split into X and Y halves internal to which is a PH domain split by two SH2 domains and a single SH3 domain, and a C-terminal C2 domain. Only the first PH domain is present in this hierarchy. PLCs (EC 3.1.4.3) play a role in the initiation of cellular activation, proliferation, differentiation and apoptosis. They are central to inositol lipid signalling pathways, facilitating intracellular Ca2+ release and protein kinase C (PKC) activation. Specificaly, PLCs catalyze the cleavage of phosphatidylinositol-4,5-bisphosphate (PIP2) and result in the release of 1,2-diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3). These products trigger the activation of protein kinase C (PKC) and the release of Ca2+ from intracellular stores. There are fourteen kinds of mammalian phospholipase C proteins which are are classified into six isotypes (beta, gamma, delta, epsilon, zeta, eta). PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

Pssm-ID: 270168 Cd Length: 121 Bit Score: 204.05 E-value: 4.82e-61

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036     22 LELGTVMTVFsFRKSTPERRTVQVIMETRQVAWSKTADK-IEGFLDIMEIKEIRPGKNSKDFERAKAV--RQKEDCCFTI 98
Cdd:cd13362    1 LERGTVMTKF-YQKKRPERRTFQVKLETRQVVWSRGGGKrAEGAVDIREIKEIRPGKNSKDFERWPDEakKLDPSCCFVI 79

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|..
gi 190036     99 LYGTQFVLSTLSLAADSKEDAVNWLSGLKILHQEAMNASTPT 140
Cdd:cd13362   80 LYGTEFRLKTLSVAATSEEECDMWIKGLRYLVEDTLSASYPL 121

SH2_C-SH2_PLC_gamma_like

cd09932

C-terminal Src homology 2 (C-SH2) domain in Phospholipase C gamma; Phospholipase C gamma is a ...

641-744

2.99e-59

C-terminal Src homology 2 (C-SH2) domain in Phospholipase C gamma; Phospholipase C gamma is a signaling molecule that is recruited to the C-terminal tail of the receptor upon autophosphorylation of a highly conserved tyrosine. PLCgamma is composed of a Pleckstrin homology (PH) domain followed by an elongation factor (EF) domain, 2 catalytic regions of PLC domains that flank 2 tandem SH2 domains (N-SH2, C-SH2), and ending with a SH3 domain and C2 domain. N-SH2 SH2 domain-mediated interactions represent a crucial step in transmembrane signaling by receptor tyrosine kinases. SH2 domains recognize phosphotyrosine (pY) in the context of particular sequence motifs in receptor phosphorylation sites. Both N-SH2 and C-SH2 have a very similar binding affinity to pY. But in growth factor stimulated cells these domains bind to different target proteins. N-SH2 binds to pY containing sites in the C-terminal tails of tyrosine kinases and other receptors. Recently it has been shown that this interaction is mediated by phosphorylation-independent interactions between a secondary binding site found exclusively on the N-SH2 domain and a region of the FGFR1 tyrosine kinase domain. This secondary site on the SH2 cooperates with the canonical pY site to regulate selectivity in mediating a specific cellular process. C-SH2 binds to an intramolecular site on PLCgamma itself which allows it to hydrolyze phosphatidylinositol-4,5-bisphosphate into diacylglycerol and inositol triphosphate. These then activate protein kinase C and release calcium. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198186 Cd Length: 104 Bit Score: 198.26 E-value: 2.99e-59

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    641 HESKPWYYDSLSRGEAEDMLMRIPRDGAFLIRKRE-GSDSYAITFRARGKVKHCRINRDGRHFVLGTSAyFESLVELVSY 719
Cdd:cd09932    1 HESKEWFHANLTREQAEEMLMRVPRDGAFLVRPSEtDPNSFAISFRAEGKIKHCRIKQEGRLFVIGTSQ-FESLVELVSY 79

                         90       100
                 ....*....|....*....|....*
gi 190036    720 YEKHSLYRKMRLRYPVTPELLERYN 744
Cdd:cd09932   80 YEKHPLYRKIKLRYPVNEELLEKYG 104

SH2_N-SH2_PLC_gamma_like

cd10341

N-terminal Src homology 2 (N-SH2) domain in Phospholipase C gamma; Phospholipase C gamma is a ...

527-627

6.24e-52

N-terminal Src homology 2 (N-SH2) domain in Phospholipase C gamma; Phospholipase C gamma is a signaling molecule that is recruited to the C-terminal tail of the receptor upon autophosphorylation of a highly conserved tyrosine. PLCgamma is composed of a Pleckstrin homology (PH) domain followed by an elongation factor (EF) domain, 2 catalytic regions of PLC domains that flank 2 tandem SH2 domains (N-SH2, C-SH2), and ending with a SH3 domain and C2 domain. N-SH2 SH2 domain-mediated interactions represent a crucial step in transmembrane signaling by receptor tyrosine kinases. SH2 domains recognize phosphotyrosine (pY) in the context of particular sequence motifs in receptor phosphorylation sites. Both N-SH2 and C-SH2 have a very similar binding affinity to pY. But in growth factor stimulated cells these domains bind to different target proteins. N-SH2 binds to pY containing sites in the C-terminal tails of tyrosine kinases and other receptors. Recently it has been shown that this interaction is mediated by phosphorylation-independent interactions between a secondary binding site found exclusively on the N-SH2 domain and a region of the FGFR1 tyrosine kinase domain. This secondary site on the SH2 cooperates with the canonical pY site to regulate selectivity in mediating a specific cellular process. C-SH2 binds to an intramolecular site on PLCgamma itself which allows it to hydrolyze phosphatidylinositol-4,5-bisphosphate into diacylglycerol and inositol triphosphate. These then activate protein kinase C and release calcium. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 199829 Cd Length: 99 Bit Score: 177.16 E-value: 6.24e-52

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    527 HFGEKWFHKKV-EKRTSAEKLLQEYCMetgGKDGTFLVRESETFPNDYTLSFWRSGRVQHCRIRSTMEGGTLKYYLTDNL 605
Cdd:cd10341    1 HFTEPWFHGKLgDGRDEAEKLLLEYCE---GGDGTFLVRESETFVGDYTLSFWRNGKVQHCRIRSRQENGEKKYYLTDNL 77

                         90       100
                 ....*....|....*....|..
gi 190036    606 RFRRMYALIQHYRETHLPCAEF 627
Cdd:cd10341   78 VFDSLYELIDYYRQNPLRCAEF 99

C2_PLC_like

cd00275

C2 domain present in Phosphoinositide-specific phospholipases C (PLC); PLCs are involved in ...

1061-1187

8.27e-45

C2 domain present in Phosphoinositide-specific phospholipases C (PLC); PLCs are involved in the hydrolysis of phosphatidylinositol-4,5-bisphosphate (PIP2) to d-myo-inositol-1,4,5-trisphosphate (1,4,5-IP3) and sn-1,2-diacylglycerol (DAG). 1,4,5-IP3 and DAG are second messengers in eukaryotic signal transduction cascades. PLC is composed of a N-terminal PH domain followed by a series of EF hands, a catalytic TIM barrel and a C-terminal C2 domain. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. Members here have a type-II topology.

Pssm-ID: 175974 [Multi-domain] Cd Length: 128 Bit Score: 158.09 E-value: 8.27e-45

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036   1061 MTLTVKVLGARHLPKLG---RSIACPFVEVEICGAEYG-NNKFKTTVVNDNGLSPIWaptQEKVTFEIYDPNLAFLRFVV 1136
Cdd:cd00275    2 LTLTIKIISGQQLPKPKgdkGSIVDPYVEVEIHGLPADdSAKFKTKVVKNNGFNPVW---NETFEFDVTVPELAFLRFVV 78

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|.
gi 190036   1137 YEEDMFSDpNFLAHATYPIKAVKSGFRSVPLKNGYSEDIELASLLVFCEMR 1187
Cdd:cd00275   79 YDEDSGDD-DFLGQACLPLDSLRQGYRHVPLLDSKGEPLELSTLFVHIDIT 128

PHsplit_PLC_gamma

Phospholipase C-gamma Split pleckstrin homology (PH) domain; PLC-gamma (PLCgamma) is activated ...

840-910

3.15e-35

Phospholipase C-gamma Split pleckstrin homology (PH) domain; PLC-gamma (PLCgamma) is activated by receptor and non-receptor tyrosine kinases due to the presence of its SH2 and SH3 domains. There are two main isoforms of PLC-gamma expressed in human specimens, PLC-gamma1 and PLC-gamma2. PLC-gamma consists of an N-terminal PH domain, a EF hand domain, a catalytic domain split into X and Y halves internal to which is a PH domain split by two SH2 domains and a single SH3 domain, and a C-terminal C2 domain. The split PH domain is present in this hierarchy. PLCs (EC 3.1.4.3) play a role in the initiation of cellular activation, proliferation, differentiation and apoptosis. They are central to inositol lipid signalling pathways, facilitating intracellular Ca2+ release and protein kinase C (PKC) activation. Specificaly, PLCs catalyze the cleavage of phosphatidylinositol-4,5-bisphosphate (PIP2) and result in the release of 1,2-diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3). These products trigger the activation of protein kinase C (PKC) and the release of Ca2+ from intracellular stores. There are fourteen kinds of mammalian phospholipase C proteins which are are classified into six isotypes (beta, gamma, delta, epsilon, zeta, eta). PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

Pssm-ID: 270054 Cd Length: 105 Bit Score: 129.90 E-value: 3.15e-35

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 190036    840 IEDNPLGSLCRGILDLNTYNVVKAPQGKNQKSFVFILEPKEQGDPPVEFATDRVEELFEWFQSIREITWKI 910
Cdd:cd13234   35 TENSPLGSLLRGILDVPSCHVVKRPEGKNSRPFVFILSPKSLSDPPLDVAADSQEELQDWVQKIREVAQTA 105

SH3_PLCgamma2

cd11969

Src homology 3 domain of Phospholipase C (PLC) gamma 2; PLCgamma2 is primarily expressed in ...

773-827

1.56e-33

Src homology 3 domain of Phospholipase C (PLC) gamma 2; PLCgamma2 is primarily expressed in haematopoietic cells, specifically in B cells. It is activated by tyrosine phosphorylation by B cell receptor (BCR) kinases and is recruited to the plasma membrane where its substrate is located. It is required in pre-BCR signaling and in the maturation of B cells. PLCs catalyze the hydrolysis of phosphatidylinositol (4,5)-bisphosphate [PtdIns(4,5)P2] to produce Ins(1,4,5)P3 and diacylglycerol (DAG). Ins(1,4,5)P3 initiates the calcium signaling cascade while DAG functions as an activator of PKC. PLCgamma contains a Pleckstrin homology (PH) domain followed by an elongation factor (EF) domain, two catalytic regions of PLC domains that flank two tandem SH2 domains, followed by a SH3 domain and C2 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212902 Cd Length: 55 Bit Score: 123.03 E-value: 1.56e-33

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 190036    773 TVKALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRIQQYFPSNYVEDI 827
Cdd:cd11969    1 TVKALYDYRAKRSDELSFCKGALIHNVSKETGGWWKGDYGGKVQHYFPSNYVEDV 55

PH-like super family

cl17171

Pleckstrin homology-like domain; The PH-like family includes the PH domain, both the Shc-like ...

475-510

6.84e-11

Pleckstrin homology-like domain; The PH-like family includes the PH domain, both the Shc-like and IRS-like PTB domains, the ran-binding domain, the EVH1 domain, a domain in neurobeachin and the third domain of FERM. All of these domains have a PH fold, but lack significant sequence similarity. They are generally involved in targeting to protein to the appropriate cellular location or interacting with a binding partner. This domain family possesses multiple functions including the ability to bind inositol phosphates and to other proteins.

The actual alignment was detected with superfamily member cd13234:

Pssm-ID: 473070 Cd Length: 105 Bit Score: 60.17 E-value: 6.84e-11

                         10        20        30
                 ....*....|....*....|....*....|....*.
gi 190036    475 HKQQGELYMWDSIDQKWTRHYCAIADAKLSFSDDIE 510
Cdd:cd13234    1 SIKNGILYLEDPINHEWYPHFFVLTSNKIYYSEETE 36

Name

Accession

Description

Interval

E-value

PI-PLCc_gamma

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-gamma; This family ...

311-458

1.61e-111

Pssm-ID: 176534 [Multi-domain] Cd Length: 229 Bit Score: 348.65 E-value: 1.61e-111

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    311 MQDMNNPLSHYWISSSHNTYLTGDQLRSESSPEAYIRCLRMGCRCIELDCWDGPDGKPVIYHGWTRTTKIKFDDVVQAIK 390
Cdd:cd08592    1 PQDMNNPLSHYWIASSHNTYLTGDQLSSESSLEAYARCLRMGCRCIELDCWDGPDGMPIIYHGHTLTSKIKFMDVLKTIK 80

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 190036    391 DHAFVTSSFPVILSIEEHCSVEQQRHMAKAFKEVFGDLLLTKPTEASADQLPSPSQLREKIIIKHKKL 458
Cdd:cd08592   81 EHAFVTSEYPVILSIENHCSLPQQRNMAQAFKEVFGDMLLTQPVDRNADQLPSPNQLKRKIIIKHKKL 148

EFh_PI-PLCgamma2

cd16215

1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2; PI-PLC-gamma2, also termed ...

145-298

3.05e-99

Pssm-ID: 320045 Cd Length: 154 Bit Score: 312.17 E-value: 3.05e-99

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    145 WLRKQIYSVDQTRRNSISLRELKTILPLINFKVSSAKFLKDKFVEIGAHKDELSFEQFHLFYKKLMFEQQKSILDEFKKD 224
Cdd:cd16215    1 WLRKQIYSVDQTRRNSISVRELKTILPQVNFKVPSAKFLKDKFQEIGAKKDELTFEQFHLFYKKLMFEQQKSILDEFKKD 80

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 190036    225 SSVFILGNTDRPDASAVYLHDFQRFLIHEQQEHWAQDLNKVRERMTKFIDDTMRETAEPFLFVDEFLTYLFSRE 298
Cdd:cd16215   81 SSVFILGNTDRPDASAVHLHDFQRFLVHEQKESWAQDLNKVRERMTKFIDDTMRETAEPFLFVDEFLTYLFSKE 154

PI-PLC-X

pfam00388

Phosphatidylinositol-specific phospholipase C, X domain; This associates with pfam00387 to ...

314-455

6.97e-83

Phosphatidylinositol-specific phospholipase C, X domain; This associates with pfam00387 to form a single structural unit.

Pssm-ID: 459795 [Multi-domain] Cd Length: 142 Bit Score: 266.68 E-value: 6.97e-83

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036      314 MNNPLSHYWISSSHNTYLTGDQLRSESSPEAYIRCLRMGCRCIELDCWDGPDGKPVIYHGWTRTTKIKFDDVVQAIKDHA 393
Cdd:pfam00388    1 MSQPLSHYFISSSHNTYLTGDQLTGESSVEAYIRALLRGCRCVELDCWDGPDGEPVVYHGYTLTSKIPFRDVLEAIKDYA 80

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 190036      394 FVTSSFPVILSIEEHCSVEQQRHMAKAFKEVFGDLLLTKPTEASADQLPSPSQLREKIIIKH 455
Cdd:pfam00388   81 FVTSPYPVILSLENHCSPEQQKKMAEILKEIFGDMLYTPPLDDDLTELPSPEDLKGKILIKG 142

PLCXc

smart00148

Phospholipase C, catalytic domain (part); domain X; Phosphoinositide-specific phospholipases C. ...

314-456

4.34e-76

Phospholipase C, catalytic domain (part); domain X; Phosphoinositide-specific phospholipases C. These enzymes contain 2 regions (X and Y) which together form a TIM barrel-like structure containing the active site residues. Phospholipase C enzymes (PI-PLC) act as signal transducers that generate two second messengers, inositol-1,4,5-trisphosphate and diacylglycerol. The bacterial enzyme appears to be a homologue of the mammalian PLCs.

Pssm-ID: 197543 [Multi-domain] Cd Length: 143 Bit Score: 247.58 E-value: 4.34e-76

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036       314 MNNPLSHYWISSSHNTYLTGDQLRSESSPEAYIRCLRMGCRCIELDCWDGPDGKPVIYHGWTRTTKIKFDDVVQAIKDHA 393
Cdd:smart00148    1 MDKPLSHYFIPSSHNTYLTGKQLWGESSVEGYIQALDAGCRCVELDCWDGPDGEPVIYHGHTFTLPIKLSEVLEAIKDFA 80

                            90       100       110       120       130       140
                    ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 190036       394 FVTSSFPVILSIEEHCSVEQQRHMAKAFKEVFGDLLLTKPTEASADQLPSPSQLREKIIIKHK 456
Cdd:smart00148   81 FVTSPYPVILSLENHCSPDQQAKMAQMFKEIFGDMLYTPPLTSSLEVLPSPEQLRGKILLKVR 143

PI-PLCc_gamma2

cd08628

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-gamma2; This subfamily ...

926-1031

1.78e-69

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-gamma2; This subfamily corresponds to the catalytic domain present in metazoan phosphoinositide-specific phospholipase C (PI-PLC, EC 3.1.4.11)-gamma isozyme 2. PI-PLC is a signaling enzyme that hydrolyze the membrane phospholipids phosphatidylinositol-4,5-bisphosphate (PIP2) to generate two important second messengers in eukaryotic signal transduction cascades, Inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG). InsP3 triggers inflow of calcium from intracellular stores, while DAG, together with calcium, activates protein kinase C, which goes on to phosphorylate other molecules, leading to altered cellular activity. Calcium is required for the catalysis. PI-PLC-gamma represents a class of mammalian PI-PLC that has an N-terminal pleckstrin homology (PH) domain, an array of EF hands, a PLC catalytic core domain, and a C2 domain. The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. Unique to PI-PLC-gamma2, a second PH domain, two SH2 (Src homology 2) regions, and one SH3 (Src homology 3) region is present within this linker region. PI-PLC-gamma2 is highly expressed in cells of hematopoietic origin. It is activated by receptor and non-receptor tyrosine kinases due to the presence of two SH2 and a single SH3 domain within the linker region. Unlike PI-PLC-gamma1, the activation of PI-PLC-gamma2 may require concurrent stimulation of PI 3-kinase.

Pssm-ID: 176565 [Multi-domain] Cd Length: 254 Bit Score: 233.79 E-value: 1.78e-69

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    926 IAIELSDLVVYCKPTSKTKDNLENPDFREIRSFVETKADSIIRQKPVDLLKYNQKGLTRVYPKGQRVDSSNYDPFRLWLC 1005
Cdd:cd08628  149 IAIELSDLVVYCKPTSKTKDNLENPDFKEIRSFVETKAPSIIRQKPVQLLKYNRKGLTRVYPKGQRVDSSNYDPFRLWLC 228

                         90       100
                 ....*....|....*....|....*.
gi 190036   1006 GSQMVALNFQTADKYMQMNHALFSLN 1031
Cdd:cd08628  229 GSQMVALNFQTADKYMQLNHALFSLN 254

PH_PLC_gamma

cd13362

Phospholipase C-gamma (PLC-gamma) pleckstrin homology (PH) domain; PLC-gamma (PLCgamma) is ...

22-140

4.82e-61

Pssm-ID: 270168 Cd Length: 121 Bit Score: 204.05 E-value: 4.82e-61

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036     22 LELGTVMTVFsFRKSTPERRTVQVIMETRQVAWSKTADK-IEGFLDIMEIKEIRPGKNSKDFERAKAV--RQKEDCCFTI 98
Cdd:cd13362    1 LERGTVMTKF-YQKKRPERRTFQVKLETRQVVWSRGGGKrAEGAVDIREIKEIRPGKNSKDFERWPDEakKLDPSCCFVI 79

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|..
gi 190036     99 LYGTQFVLSTLSLAADSKEDAVNWLSGLKILHQEAMNASTPT 140
Cdd:cd13362   80 LYGTEFRLKTLSVAATSEEECDMWIKGLRYLVEDTLSASYPL 121

SH2_C-SH2_PLC_gamma_like

cd09932

C-terminal Src homology 2 (C-SH2) domain in Phospholipase C gamma; Phospholipase C gamma is a ...

641-744

2.99e-59

Pssm-ID: 198186 Cd Length: 104 Bit Score: 198.26 E-value: 2.99e-59

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    641 HESKPWYYDSLSRGEAEDMLMRIPRDGAFLIRKRE-GSDSYAITFRARGKVKHCRINRDGRHFVLGTSAyFESLVELVSY 719
Cdd:cd09932    1 HESKEWFHANLTREQAEEMLMRVPRDGAFLVRPSEtDPNSFAISFRAEGKIKHCRIKQEGRLFVIGTSQ-FESLVELVSY 79

                         90       100
                 ....*....|....*....|....*
gi 190036    720 YEKHSLYRKMRLRYPVTPELLERYN 744
Cdd:cd09932   80 YEKHPLYRKIKLRYPVNEELLEKYG 104

PLCYc

smart00149

Phospholipase C, catalytic domain (part); domain Y; Phosphoinositide-specific phospholipases C. ...

931-1043

5.78e-53

Phospholipase C, catalytic domain (part); domain Y; Phosphoinositide-specific phospholipases C. These enzymes contain 2 regions (X and Y) which together form a TIM barrel-like structure containing the active site residues. Phospholipase C enzymes (PI-PLC) act as signal transducers that generate two second messengers, inositol-1,4,5-trisphosphate and diacylglycerol. The bacterial enzyme appears to be a homologue of the mammalian PLCs.

Pssm-ID: 128454 [Multi-domain] Cd Length: 115 Bit Score: 180.90 E-value: 5.78e-53

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036       931 SDLVVYCKPTSKT--KDNLENPDFREIRSFVETKADSIIRQKPVDLLKYNQKGLTRVYPKGQRVDSSNYDPFRLWLCGSQ 1008
Cdd:smart00149    1 SDLVIYCAPVKFRsfESAESKNPFYEMSSFSETKAKKLLKKSPTDFVRYNQRQLSRVYPKGTRVDSSNYNPQVFWNHGCQ 80

                            90       100       110
                    ....*....|....*....|....*....|....*
gi 190036      1009 MVALNFQTADKYMQMNHALFSLNGRTGYVLQPESM 1043
Cdd:smart00149   81 MVALNFQTPDKPMQLNQGMFRANGGCGYVLKPDFL 115

PI-PLC-Y

pfam00387

Phosphatidylinositol-specific phospholipase C, Y domain; This associates with pfam00388 to ...

930-1041

2.68e-52

Phosphatidylinositol-specific phospholipase C, Y domain; This associates with pfam00388 to form a single structural unit.

Pssm-ID: 459794 Cd Length: 114 Bit Score: 178.81 E-value: 2.68e-52

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036      930 LSDLVVYCKPTS-KTKDNLENPDFREIRSFVETKADSIIRQKPVDLLKYNQKGLTRVYPKGQRVDSSNYDPFRLWLCGSQ 1008
Cdd:pfam00387    1 LSDLVVYTQSVKfKSFSTPESKTPNHIFSFSESKALKLIKSSSAAFVKHNRRHLMRVYPKGTRVDSSNFNPQPFWNCGVQ 80

                           90       100       110
                   ....*....|....*....|....*....|...
gi 190036     1009 MVALNFQTADKYMQMNHALFSLNGRTGYVLQPE 1041
Cdd:pfam00387   81 MVALNWQTPDEGMQLNEGMFADNGGCGYVLKPE 113

SH2_N-SH2_PLC_gamma_like

cd10341

N-terminal Src homology 2 (N-SH2) domain in Phospholipase C gamma; Phospholipase C gamma is a ...

527-627

6.24e-52

Pssm-ID: 199829 Cd Length: 99 Bit Score: 177.16 E-value: 6.24e-52

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    527 HFGEKWFHKKV-EKRTSAEKLLQEYCMetgGKDGTFLVRESETFPNDYTLSFWRSGRVQHCRIRSTMEGGTLKYYLTDNL 605
Cdd:cd10341    1 HFTEPWFHGKLgDGRDEAEKLLLEYCE---GGDGTFLVRESETFVGDYTLSFWRNGKVQHCRIRSRQENGEKKYYLTDNL 77

                         90       100
                 ....*....|....*....|..
gi 190036    606 RFRRMYALIQHYRETHLPCAEF 627
Cdd:cd10341   78 VFDSLYELIDYYRQNPLRCAEF 99

C2_PLC_like

cd00275

C2 domain present in Phosphoinositide-specific phospholipases C (PLC); PLCs are involved in ...

1061-1187

8.27e-45

Pssm-ID: 175974 [Multi-domain] Cd Length: 128 Bit Score: 158.09 E-value: 8.27e-45

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036   1061 MTLTVKVLGARHLPKLG---RSIACPFVEVEICGAEYG-NNKFKTTVVNDNGLSPIWaptQEKVTFEIYDPNLAFLRFVV 1136
Cdd:cd00275    2 LTLTIKIISGQQLPKPKgdkGSIVDPYVEVEIHGLPADdSAKFKTKVVKNNGFNPVW---NETFEFDVTVPELAFLRFVV 78

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|.
gi 190036   1137 YEEDMFSDpNFLAHATYPIKAVKSGFRSVPLKNGYSEDIELASLLVFCEMR 1187
Cdd:cd00275   79 YDEDSGDD-DFLGQACLPLDSLRQGYRHVPLLDSKGEPLELSTLFVHIDIT 128

PHsplit_PLC_gamma

Phospholipase C-gamma Split pleckstrin homology (PH) domain; PLC-gamma (PLCgamma) is activated ...

840-910

3.15e-35

Pssm-ID: 270054 Cd Length: 105 Bit Score: 129.90 E-value: 3.15e-35

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 190036    840 IEDNPLGSLCRGILDLNTYNVVKAPQGKNQKSFVFILEPKEQGDPPVEFATDRVEELFEWFQSIREITWKI 910
Cdd:cd13234   35 TENSPLGSLLRGILDVPSCHVVKRPEGKNSRPFVFILSPKSLSDPPLDVAADSQEELQDWVQKIREVAQTA 105

SH3_PLCgamma2

cd11969

Src homology 3 domain of Phospholipase C (PLC) gamma 2; PLCgamma2 is primarily expressed in ...

773-827

1.56e-33

Pssm-ID: 212902 Cd Length: 55 Bit Score: 123.03 E-value: 1.56e-33

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 190036    773 TVKALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRIQQYFPSNYVEDI 827
Cdd:cd11969    1 TVKALYDYRAKRSDELSFCKGALIHNVSKETGGWWKGDYGGKVQHYFPSNYVEDV 55

PLN02222

phosphoinositide phospholipase C 2

248-528

2.58e-33

phosphoinositide phospholipase C 2

Pssm-ID: 177868 [Multi-domain] Cd Length: 581 Bit Score: 137.08 E-value: 2.58e-33

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036     248 RFLIHEQQEHWAqdlnkVRERMTKFIDDTMRETAEPFLFVDEFLTYLFSRENS-IWDEKYDavdmQDMNNPLSHYWISSS 326
Cdd:PLN02222   47 RFLIDVQKQDKA-----TREDAQSIINSASSLLHRNGLHLDAFFKYLFGDNNPpLALHEVH----HDMDAPISHYFIFTG 117

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036     327 HNTYLTGDQLRSESSPEAYIRCLRMGCRCIELDCWDGPDGKPV-IYHGWTRTTKIKFDDVVQAIKDHAFVTSSFPVILSI 405
Cdd:PLN02222  118 HNSYLTGNQLSSDCSEVPIIDALKKGVRVIELDIWPNSDKDDIdVLHGMTLTTPVGLIKCLKAIRAHAFDVSDYPVVVTL 197

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036     406 EEHCSVEQQRHMAKAFKEVFGDLLLTKPTEASADQLPSPSQLREKIIIKHKKlgPRGDVDVNMEDKKDEHKQQGELYMWD 485
Cdd:PLN02222  198 EDHLTPDLQSKVAEMVTEIFGEILFTPPVGESLKEFPSPNSLKKRIIISTKP--PKEYKEGKDDEVVQKGKDLGDEEVWG 275

                         250       260       270       280
                  ....*....|....*....|....*....|....*....|....
gi 190036     486 SIDQKWTRHYCAIADAKLSFS-DDIEQTMEEEVPQDIPPTELHF 528
Cdd:PLN02222  276 REVPSFIQRNKSVDKNDSNGDdDDDDDDGEDKSKKNAPPQYKHL 319

SH2

SH2 domain;

532-617

1.74e-26

SH2 domain;

Pssm-ID: 425423 [Multi-domain] Cd Length: 77 Bit Score: 103.83 E-value: 1.74e-26

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036      532 WFHKKVEkRTSAEKLLQEycmetGGKDGTFLVRESETFPNDYTLSFWRSGRVQHCRIRSTMEGgtlKYYLTDNLRFRRMY 611
Cdd:pfam00017    1 WYHGKIS-RQEAERLLLN-----GKPDGTFLVRESESTPGGYTLSVRDDGKVKHYKIQSTDNG---GYYISGGVKFSSLA 71


                   ....*.
gi 190036      612 ALIQHY 617
Cdd:pfam00017   72 ELVEHY 77

SH2

SH2 domain;

646-720

4.59e-24

SH2 domain;

Pssm-ID: 425423 [Multi-domain] Cd Length: 77 Bit Score: 96.90 E-value: 4.59e-24

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 190036      646 WYYDSLSRGEAEDMLMRIPRDGAFLIRKREGSD-SYAITFRARGKVKHCRINRDGR-HFVLGTSAYFESLVELVSYY 720
Cdd:pfam00017    1 WYHGKISRQEAERLLLNGKPDGTFLVRESESTPgGYTLSVRDDGKVKHYKIQSTDNgGYYISGGVKFSSLAELVEHY 77

SH2

Src homology 2 domains; Src homology 2 domains bind phosphotyrosine-containing polypeptides ...

530-623

1.69e-22

Src homology 2 domains; Src homology 2 domains bind phosphotyrosine-containing polypeptides via 2 surface pockets. Specificity is provided via interaction with residues that are distinct from the phosphotyrosine. Only a single occurrence of a SH2 domain has been found in S. cerevisiae.

Pssm-ID: 214585 [Multi-domain] Cd Length: 84 Bit Score: 92.68 E-value: 1.69e-22

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036       530 EKWFHKKVEkRTSAEKLLQeycmetGGKDGTFLVRESETFPNDYTLSFWRSGRVQHCRIRSTMEGgtlKYYLTDNLRFRR 609
Cdd:smart00252    1 QPWYHGFIS-REEAEKLLK------NEGDGDFLVRDSESSPGDYVLSVRVKGKVKHYRIRRNEDG---KFYLEGGRKFPS 70

                            90
                    ....*....|....
gi 190036       610 MYALIQHYRETHLP 623
Cdd:smart00252   71 LVELVEHYQKNSLG 84

PLN02222

phosphoinositide phospholipase C 2

938-1185

3.91e-22

phosphoinositide phospholipase C 2

Pssm-ID: 177868 [Multi-domain] Cd Length: 581 Bit Score: 102.42 E-value: 3.91e-22

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036     938 KPTSKTKDNLE-NPDFREIRSFVETKADSIIRQKPVDLLKYNQKGLTRVYPKGQRVDSSNYDPFRLWLCGSQMVALNFQT 1016
Cdd:PLN02222  326 KPKGGITECLKvDPDKVRRLSLSEEQLEKAAEKYAKQIVRFTQHNLLRIYPKGTRVTSSNYNPLVGWSHGAQMVAFNMQG 405

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    1017 ADKYMQMNHALFSLNGRTGYVLQPESMRTEKYDP--MPPESQRKILMTLTVKV-LGA------RHLPKLGRSIACPFVEV 1087
Cdd:PLN02222  406 YGRSLWLMQGMFRANGGCGYIKKPDLLLKSGSDSdiFDPKATLPVKTTLRVTIyMGEgwyfdfRHTHFDQYSPPDFYTRV 485

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    1088 EICGAEYGNNKFKTTVVNDNglspiWAPTQEKV-TFEIYDPNLAFLRFVVYEEDMFSDPNFLAHATYPIKAVKSGFRSVP 1166
Cdd:PLN02222  486 GIAGVPGDTVMKKTKTLEDN-----WIPAWDEVfEFPLTVPELALLRLEVHEYDMSEKDDFGGQTCLPVWELSQGIRAFP 560

                         250
                  ....*....|....*....
gi 190036    1167 LKNGYSEDIELASLLVFCE 1185
Cdd:PLN02222  561 LHSRKGEKYKSVKLLVKVE 579

SH2

Src homology 2 domains; Src homology 2 domains bind phosphotyrosine-containing polypeptides ...

645-726

2.37e-21

Pssm-ID: 214585 [Multi-domain] Cd Length: 84 Bit Score: 89.21 E-value: 2.37e-21

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036       645 PWYYDSLSRGEAEDMLMRIPrDGAFLIRKREGS-DSYAITFRARGKVKHCRINRDGRH-FVLGTSAYFESLVELVSYYEK 722
Cdd:smart00252    2 PWYHGFISREEAEKLLKNEG-DGDFLVRDSESSpGDYVLSVRVKGKVKHYRIRRNEDGkFYLEGGRKFPSLVELVEHYQK 80


                    ....
gi 190036       723 HSLY 726
Cdd:smart00252   81 NSLG 84

SH3

smart00326

Src homology 3 domains; Src homology 3 (SH3) domains bind to target proteins through sequences ...

770-825

3.17e-18

Src homology 3 domains; Src homology 3 (SH3) domains bind to target proteins through sequences containing proline and hydrophobic amino acids. Pro-containing polypeptides may bind to SH3 domains in 2 different binding orientations.

Pssm-ID: 214620 [Multi-domain] Cd Length: 56 Bit Score: 79.50 E-value: 3.17e-18

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|....*.
gi 190036       770 PQRTVKALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRIQQYFPSNYVE 825
Cdd:smart00326    1 EGPQVRALYDYTAQDPDELSFKKGDIITVLEKSDDGWWKGRLGRGKEGLFPSNYVE 56

smart00239

Protein kinase C conserved region 2 (CalB); Ca2+-binding motif present in phospholipases, ...

1062-1167

5.01e-18

Protein kinase C conserved region 2 (CalB); Ca2+-binding motif present in phospholipases, protein kinases C, and synaptotagmins (among others). Some do not appear to contain Ca2+-binding sites. Particular C2s appear to bind phospholipids, inositol polyphosphates, and intracellular proteins. Unusual occurrence in perforin. Synaptotagmin and PLC C2s are permuted in sequence with respect to N- and C-terminal beta strands. SMART detects C2 domains using one or both of two profiles.

Pssm-ID: 214577 [Multi-domain] Cd Length: 101 Bit Score: 80.61 E-value: 5.01e-18

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036      1062 TLTVKVLGARHLPKLGRSIAC-PFVEVEICGAeyGNNKFKTTVVNDNgLSPIWaptQEKVTFEIYDPNLAFLRFVVYEED 1140
Cdd:smart00239    1 TLTVKIISARNLPPKDKGGKSdPYVKVSLDGD--PKEKKKTKVVKNT-LNPVW---NETFEFEVPPPELAELEIEVYDKD 74

                            90       100
                    ....*....|....*....|....*..
gi 190036      1141 MFSDPNFLAHATYPIKAVKSGFRSVPL 1167
Cdd:smart00239   75 RFGRDDFIGQVTIPLSDLLLGGRHEKL 101

pfam00168

C2 domain;

1062-1161

3.93e-17

C2 domain;

Pssm-ID: 425499 [Multi-domain] Cd Length: 104 Bit Score: 78.13 E-value: 3.93e-17

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036     1062 TLTVKVLGARHLPKLGRSIAC-PFVEVEICGaeyGNNKFKTTVVNdNGLSPIWaptQEKVTFEIYDPNLAFLRFVVYEED 1140
Cdd:pfam00168    2 RLTVTVIEAKNLPPKDGNGTSdPYVKVYLLD---GKQKKKTKVVK-NTLNPVW---NETFTFSVPDPENAVLEIEVYDYD 74

                           90       100
                   ....*....|....*....|.
gi 190036     1141 MFSDPNFLAHATYPIKAVKSG 1161
Cdd:pfam00168   75 RFGRDDFIGEVRIPLSELDSG 95

SH3_1

pfam00018

SH3 domain; SH3 (Src homology 3) domains are often indicative of a protein involved in signal ...

775-821

2.06e-15

SH3 domain; SH3 (Src homology 3) domains are often indicative of a protein involved in signal transduction related to cytoskeletal organization. First described in the Src cytoplasmic tyrosine kinase. The structure is a partly opened beta barrel.

Pssm-ID: 394975 [Multi-domain] Cd Length: 47 Bit Score: 71.08 E-value: 2.06e-15

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*..
gi 190036      775 KALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRIQQYFPS 821
Cdd:pfam00018    1 VALYDYTAQEPDELSFKKGDIIIVLEKSEDGWWKGRNKGGKEGLIPS 47

PHsplit_PLC_gamma

Phospholipase C-gamma Split pleckstrin homology (PH) domain; PLC-gamma (PLCgamma) is activated ...

475-510

6.84e-11

Pssm-ID: 270054 Cd Length: 105 Bit Score: 60.17 E-value: 6.84e-11

                         10        20        30
                 ....*....|....*....|....*....|....*.
gi 190036    475 HKQQGELYMWDSIDQKWTRHYCAIADAKLSFSDDIE 510
Cdd:cd13234    1 SIKNGILYLEDPINHEWYPHFFVLTSNKIYYSEETE 36

PH_12

pfam16457

Pleckstrin homology domain;

65-129

1.08e-05

Pleckstrin homology domain;

Pssm-ID: 465123 [Multi-domain] Cd Length: 128 Bit Score: 46.10 E-value: 1.08e-05

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 190036       65 LDIMEIKEIRPGKNSKDF--ERAKAVRQKEDCCFTILYGTQFVlSTLSLAADSKEDAVNWLSGLKIL 129
Cdd:pfam16457   61 IDLSDIKEVVTGKECPHVreSGKKSKKTSSTLAFSLIYGADEY-ELLDFVAPSESVAAIWLDGLNML 126

Name

Accession

Description

Interval

E-value

PI-PLCc_gamma

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-gamma; This family ...

311-458

1.61e-111

Pssm-ID: 176534 [Multi-domain] Cd Length: 229 Bit Score: 348.65 E-value: 1.61e-111

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    311 MQDMNNPLSHYWISSSHNTYLTGDQLRSESSPEAYIRCLRMGCRCIELDCWDGPDGKPVIYHGWTRTTKIKFDDVVQAIK 390
Cdd:cd08592    1 PQDMNNPLSHYWIASSHNTYLTGDQLSSESSLEAYARCLRMGCRCIELDCWDGPDGMPIIYHGHTLTSKIKFMDVLKTIK 80

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 190036    391 DHAFVTSSFPVILSIEEHCSVEQQRHMAKAFKEVFGDLLLTKPTEASADQLPSPSQLREKIIIKHKKL 458
Cdd:cd08592   81 EHAFVTSEYPVILSIENHCSLPQQRNMAQAFKEVFGDMLLTQPVDRNADQLPSPNQLKRKIIIKHKKL 148

PI-PLCc_gamma2

cd08628

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-gamma2; This subfamily ...

311-458

2.35e-108

Pssm-ID: 176565 [Multi-domain] Cd Length: 254 Bit Score: 340.88 E-value: 2.35e-108

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    311 MQDMNNPLSHYWISSSHNTYLTGDQLRSESSPEAYIRCLRMGCRCIELDCWDGPDGKPVIYHGWTRTTKIKFDDVVQAIK 390
Cdd:cd08628    1 PQDMNNPLSHYWISSSHNTYLTGDQLRSESSTEAYIRCLRMGCRCIELDCWDGPDGKPIIYHGWTRTTKIKFDDVVQAIK 80

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 190036    391 DHAFVTSSFPVILSIEEHCSVEQQRHMAKAFKEVFGDLLLTKPTEASADQLPSPSQLREKIIIKHKKL 458
Cdd:cd08628   81 DHAFVTSEYPVILSIEEHCSVEQQRHMAKVFKEVFGDKLLMKPLEASADQLPSPTQLKEKIIIKHKKL 148

EFh_PI-PLCgamma2

cd16215

1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2; PI-PLC-gamma2, also termed ...

145-298

3.05e-99

Pssm-ID: 320045 Cd Length: 154 Bit Score: 312.17 E-value: 3.05e-99

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    145 WLRKQIYSVDQTRRNSISLRELKTILPLINFKVSSAKFLKDKFVEIGAHKDELSFEQFHLFYKKLMFEQQKSILDEFKKD 224
Cdd:cd16215    1 WLRKQIYSVDQTRRNSISVRELKTILPQVNFKVPSAKFLKDKFQEIGAKKDELTFEQFHLFYKKLMFEQQKSILDEFKKD 80

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 190036    225 SSVFILGNTDRPDASAVYLHDFQRFLIHEQQEHWAQDLNKVRERMTKFIDDTMRETAEPFLFVDEFLTYLFSRE 298
Cdd:cd16215   81 SSVFILGNTDRPDASAVHLHDFQRFLVHEQKESWAQDLNKVRERMTKFIDDTMRETAEPFLFVDEFLTYLFSKE 154

PI-PLCc_eukaryota

cd08558

Catalytic domain of eukaryotic phosphoinositide-specific phospholipase C and similar proteins; ...

312-457

7.65e-99

Catalytic domain of eukaryotic phosphoinositide-specific phospholipase C and similar proteins; This family corresponds to the catalytic domain present in eukaryotic phosphoinositide-specific phospholipase C (PI-PLC, EC 3.1.4.11) and similar proteins. The higher eukaryotic PI-PLCs play a critical role in most signal transduction pathways, controlling numerous cellular events such as cell growth, proliferation, excitation and secretion. They strictly require Ca2+ for the catalytic activity. They display a clear preference towards the hydrolysis of the more highly phosphorylated membrane phospholipids PI-analogues, phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol-4-phosphate (PIP), to generate two important second messengers in eukaryotic signal transduction cascades, inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG). InsP3 triggers inflow of calcium from intracellular stores, while DAG, together with calcium, activates protein kinase C, which then phosphorylates other molecules, leading to altered cellular activity. The eukaryotic PI-PLCs have a multidomain organization that consists of a PLC catalytic core domain, and various regulatory domains, such as the pleckstrin homology (PH) domain, EF-hand motif, and C2 domain. The catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a linker region. The catalytic mechanism of eukaryotic PI-PLCs is based on general base and acid catalysis utilizing two well conserved histidines and consists of two steps, a phosphotransfer and a phosphodiesterase reaction. The mammalian PI-PLCs consist of 13 isozymes, which are classified into six-subfamilies, PI-PLC-delta (1,3 and 4), -beta(1-4), -gamma(1,2), -epsilon, -zeta, and -eta (1,2). Ca2+ is required for the activation of all forms of mammalian PI-PLCs, and the concentration of calcium influences substrate specificity. This family also includes metazoan phospholipase C related but catalytically inactive proteins (PRIP), which belong to a group of novel inositol trisphosphate binding proteins. Due to the replacement of critical catalytic residues, PRIP does not have PLC enzymatic activity.

Pssm-ID: 176501 [Multi-domain] Cd Length: 226 Bit Score: 314.00 E-value: 7.65e-99

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    312 QDMNNPLSHYWISSSHNTYLTGDQLRSESSPEAYIRCLRMGCRCIELDCWDGPDGKPVIYHGWTRTTKIKFDDVVQAIKD 391
Cdd:cd08558    2 QDMTQPLSHYFISSSHNTYLTGDQLTGESSVEAYIRALLRGCRCVELDCWDGPDGEPVVYHGHTLTSKILFKDVIEAIKE 81

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 190036    392 HAFVTSSFPVILSIEEHCSVEQQRHMAKAFKEVFGDLLLTKPTEASADQLPSPSQLREKIIIKHKK 457
Cdd:cd08558   82 YAFVTSPYPVILSLENHCSLEQQKKMAQILKEIFGDKLLTPPLDENPVQLPSPEQLKGKILIKGKK 147

PI-PLCc_gamma1

cd08627

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-gamma1; This subfamily ...

312-458

9.69e-89

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-gamma1; This subfamily corresponds to the catalytic domain present in metazoan phosphoinositide-specific phospholipase C (PI-PLC, EC 3.1.4.11)-gamma isozyme 1. PI-PLC is a signaling enzyme that hydrolyzes the membrane phospholipids phosphatidylinositol-4,5-bisphosphate (PIP2) to generate two important second messengers in eukaryotic signal transduction cascades, Inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG). InsP3 triggers inflow of calcium from intracellular stores, while DAG, together with calcium, activates protein kinase C, which goes on to phosphorylate other molecules, leading to altered cellular activity. Calcium is required for the catalysis. PI-PLC-gamma represents a class of mammalian PI-PLC that has an N-terminal pleckstrin homology (PH) domain, an array of EF hands, a PLC catalytic core domain, and a C2 domain. The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. Unique to PI-PLC-gamma1, a second PH domain, two SH2 (Src homology 2) regions, and one SH3 (Src homology 3) region is present within this linker region. PI-PLC-gamma1 is ubiquitously expressed. It is activated by receptor and non-receptor tyrosine kinases due to the presence of two SH2 and a single SH3 domain within the linker region.

Pssm-ID: 176564 [Multi-domain] Cd Length: 229 Bit Score: 286.54 E-value: 9.69e-89

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    312 QDMNNPLSHYWISSSHNTYLTGDQLRSESSPEAYIRCLRMGCRCIELDCWDGPDGKPVIYHGWTRTTKIKFDDVVQAIKD 391
Cdd:cd08627    2 EEMNNPLSHYWISSSHNTYLTGDQFSSESSLEAYARCLRMGCRCIELDCWDGPDGMPVIYHGHTLTTKIKFSDVLHTIKE 81

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 190036    392 HAFVTSSFPVILSIEEHCSVEQQRHMAKAFKEVFGDLLLTKPTEASADQLPSPSQLREKIIIKHKKL 458
Cdd:cd08627   82 HAFVTSEYPIILSIEDHCSIVQQRNMAQHFKKVFGDMLLTKPVDINADGLPSPNQLKRKILIKHKKL 148

PI-PLC-X

pfam00388

Phosphatidylinositol-specific phospholipase C, X domain; This associates with pfam00387 to ...

314-455

6.97e-83

Phosphatidylinositol-specific phospholipase C, X domain; This associates with pfam00387 to form a single structural unit.

Pssm-ID: 459795 [Multi-domain] Cd Length: 142 Bit Score: 266.68 E-value: 6.97e-83

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036      314 MNNPLSHYWISSSHNTYLTGDQLRSESSPEAYIRCLRMGCRCIELDCWDGPDGKPVIYHGWTRTTKIKFDDVVQAIKDHA 393
Cdd:pfam00388    1 MSQPLSHYFISSSHNTYLTGDQLTGESSVEAYIRALLRGCRCVELDCWDGPDGEPVVYHGYTLTSKIPFRDVLEAIKDYA 80

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 190036      394 FVTSSFPVILSIEEHCSVEQQRHMAKAFKEVFGDLLLTKPTEASADQLPSPSQLREKIIIKH 455
Cdd:pfam00388   81 FVTSPYPVILSLENHCSPEQQKKMAEILKEIFGDMLYTPPLDDDLTELPSPEDLKGKILIKG 142

PI-PLCc_delta

cd08593

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-delta; This subfamily ...

312-458

2.24e-80

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-delta; This subfamily corresponds to the catalytic domain present in metazoan phosphoinositide-specific phospholipase C (PI-PLC, EC 3.1.4.11)-delta isozymes. PI-PLC is a signaling enzyme that hydrolyzes the membrane phospholipids phosphatidylinositol-4,5-bisphosphate (PIP2) to generate two important second messengers in eukaryotic signal transduction cascades, Inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG). InsP3 triggers inflow of calcium from intracellular stores, while DAG, together with calcium, activates protein kinase C, which then phosphorylates other molecules, leading to altered cellular activity. Calcium is required for the catalysis. PLC-delta represents a class of mammalian PI-PLC that has an N-terminal pleckstrin homology (PH) domain, an array of EF hands, a PLC catalytic core domain, and a C-terminal C2 domain. This CD corresponds to the catalytic domain which is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. There are three PI-PLC-delta isozymes (1,3 and 4). PI-PLC-delta1 is relatively well characterized. It is activated by high calcium levels generated by other PI-PLC family members, and therefore functions as a calcium amplifier within the cell. Different PI-PLC-delta isozymes have different tissue distribution and different subcellular locations. PI-PLC-delta1 is mostly a cytoplasmic protein, PI-PLC-delta3 is located in the membrane, and PI-PLC-delta4 is predominantly detected in the cell nucleus. Aside from three PI-PLC-delta isozymes identified in mammals, some eukaryotic PI-PLC-delta homologs have been classified to this CD.

Pssm-ID: 176535 [Multi-domain] Cd Length: 257 Bit Score: 264.20 E-value: 2.24e-80

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    312 QDMNNPLSHYWISSSHNTYLTGDQLRSESSPEAYIRCLRMGCRCIELDCWDGPDGKPVIYHGWTRTTKIKFDDVVQAIKD 391
Cdd:cd08593    2 QDMTQPLSHYFIASSHNTYLLEDQLKGPSSTEAYIRALKKGCRCVELDCWDGPDGEPIIYHGHTLTSKILFKDVIQAIRE 81

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 190036    392 HAFVTSSFPVILSIEEHCSVEQQRHMAKAFKEVFGDLLLTKPTEASADQLPSPSQLREKIIIKHKKL 458
Cdd:cd08593   82 YAFKVSPYPVILSLENHCSVEQQKVMAQHLKSILGDKLLTQPLDGVLTALPSPEELKGKILVKGKKL 148

PLCXc

smart00148

Phospholipase C, catalytic domain (part); domain X; Phosphoinositide-specific phospholipases C. ...

314-456

4.34e-76

Pssm-ID: 197543 [Multi-domain] Cd Length: 143 Bit Score: 247.58 E-value: 4.34e-76

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036       314 MNNPLSHYWISSSHNTYLTGDQLRSESSPEAYIRCLRMGCRCIELDCWDGPDGKPVIYHGWTRTTKIKFDDVVQAIKDHA 393
Cdd:smart00148    1 MDKPLSHYFIPSSHNTYLTGKQLWGESSVEGYIQALDAGCRCVELDCWDGPDGEPVIYHGHTFTLPIKLSEVLEAIKDFA 80

                            90       100       110       120       130       140
                    ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 190036       394 FVTSSFPVILSIEEHCSVEQQRHMAKAFKEVFGDLLLTKPTEASADQLPSPSQLREKIIIKHK 456
Cdd:smart00148   81 FVTSPYPVILSLENHCSPDQQAKMAQMFKEIFGDMLYTPPLTSSLEVLPSPEQLRGKILLKVR 143

PI-PLC1c_yeast

cd08598

Catalytic domain of putative yeast phosphatidylinositide-specific phospholipases C; This ...

312-457

2.38e-74

Catalytic domain of putative yeast phosphatidylinositide-specific phospholipases C; This family corresponds to the catalytic domain present in a group of putative phosphoinositide-specific phospholipase C (PI-PLC, EC 3.1.4.11) encoded by PLC1 genes from yeasts, which are homologs of the delta isoforms of mammalian PI-PLC in terms of overall sequence similarity and domain organization. Mammalian PI-PLC is a signaling enzyme that hydrolyzes the membrane phospholipids phosphatidylinositol-4,5-bisphosphate (PIP2) to generate two important second messengers in eukaryotic signal transduction cascades, inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG). InsP3 triggers inflow of calcium from intracellular stores, while DAG, together with calcium, activates protein kinase C, which then phosphorylates other molecules, leading to altered cellular activity. Calcium is required for the catalysis. The prototype of this CD is protein Plc1p encoded by PLC1 genes from Saccharomyces cerevisiae. Plc1p contains both highly conserved X- and Y- regions of PLC catalytic core domain, as well as a presumptive EF-hand like calcium binding motif. Experiments show that Plc1p displays calcium dependent catalytic properties with high similarity to those of the mammalian PLCs, and plays multiple roles in modulating the membrane/protein interactions in filamentation control. CaPlc1p encoded by CAPLC1 from the closely related yeast Candida albicans, an orthologue of S. cerevisiae Plc1p, is also included in this group. Like Plc1p, CaPlc1p has conserved presumptive catalytic domain, shows PLC activity when expressed in E. coli, and is involved in multiple cellular processes. There are two other gene copies of CAPLC1 in C. albicans, CAPLC2 (also named as PIPLC) and CAPLC3. Experiments show CaPlc1p is the only enzyme in C. albicans which functions as PLC. The biological functions of CAPLC2 and CAPLC3 gene products must be clearly different from CaPlc1p, but their exact roles remain unclear. Moreover, CAPLC2 and CAPLC3 gene products are more similar to extracellular bacterial PI-PLC than to the eukaryotic PI-PLC, and they are not included in this subfamily.

Pssm-ID: 176540 [Multi-domain] Cd Length: 231 Bit Score: 246.39 E-value: 2.38e-74

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    312 QDMNNPLSHYWISSSHNTYLTGDQLRSESSPEAYIRCLRMGCRCIELDCWDGPDGKPVIYHGWTRTTKIKFDDVVQAIKD 391
Cdd:cd08598    2 EDLSRPLNEYFISSSHNTYLLGRQLAGDSSVEGYIRALQRGCRCVEIDVWDGDDGEPVVTHGYTLTSSVPFRDVCRAIKK 81

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 190036    392 HAFVTSSFPVILSIEEHCSVEQQRHMAKAFKEVFGDLLLTKPTEASADQLPSPSQLREKIIIKHKK 457
Cdd:cd08598   82 YAFVTSPYPLILSLEVHCDAEQQERMVEIMKETFGDLLVTEPLDGLEDELPSPEELRGKILIKVKK 147

PI-PLCc_PRIP_metazoa

cd08597

Catalytic domain of metazoan phospholipase C related, but catalytically inactive protein; This ...

312-461

1.86e-70

Catalytic domain of metazoan phospholipase C related, but catalytically inactive protein; This family corresponds to the catalytic domain present in metazoan phospholipase C related, but catalytically inactive proteins (PRIP), which belong to a group of novel Inositol 1,4,5-trisphosphate (InsP3) binding protein. PRIP has a primary structure and domain architecture, incorporating a pleckstrin homology (PH) domain, an array of EF hands, a PLC catalytic core domain with highly conserved X- and Y-regions split by a linker sequence, and a C-terminal C2 domain, similar to phosphoinositide-specific phospholipases C (PI-PLC, EC 3.1.4.11)-delta isoforms. Due to replacement of critical catalytic residues, PRIP do not have PLC enzymatic activity. PRIP consists of two subfamilies, PRIP-1(previously known as p130 or PLC-1), which is predominantly expressed in the brain, and PRIP-2 (previously known as PLC-2), which exhibits a relatively ubiquitous expression. Experiments show both, PRIP-1 and PRIP-2, are involved in InsP3-mediated calcium signaling pathway and GABA(A)receptor-mediated signaling pathway. In addition, PRIP-2 acts as a negative regulator of B-cell receptor signaling and immune responses.

Pssm-ID: 176539 [Multi-domain] Cd Length: 260 Bit Score: 236.55 E-value: 1.86e-70

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    312 QDMNNPLSHYWISSSHNTYLTGDQLRSESSPEAYIRCLRMGCRCIELDCWDGPDGKPVIYHGWTRTTKIKFDDVVQAIKD 391
Cdd:cd08597    2 QDMTQPLSHYFIASSHNTYLIEDQLRGPSSVEGYVRALQRGCRCVELDCWDGPNGEPVIYHGHTLTSKISFRSVIEAINE 81

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    392 HAFVTSSFPVILSIEEHCSVEQQRHMAKAFKEVFGDLLLTKPTEASADQLPSPSQLREKIIIKHKKLGPR 461
Cdd:cd08597   82 YAFVASEYPLILCIENHCSEKQQLVMAQYLKEIFGDKLYTEPPNEGESYLPSPHDLKGKIIIKGKKLKRR 151

PI-PLCc_beta

cd08591

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-beta; This subfamily ...

312-458

1.53e-69

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-beta; This subfamily corresponds to the catalytic domain present in metazoan phosphoinositide-specific phospholipase C (PI-PLC, EC 3.1.4.11)-beta isozymes. PI-PLC is a signaling enzyme that hydrolyzes the membrane phospholipids phosphatidylinositol-4,5-bisphosphate (PIP2) to generate two important second messengers in eukaryotic signal transduction cascades, Inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG). InsP3 triggers inflow of calcium from intracellular stores, while DAG, together with calcium, activates protein kinase C, which goes on to phosphorylate other molecules, leading to altered cellular activity. Calcium is required for the catalysis. PLC-beta represents a class of mammalian PI-PLC that has an N-terminal pleckstrin homology (PH) domain, an array of EF hands, a PLC catalytic core domain, a C2 domain, and a unique C-terminal coiled-coil (CT) domain necessary for homodimerization. The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. There are four PLC-beta isozymes (1-4). They are activated by the heterotrimeric G protein alpha q subunits through their C2 domain and long C-terminal extension. The beta-gamma subunits of heterotrimeric G proteins are known to activate the PLC-beta2 and -beta3 isozymes only. Aside from four PLC-beta isozymes identified in mammals, some eukaryotic PLC-beta homologs have been classified into this subfamily, such as NorpA and PLC-21 from Drosophila and PLC-beta from turkey, Xenopus, sponge, and hydra.

Pssm-ID: 176533 [Multi-domain] Cd Length: 257 Bit Score: 233.77 E-value: 1.53e-69

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    312 QDMNNPLSHYWISSSHNTYLTGDQLRSESSPEAYIRCLRMGCRCIELDCWDG--PDGKPVIYHGWTRTTKIKFDDVVQAI 389
Cdd:cd08591    2 QDMDQPLSHYFINSSHNTYLTGRQFGGKSSVEMYRQVLLSGCRCIELDCWDGkgEDEEPIITHGKTMCTEILFKDVIEAI 81

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 190036    390 KDHAFVTSSFPVILSIEEHCSVEQQRHMAKAFKEVFGDLLLTKPTE----ASADQLPSPSQLREKIIIKHKKL 458
Cdd:cd08591   82 AETAFKTSEYPVILSFENHCSSKQQAKMAEYCREIFGDLLLTEPLEkyplEPGVPLPSPNDLKRKILIKNKKL 154

PI-PLCc_gamma2

cd08628

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-gamma2; This subfamily ...

926-1031

1.78e-69

Pssm-ID: 176565 [Multi-domain] Cd Length: 254 Bit Score: 233.79 E-value: 1.78e-69

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    926 IAIELSDLVVYCKPTSKTKDNLENPDFREIRSFVETKADSIIRQKPVDLLKYNQKGLTRVYPKGQRVDSSNYDPFRLWLC 1005
Cdd:cd08628  149 IAIELSDLVVYCKPTSKTKDNLENPDFKEIRSFVETKAPSIIRQKPVQLLKYNRKGLTRVYPKGQRVDSSNYDPFRLWLC 228

                         90       100
                 ....*....|....*....|....*.
gi 190036   1006 GSQMVALNFQTADKYMQMNHALFSLN 1031
Cdd:cd08628  229 GSQMVALNFQTADKYMQLNHALFSLN 254

PI-PLCc_delta1

cd08629

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-delta1; This subfamily ...

312-458

5.16e-68

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-delta1; This subfamily corresponds to the catalytic domain present in metazoan phosphoinositide-specific phospholipase C (PI-PLC, EC 3.1.4.11)-delta1 isozymes. PI-PLC is a signaling enzyme that hydrolyzes the membrane phospholipids phosphatidylinositol-4,5-bisphosphate (PIP2) to generate two important second messengers in eukaryotic signal transduction cascades, Inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG). InsP3 triggers inflow of calcium from intracellular stores, while DAG, together with calcium, activates protein kinase C, which then phosphorylates other molecules, leading to altered cellular activity. Calcium is required for the catalysis. PLC-delta represents a class of mammalian PI-PLC that has an N-terminal pleckstrin homology (PH) domain, an array of EF hands, a PLC catalytic core domain, and a C-terminal C2 domain. This subfamily corresponds to the catalytic domain which is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. There are three PI-PLC-delta isozymes (1,3 and 4). PI-PLC-delta1 is relatively well characterized. It is activated by high calcium levels generated by other PI-PLC family members, and therefore functions as a calcium amplifier within the cell. Unlike PI-PLC-delta 4, PI-PLC-delta1 and 3 possess a putative nuclear export sequence (NES) located in the EF-hand domain, which may be responsible transporting PI-PLC-delta1and 3 from the cell nucleus. Experiments show PI-PLC-delta1 is essential for normal hair formation.

Pssm-ID: 176566 [Multi-domain] Cd Length: 258 Bit Score: 229.54 E-value: 5.16e-68

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    312 QDMNNPLSHYWISSSHNTYLTGDQLRSESSPEAYIRCLRMGCRCIELDCWDGPDGKPVIYHGWTRTTKIKFDDVVQAIKD 391
Cdd:cd08629    2 QDMDQPLSHYLVSSSHNTYLLEDQLTGPSSTEAYIRALCKGCRCLELDCWDGPNQEPIIYHGYTFTSKILFCDVLRAIRD 81

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 190036    392 HAFVTSSFPVILSIEEHCSVEQQRHMAKAFKEVFGDLLLTKPTEASADQLPSPSQLREKIIIKHKKL 458
Cdd:cd08629   82 YAFKASPYPVILSLENHCSLEQQRVMARHLRAILGPILLDQPLDGVTTSLPSPEQLKGKILLKGKKL 148

PI-PLCc_eta

cd08594

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-eta; This family ...

312-457

3.25e-67

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-eta; This family corresponds to the catalytic domain present in metazoan phosphoinositide-specific phospholipase C (PI-PLC, EC 3.1.4.11)-eta isozymes. PI-PLC is a signaling enzyme that hydrolyzes the membrane phospholipids phosphatidylinositol-4,5-bisphosphate (PIP2) to generate two important second messengers in eukaryotic signal transduction cascades, Inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG). InsP3 triggers inflow of calcium from intracellular stores, while DAG, together with calcium, activates protein kinase C, which then phosphorylates other molecules, leading to altered cellular activity. Calcium is required for the catalysis. PI-PLC-eta represents a class of neuron-speific PI-PLC that has an N-terminal pleckstrin homology (PH) domain, an array of EF hands, a PLC catalytic core domain, a C2 domain, and a unique C-terminal tail that terminates with a PDZ-binding motif, a potential interaction site for other signaling proteins. The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. There are two PI-PLC-eta isozymes (1-2), both neuron-specific enzymes. They function as calcium sensors that are activated by small increases in intracellular calcium concentrations. The PI-PLC-eta isozymes are also activated through GPCR stimulation. Aside from the PI-PLC-eta isozymes identified in mammals, their eukaryotic homologs are also present in this family.

Pssm-ID: 176536 [Multi-domain] Cd Length: 227 Bit Score: 226.22 E-value: 3.25e-67

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    312 QDMNNPLSHYWISSSHNTYLTGDQLRSESSPEAYIRCLRMGCRCIELDCWDGPDGKPVIYHGWTRTTKIKFDDVVQAIKD 391
Cdd:cd08594    2 QDMTQPLSHYFIASSHNTYLTGDQLLSQSRVDMYARVLQAGCRCVEVDCWDGPDGEPVVHHGYTLTSKILFRDVIETINK 81

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 190036    392 HAFVTSSFPVILSIEEHCSVEQQRHMAKAFKEVFGDLL-LTKPTEASADQLPSPSQLREKIIIKHKK 457
Cdd:cd08594   82 YAFIKNEYPVILSIENHCSVQQQKKMAQYLKEILGDKLdLSSVISGDSKQLPSPQSLKGKILIKGKK 148

PI-PLCc_epsilon

cd08596

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-epsilon; This family ...

312-457

1.43e-65

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-epsilon; This family corresponds to the catalytic domain present in metazoan phosphoinositide-specific phospholipase C (PI-PLC, EC 3.1.4.11)-epsilon isozymes. PI-PLC is a signaling enzyme that hydrolyzes the membrane phospholipids phosphatidylinositol-4,5-bisphosphate (PIP2) to generate two important second messengers in eukaryotic signal transduction cascades, inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG). InsP3 triggers inflow of calcium from intracellular stores, while DAG, together with calcium, activates protein kinase C, which then phosphorylates other molecules, leading to altered cellular activity. Calcium is required for the catalysis. PI-PLC-epsilon represents a class of mammalian PI-PLC that has an N-terminal CDC25 homology domain with a guanyl-nucleotide exchange factor (GFF) activity, a pleckstrin homology (PH) domain, an array of EF hands, a PLC catalytic core domain, a C2 domain, and two predicted RA (Ras association) domains that are implicated in the binding of small GTPases, such as Ras or Rap, from the Ras family. The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. There is one PI-PLC-epsilon isozyme (1). PI-PLC-epsilon is activated by G alpha(12/13), G beta gamma, and activated members of Ras and Rho small GTPases. Aside from PI-PLC-epsilon identified in mammals, its eukaryotic homologs have been classified with this family.

Pssm-ID: 176538 [Multi-domain] Cd Length: 254 Bit Score: 222.42 E-value: 1.43e-65

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    312 QDMNNPLSHYWISSSHNTYLTGDQLRSESSPEAYIRCLRMGCRCIELDCWDGPDGKPVIYHGWTRTTKIKFDDVVQAIKD 391
Cdd:cd08596    2 EDLQYPLSYYYIESSHNTYLTGHQLKGESSVELYSQVLLTGCRCVELDCWDGDDGMPIIYHGHTLTTKIPFKDVVEAINR 81

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    392 HAFVTSSFPVILSIEEHCSVEQQRHMAKAFKEVFGDLLLTK---PTEASAD-QLPSPSQLREKIIIKHKK 457
Cdd:cd08596   82 SAFITSDYPVILSIENHCSLQQQRKMAEIFKTVFGEKLVTKflfESDFSDDpSLPSPLQLKNKILLKNKK 151

PI-PLCc_delta3

cd08630

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-delta3; This subfamily ...

312-458

1.61e-65

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-delta3; This subfamily corresponds to the catalytic domain present in metazoan phosphoinositide-specific phospholipase C (PI-PLC, EC 3.1.4.11)-delta3 isozymes. PI-PLC is a signaling enzyme that hydrolyzes the membrane phospholipids phosphatidylinositol-4,5-bisphosphate (PIP2) to generate two important second messengers in eukaryotic signal transduction cascades, Inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG). InsP3 triggers inflow of calcium from intracellular stores, while DAG, together with calcium, activates protein kinase C, which then phosphorylates other molecules, leading to altered cellular activity. Calcium is required for the catalysis. PLC-delta represents a class of mammalian PI-PLC that has an N-terminal pleckstrin homology (PH) domain, an array of EF hands, a PLC catalytic core domain, and a C-terminal C2 domain. This family corresponds to the catalytic domain which is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. There are three PI-PLC-delta isozymes (1,3 and 4). Unlike PI-PLC-delta 4, PI-PLC-delta1 and 3 possess a putative nuclear export sequence (NES) located in the EF-hand domain, which may be responsible transporting PI-PLC-delta1 and 3 from the cell nucleus.

Pssm-ID: 176567 [Multi-domain] Cd Length: 258 Bit Score: 222.59 E-value: 1.61e-65

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    312 QDMNNPLSHYWISSSHNTYLTGDQLRSESSPEAYIRCLRMGCRCIELDCWDGPDGKPVIYHGWTRTTKIKFDDVVQAIKD 391
Cdd:cd08630    2 QDMSQPLAHYFISSSHNTYLTDSQIGGPSSTEAYVRAFAQGCRCVELDCWEGPGGEPVIYHGHTLTSKILFRDVIQAVRQ 81

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 190036    392 HAFVTSSFPVILSIEEHCSVEQQRHMAKAFKEVFGDLLLTKP-TEASADQLPSPSQLREKIIIKHKKL 458
Cdd:cd08630   82 HAFTASPYPVILSLENHCGLEQQAAMARHLQTILGDMLVTQPlDSLNPEELPSPEELKGRVLVKGKKL 149

EFh_PI-PLCgamma

cd16201

EF-hand motif found in phosphoinositide phospholipase C gamma isozymes (PI-PLC-gamma); ...

145-298

9.77e-62

EF-hand motif found in phosphoinositide phospholipase C gamma isozymes (PI-PLC-gamma); PI-PLC-gamma isozymes represent a class of metazoan PI-PLCs that hydrolyze the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2) to propagate diverse intracellular responses that underlie the physiological action of many hormones, neurotransmitters, and growth factors. They can form a complex with the phosphorylated cytoplasmic domains of the immunoglobulin Ig-alpha and Ig-beta subunits of the B cell receptor (BCR), the membrane-tethered Src family kinase Lyn, phosphorylated spleen tyrosine kinase (Syk), the phosphorylated adaptor protein B-cell linker (BLNK), and activated Bruton's tyrosine kinase (Btk). Like other PI-PLC isozymes, PI-PLC-gamma isozymes contain a core set of domains, including an N-terminal pleckstrin homology (PH) domain, four atypical EF-hand motifs, a PLC catalytic core, and a single C2 domain. The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. Unique to PI-PLC-gamma, a second PH domain, which is split by two SH2 (Src homology 2) domains, and one SH3 (Src homology 3) domain, are present within this linker. The SH2 and SH3 domains are responsible for the binding of phosphotyrosine-containing sequences and proline-rich sequences, respectively. There are two PI-PLC-gamma isozymes (1-2), both of which are activated by receptor and non-receptor tyrosine kinases due to the presence of SH2 and SH3 domains.

Pssm-ID: 320031 [Multi-domain] Cd Length: 145 Bit Score: 207.04 E-value: 9.77e-62

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    145 WLRKQIYSVDQTRRNSISLRELKTILPLINFKVSSaKFLKDKFVEIGAH-KDELSFEQFHLFYKKLMFEQqkSILDEFKK 223
Cdd:cd16201    1 WLRKEFYSMDRTRRETVTLKDLKAFLPRVNCKIST-NKLREKFQEVDTRrRGELGFDDFAQLYHKLMFDQ--KIIEDFFK 77

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 190036    224 DSSvfilgntDRPDASAVYLHDFQRFLIHEQQEHWAQDLNKVRERMTKFIDDTMRETAEPFLFVDEFLTYLFSRE 298
Cdd:cd16201   78 KYS-------YSSDGQTVTLEDFQRFLLEEQKEPWANDPNAVREFMRDFLQDPLRDVQEPYFTLDEFLDYLFSKE 145

PI-PLCc_delta4

cd08631

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-delta4; This subfamily ...

312-458

1.15e-61

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-delta4; This subfamily corresponds to the catalytic domain present in metazoan phosphoinositide-specific phospholipase C (PI-PLC, EC 3.1.4.11)-delta4 isozymes. PI-PLC is a signaling enzyme that hydrolyzes the membrane phospholipids phosphatidylinositol-4,5-bisphosphate (PIP2) to generate two important second messengers in eukaryotic signal transduction cascades, Inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG). InsP3 triggers inflow of calcium from intracellular stores, while DAG, together with calcium, activates protein kinase C, which then phosphorylates other molecules, leading to altered cellular activity. Calcium is required for the catalysis. PLC-delta represents a class of mammalian PI-PLC that has an N-terminal pleckstrin homology (PH) domain, an array of EF hands, a PLC catalytic core domain, and a C-terminal C2 domain. This CD corresponds to the catalytic domain which is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. There are three PI-PLC-delta isozymes (1,3 and 4). Unlike PI-PLC-delta 1 and 3, a putative nuclear export sequence (NES) located in the EF-hand domain, which may be responsible transporting PI-PLC-delta1 and 3 from the cell nucleus, is not present in PI-PLC-delta4. Experiments show PI-PLC-delta4 is required for the acrosome reaction in fertilization.

Pssm-ID: 176568 [Multi-domain] Cd Length: 258 Bit Score: 211.34 E-value: 1.15e-61

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    312 QDMNNPLSHYWISSSHNTYLTGDQLRSESSPEAYIRCLRMGCRCIELDCWDGPDGKPVIYHGWTRTTKIKFDDVVQAIKD 391
Cdd:cd08631    2 QDMTQPLCHYFICSSHNTYLMEDQLRGQSSVEGYIRALKRGCRCVEVDVWDGPNGEPIVYHGHTFTSKILFKDVVAAVAQ 81

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 190036    392 HAFVTSSFPVILSIEEHCSVEQQRHMAKAFKEVFGDLLLTKPTEASAD-QLPSPSQLREKIIIKHKKL 458
Cdd:cd08631   82 YAFQVSDYPVILSLENHCGVEQQQTMAQHLTEILGEKLLSTTLDGVLPtQLPSPEELRGKILLKGKKI 149

PI-PLCc_eta1

cd08632

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-eta1; This subfamily ...

312-458

3.85e-61

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-eta1; This subfamily corresponds to the catalytic domain present in metazoan phosphoinositide-specific phospholipase C (PI-PLC, EC 3.1.4.11)-eta isozyme 1. PI-PLC is a signaling enzyme that hydrolyzes the membrane phospholipids phosphatidylinositol-4,5-bisphosphate (PIP2) to generate two important second messengers in eukaryotic signal transduction cascades, Inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG). InsP3 triggers inflow of calcium from intracellular stores, while DAG, together with calcium, activates protein kinase C, which then phosphorylates other molecules, leading to altered cellular activity. Calcium is required for the catalysis. PI-PLC-eta represents a class of neuron-speific PI-PLC that has an N-terminal pleckstrin homology (PH) domain, an array of EF hands, a PLC catalytic core domain, a C2 domain, and a unique C-terminal tail that terminates with a PDZ-binding motif, a potential interaction site for other signaling proteins. The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. PI-PLC-eta1 is a neuron-specific enzyme and expressed in only nerve tissues such as the brain and spinal cord. It may perform a fundamental role in the brain.

Pssm-ID: 176569 [Multi-domain] Cd Length: 253 Bit Score: 209.89 E-value: 3.85e-61

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    312 QDMNNPLSHYWISSSHNTYLTGDQLRSESSPEAYIRCLRMGCRCIELDCWDGPDGKPVIYHGWTRTTKIKFDDVVQAIKD 391
Cdd:cd08632    2 QDMDQPLCNYFIASSHNTYLTGDQLLSQSKVDMYARVLQAGCRCVEVDCWDGPDGEPVVHHGYTLTSKITFRDVIETINK 81

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 190036    392 HAFVTSSFPVILSIEEHCSVEQQRHMAKAFKEVFGDLL-LTKPTEASADQLPSPSQLREKIIIKHKKL 458
Cdd:cd08632   82 YAFVKNEFPVILSIENHCSIQQQKKIAQYLKEIFGDKLdLSSVLTGDPKQLPSPQLLKGKILVKGKKL 149

PH_PLC_gamma

cd13362

Phospholipase C-gamma (PLC-gamma) pleckstrin homology (PH) domain; PLC-gamma (PLCgamma) is ...

22-140

4.82e-61

Pssm-ID: 270168 Cd Length: 121 Bit Score: 204.05 E-value: 4.82e-61

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036     22 LELGTVMTVFsFRKSTPERRTVQVIMETRQVAWSKTADK-IEGFLDIMEIKEIRPGKNSKDFERAKAV--RQKEDCCFTI 98
Cdd:cd13362    1 LERGTVMTKF-YQKKRPERRTFQVKLETRQVVWSRGGGKrAEGAVDIREIKEIRPGKNSKDFERWPDEakKLDPSCCFVI 79

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|..
gi 190036     99 LYGTQFVLSTLSLAADSKEDAVNWLSGLKILHQEAMNASTPT 140
Cdd:cd13362   80 LYGTEFRLKTLSVAATSEEECDMWIKGLRYLVEDTLSASYPL 121

PI-PLCc_eta2

cd08633

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-eta2; This subfamily ...

312-458

1.30e-59

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-eta2; This subfamily corresponds to the catalytic domain present in metazoan phosphoinositide-specific phospholipase C (PI-PLC, EC 3.1.4.11)-eta isozyme 2. PI-PLC is a signaling enzyme that hydrolyzes the membrane phospholipids phosphatidylinositol-4,5-bisphosphate (PIP2) to generate two important second messengers in eukaryotic signal transduction cascades, Inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG). InsP3 triggers inflow of calcium from intracellular stores, while DAG, together with calcium, activates protein kinase C, which then phosphorylates other molecules, leading to altered cellular activity. Calcium is required for the catalysis. PI-PLC-eta represents a class of neuron-speific PI-PLC that has an N-terminal pleckstrin homology (PH) domain, an array of EF hands, a PLC catalytic core domain, a C2 domain, and a unique C-terminal tail that terminates with a PDZ-binding motif, a potential interaction site for other signaling proteins. The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. PI-PLC-eta2 is a neuron-specific enzyme and expressed in the brain. It may in part function downstream of G-protein-coupled receptors and play an important role in the formation and maintenance of the neuronal network in the postnatal brain.

Pssm-ID: 176570 [Multi-domain] Cd Length: 254 Bit Score: 205.27 E-value: 1.30e-59

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    312 QDMNNPLSHYWISSSHNTYLTGDQLRSESSPEAYIRCLRMGCRCIELDCWDGPDGKPVIYHGWTRTTKIKFDDVVQAIKD 391
Cdd:cd08633    2 QDMTQPLSHYFITSSHNTYLSGDQLMSQSRVDMYAWVLQAGCRCVEVDCWDGPDGEPIVHHGYTLTSKILFKDVIETINK 81

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 190036    392 HAFVTSSFPVILSIEEHCSVEQQRHMAKAFKEVFGDLL-LTKPTEASADQLPSPSQLREKIIIKHKKL 458
Cdd:cd08633   82 YAFIKNEYPVILSIENHCSVPQQKKMAQYLTEILGDKLdLSSVISNDCTRLPSPEILKGKILVKGKKL 149

SH2_C-SH2_PLC_gamma_like

cd09932

C-terminal Src homology 2 (C-SH2) domain in Phospholipase C gamma; Phospholipase C gamma is a ...

641-744

2.99e-59

Pssm-ID: 198186 Cd Length: 104 Bit Score: 198.26 E-value: 2.99e-59

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    641 HESKPWYYDSLSRGEAEDMLMRIPRDGAFLIRKRE-GSDSYAITFRARGKVKHCRINRDGRHFVLGTSAyFESLVELVSY 719
Cdd:cd09932    1 HESKEWFHANLTREQAEEMLMRVPRDGAFLVRPSEtDPNSFAISFRAEGKIKHCRIKQEGRLFVIGTSQ-FESLVELVSY 79

                         90       100
                 ....*....|....*....|....*
gi 190036    720 YEKHSLYRKMRLRYPVTPELLERYN 744
Cdd:cd09932   80 YEKHPLYRKIKLRYPVNEELLEKYG 104

PI-PLCc_beta4

cd08626

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-beta4; This subfamily ...

312-458

3.55e-59

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-beta4; This subfamily corresponds to the catalytic domain present in metazoan phosphoinositide-specific phospholipase C (PI-PLC, EC 3.1.4.11)-beta isozyme 4. PI-PLC is a signaling enzyme that hydrolyzes the membrane phospholipids phosphatidylinositol-4,5-bisphosphate (PIP2) to generate two important second messengers in eukaryotic signal transduction cascades, Inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG). InsP3 triggers inflow of calcium from intracellular stores, while DAG, together with calcium, activates protein kinase C, which goes on to phosphorylate other molecules, leading to altered cellular activity. Calcium is required for the catalysis. PLC-beta represents a class of mammalian PI-PLC that has an N-terminal pleckstrin homology (PH) domain, an array of EF hands, a PLC catalytic core domain, a C2 domain, and a unique C-terminal coiled-coil (CT) domain necessary for homodimerization. The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. PI-PLC-beta4 is expressed in high concentrations in cerebellar Purkinje and granule cells, the median geniculate body, and the lateral geniculate nucleus. It is activated by the heterotrimeric G protein alpha q subunits through their C2 domain and long C-terminal extension.

Pssm-ID: 176563 [Multi-domain] Cd Length: 257 Bit Score: 204.23 E-value: 3.55e-59

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    312 QDMNNPLSHYWISSSHNTYLTGDQLRSESSPEAYIRCLRMGCRCIELDCWDGP--DGKPVIYHGWTRTTKIKFDDVVQAI 389
Cdd:cd08626    2 QDMDQPLAHYFINSSHNTYLTGRQFGGKSSVEMYRQVLLAGCRCIELDCWDGKgeDQEPIITHGKAMCTDILFKDVIQAI 81

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 190036    390 KDHAFVTSSFPVILSIEEHCSVEQQRHMAKAFKEVFGDLLLTKPTEA----SADQLPSPSQLREKIIIKHKKL 458
Cdd:cd08626   82 KDTAFVTSDYPVILSFENHCSKPQQYKLAKYCEEIFGDLLLTKPLEShplePGVPLPSPNKLKRKILIKNKRL 154

PI-PLCc_zeta

cd08595

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-zeta; This family ...

312-457

2.36e-57

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-zeta; This family corresponds to the catalytic domain presenting in metazoan phosphoinositide-specific phospholipase C (PI-PLC, EC 3.1.4.11)-zeta isozyme. PI-PLC is a signaling enzyme that hydrolyzes the membrane phospholipids phosphatidylinositol-4,5-bisphosphate (PIP2) to generate two important second messengers in eukaryotic signal transduction cascades, inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG). InsP3 triggers inflow of calcium from intracellular stores, while DAG, together with calcium, activates protein kinase C, which then phosphorylates other molecules, leading to altered cellular activity. Calcium is required for the catalysis. PI-PLC-zeta represents a class of sperm-specific PI-PLC that has an N-terminal EF-hand domain, a PLC catalytic core domain, and a C-terminal C2 domain. The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. There is one PLC-zeta isozyme (1). PLC-zeta plays a fundamental role in vertebrate fertilization by initiating intracellular calcium oscillations that trigger the embryo development. However, the mechanism of its activation still remains unclear. Aside from PI-PLC-zeta identified in mammals, its eukaryotic homologs have been classified with this family.

Pssm-ID: 176537 [Multi-domain] Cd Length: 257 Bit Score: 199.01 E-value: 2.36e-57

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    312 QDMNNPLSHYWISSSHNTYLTGDQLRSESSPEAYIRCLRMGCRCIELDCWDGPDGKPVIYHGWTRTTKIKFDDVVQAIKD 391
Cdd:cd08595    2 QDMDHPLSDYFISSSHNTYLVSDQLVGPSDLDGYVSALRKGCRCLEIDCWDGADNEPVVYHGYTLTSKILFKEVITTVEK 81

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 190036    392 HAFVTSSFPVILSIEEHCSVEQQRHMAKAFKEVFGDLLLTKPT-EASADQLPSPSQLREKIIIKHKK 457
Cdd:cd08595   82 YAFEKSDYPVVLSLENHCSTEQQEIMAHYLVSILGEKLLRAPIdDPATGELPSPEALKFKILVKNKK 148

PI-PLCc_plant

cd08599

Catalytic domain of plant phosphatidylinositide-specific phospholipases C; This family ...

312-456

1.06e-55

Catalytic domain of plant phosphatidylinositide-specific phospholipases C; This family corresponds to the catalytic domain present in a group of phosphoinositide-specific phospholipases C (PI-PLC, EC 3.1.4.11) encoded by PLC genes from higher plants, which are homologs of mammalian PI-PLC in terms of overall sequence similarity and domain organization. Mammalian PI-PLC is a signaling enzyme that hydrolyzes the membrane phospholipids phosphatidylinositol-4,5-bisphosphate (PIP2) to generate two important second messengers in eukaryotic signal transduction cascades, inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG). InsP3 triggers inflow of calcium from intracellular stores, while DAG, together with calcium, activates protein kinase C, which then phosphorylates other molecules, leading to altered cellular activity. Calcium is required for the catalysis. The domain arrangement of plant PI-PLCs is structurally similar to the mammalian PLC-zeta isoform, which lacks the N-terminal pleckstrin homology (PH) domain, but contains EF-hand like motifs (which are absent in a few plant PLCs), a PLC catalytic core domain with X- and Y- highly conserved regions split by a linker sequence, and a C2 domain. However, at the sequence level, the plant PI-PLCs are closely related to the mammalian PLC-delta isoform. Experiments show that plant PLCs display calcium dependent PLC catalytic properties, although they lack some of the N-terminal motifs found in their mammalian counterparts. A putative calcium binding site may be located at the region spanning the X- and Y- domains.

Pssm-ID: 176541 [Multi-domain] Cd Length: 228 Bit Score: 192.97 E-value: 1.06e-55

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    312 QDMNNPLSHYWISSSHNTYLTGDQLRSESSPEAYIRCLRMGCRCIELDCWDGPDGKPVIYHGWTRTTKIKFDDVVQAIKD 391
Cdd:cd08599    2 HDMTAPLSHYFIFSSHNSYLTGNQLSSRSSTAPIIEALLRGCRVIELDLWPGGRGDICVLHGGTLTKPVKFEDCIKAIKE 81

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 190036    392 HAFVTSSFPVILSIEEHCSVEQQRHMAKAFKEVFGDLLLTKPTEASADQLPSPSQLREKIIIKHK 456
Cdd:cd08599   82 NAFTASEYPVIITLENHLSPELQAKAAQILRETLGDKLFYPDSEDLPEEFPSPEELKGKILISDK 146

PI-PLCc_beta2

cd08624

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-beta2; This subfamily ...

312-457

2.70e-54

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-beta2; This subfamily corresponds to the catalytic domain present in metazoan phosphoinositide-specific phospholipase C (PI-PLC, EC 3.1.4.11)-beta isozyme 2. PI-PLC is a signaling enzyme that hydrolyzes the membrane phospholipids phosphatidylinositol-4,5-bisphosphate (PIP2) to generate two important second messengers in eukaryotic signal transduction cascades, Inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG). InsP3 triggers inflow of calcium from intracellular stores, while DAG, together with calcium, activates protein kinase C, which goes on to phosphorylate other molecules, leading to altered cellular activity. Calcium is required for the catalysis. PLC-beta represents a class of mammalian PI-PLC that has an N-terminal pleckstrin homology (PH) domain, an array of EF hands, a PLC catalytic core domain, a C2 domain, and a unique C-terminal coiled-coil (CT) domain necessary for homodimerization. The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. PI-PLC-beta2 is expressed at highest levels in cells of hematopoietic origin. It is activated by the heterotrimeric G protein alpha q subunits through their C2 domain and long C-terminal extension. It is also activated by the beta-gamma subunits of heterotrimeric G proteins.

Pssm-ID: 176561 [Multi-domain] Cd Length: 261 Bit Score: 190.27 E-value: 2.70e-54

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    312 QDMNNPLSHYWISSSHNTYLTGDQLRSESSPEAYIRCLRMGCRCIELDCWDG--PDGKPVIYHGWTRTTKIKFDDVVQAI 389
Cdd:cd08624    2 QDMTQPLNHYFINSSHNTYLTAGQFSGLSSPEMYRQVLLSGCRCVELDCWKGkpPDEEPIITHGFTMTTEILFKDAIEAI 81

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 190036    390 KDHAFVTSSFPVILSIEEHC-SVEQQRHMAKAFKEVFGDLLLTKPTE----ASADQLPSPSQLREKIIIKHKK 457
Cdd:cd08624   82 AESAFKTSPYPVILSFENHVdSPKQQAKMAEYCRTIFGDMLLTEPLEkyplKPGVPLPSPEDLRGKILIKNKK 154

PLCYc

smart00149

Phospholipase C, catalytic domain (part); domain Y; Phosphoinositide-specific phospholipases C. ...

931-1043

5.78e-53

Pssm-ID: 128454 [Multi-domain] Cd Length: 115 Bit Score: 180.90 E-value: 5.78e-53

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036       931 SDLVVYCKPTSKT--KDNLENPDFREIRSFVETKADSIIRQKPVDLLKYNQKGLTRVYPKGQRVDSSNYDPFRLWLCGSQ 1008
Cdd:smart00149    1 SDLVIYCAPVKFRsfESAESKNPFYEMSSFSETKAKKLLKKSPTDFVRYNQRQLSRVYPKGTRVDSSNYNPQVFWNHGCQ 80

                            90       100       110
                    ....*....|....*....|....*....|....*
gi 190036      1009 MVALNFQTADKYMQMNHALFSLNGRTGYVLQPESM 1043
Cdd:smart00149   81 MVALNFQTPDKPMQLNQGMFRANGGCGYVLKPDFL 115

PI-PLC-Y

pfam00387

Phosphatidylinositol-specific phospholipase C, Y domain; This associates with pfam00388 to ...

930-1041

2.68e-52

Phosphatidylinositol-specific phospholipase C, Y domain; This associates with pfam00388 to form a single structural unit.

Pssm-ID: 459794 Cd Length: 114 Bit Score: 178.81 E-value: 2.68e-52

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036      930 LSDLVVYCKPTS-KTKDNLENPDFREIRSFVETKADSIIRQKPVDLLKYNQKGLTRVYPKGQRVDSSNYDPFRLWLCGSQ 1008
Cdd:pfam00387    1 LSDLVVYTQSVKfKSFSTPESKTPNHIFSFSESKALKLIKSSSAAFVKHNRRHLMRVYPKGTRVDSSNFNPQPFWNCGVQ 80

                           90       100       110
                   ....*....|....*....|....*....|...
gi 190036     1009 MVALNFQTADKYMQMNHALFSLNGRTGYVLQPE 1041
Cdd:pfam00387   81 MVALNWQTPDEGMQLNEGMFADNGGCGYVLKPE 113

SH2_N-SH2_PLC_gamma_like

cd10341

N-terminal Src homology 2 (N-SH2) domain in Phospholipase C gamma; Phospholipase C gamma is a ...

527-627

6.24e-52

Pssm-ID: 199829 Cd Length: 99 Bit Score: 177.16 E-value: 6.24e-52

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    527 HFGEKWFHKKV-EKRTSAEKLLQEYCMetgGKDGTFLVRESETFPNDYTLSFWRSGRVQHCRIRSTMEGGTLKYYLTDNL 605
Cdd:cd10341    1 HFTEPWFHGKLgDGRDEAEKLLLEYCE---GGDGTFLVRESETFVGDYTLSFWRNGKVQHCRIRSRQENGEKKYYLTDNL 77

                         90       100
                 ....*....|....*....|..
gi 190036    606 RFRRMYALIQHYRETHLPCAEF 627
Cdd:cd10341   78 VFDSLYELIDYYRQNPLRCAEF 99

PI-PLCc_beta3

cd08625

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-beta3; This subfamily ...

313-458

4.37e-49

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-beta3; This subfamily corresponds to the catalytic domain present in metazoan phosphoinositide-specific phospholipase C (PI-PLC, EC 3.1.4.11)-beta isozyme 3. PI-PLC is a signaling enzyme that hydrolyzes the membrane phospholipids phosphatidylinositol-4,5-bisphosphate (PIP2) to generate two important second messengers in eukaryotic signal transduction cascades, Inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG). InsP3 triggers inflow of calcium from intracellular stores, while DAG, together with calcium, activates protein kinase C, which goes on to phosphorylate other molecules, leading to altered cellular activity. Calcium is required for the catalysis. PLC-beta represents a class of mammalian PI-PLC that has an N-terminal pleckstrin homology (PH) domain, an array of EF hands, a PLC catalytic core domain, a C2 domain, and a unique C-terminal coiled-coil (CT) domain necessary for homodimerization. The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. PI-PLC-beta3 is widely expressed at highest levels in brain, liver, and parotid gland. It is activated by the heterotrimeric G protein alpha q subunits through their C2 domain and long C-terminal extension. It is also activated by the beta-gamma subunits of heterotrimeric G proteins.

Pssm-ID: 176562 [Multi-domain] Cd Length: 258 Bit Score: 175.24 E-value: 4.37e-49

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    313 DMNNPLSHYWISSSHNTYLTGDQLRSESSPEAYIRCLRMGCRCIELDCWDG--PDGKPVIYHGWTRTTKIKFDDVVQAIK 390
Cdd:cd08625    3 DMNQPLSHYFINSSHNTYLTAGQLTGLSSVEMYRQVLLTGCRCIELDCWKGrpPEEEPFITHGFTMTTEIPFKDVIEAIA 82

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 190036    391 DHAFVTSSFPVILSIEEHC-SVEQQRHMAKAFKEVFGDLLLTKPTE----ASADQLPSPSQLREKIIIKHKKL 458
Cdd:cd08625   83 ESAFKTSPYPVILSFENHVdSAKQQAKMAEYCRSIFGDALLIDPLDkyplVPGVQLPSPQELMGKILVKNKKM 155

EFh_PI-PLCgamma1_like

cd16216

EF-hand motif found in 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1-like ...

145-298

1.71e-47

EF-hand motif found in 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1-like proteins; This family corresponds to a small group of uncharacterized 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1-like (PI-PLC-gamma1-like) proteins. Although their biological function remains unclear, they shows high sequence similarity with other phosphoinositide phospholipase C gamma proteins. They contain a core set of domains, including an N-terminal pleckstrin homology (PH) domain, four atypical EF-hand motifs, a PLC catalytic core, and a single C2 domain. The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. A second PH domain, which is split by two SH2 (Src homology 2) domains, and one SH3 (Src homology 3) domain, are present within this linker.

Pssm-ID: 320046 Cd Length: 150 Bit Score: 166.65 E-value: 1.71e-47

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    145 WLRKQIYSVDQTRRNSISLRELKTILPLINFKVSSAKFLKDKFVEIGAhKDELSFEQFHLFYKKLMFEQQKSILDEFKKD 224
Cdd:cd16216    1 WLRKQFDGMDRSREGSITVKDLKALLPQVNYRVPNMRFLRDKLVEVEA-RSELTFPHFIQFYKNLMFDAQKSIIEQLELS 79

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 190036    225 ssvFILGNTDRPDASAVYLHDFQRFLIHEQQEHWAQDLNKVRERMTKFIDDTMRETAEPFLFVDEFLTYLFSRE 298
Cdd:cd16216   80 ---FPLRNVDRPELCQISLYDFQKFLQHDQKESWASDVGRVRDYLCGYLKESSNEAPEPSLQLDEFLTYLFSKE 150

C2_PLC_like

cd00275

C2 domain present in Phosphoinositide-specific phospholipases C (PLC); PLCs are involved in ...

1061-1187

8.27e-45

Pssm-ID: 175974 [Multi-domain] Cd Length: 128 Bit Score: 158.09 E-value: 8.27e-45

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036   1061 MTLTVKVLGARHLPKLG---RSIACPFVEVEICGAEYG-NNKFKTTVVNDNGLSPIWaptQEKVTFEIYDPNLAFLRFVV 1136
Cdd:cd00275    2 LTLTIKIISGQQLPKPKgdkGSIVDPYVEVEIHGLPADdSAKFKTKVVKNNGFNPVW---NETFEFDVTVPELAFLRFVV 78

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|.
gi 190036   1137 YEEDMFSDpNFLAHATYPIKAVKSGFRSVPLKNGYSEDIELASLLVFCEMR 1187
Cdd:cd00275   79 YDEDSGDD-DFLGQACLPLDSLRQGYRHVPLLDSKGEPLELSTLFVHIDIT 128

PI-PLCc_gamma

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-gamma; This family ...

952-1031

1.38e-44

Pssm-ID: 176534 [Multi-domain] Cd Length: 229 Bit Score: 161.44 E-value: 1.38e-44

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    952 FREIRSFVETKADSII-RQKPVDLLKYNQKGLTRVYPKGQRVDSSNYDPFRLWLCGSQMVALNFQTADKYMQMNHALFSL 1030
Cdd:cd08592  149 FYEMSSFPETKAEKYLnRQKGKIFLKYNRRQLSRVYPKGQRVDSSNYDPVPMWNCGSQMVALNFQTPDKPMQLNQALFML 228


                 .
gi 190036   1031 N 1031
Cdd:cd08592  229 N 229

PI-PLCc

cd00137

Catalytic domain of prokaryotic and eukaryotic phosphoinositide-specific phospholipase C; This ...

312-459

7.92e-43

Catalytic domain of prokaryotic and eukaryotic phosphoinositide-specific phospholipase C; This subfamily corresponds to the catalytic domain present in prokaryotic and eukaryotic phosphoinositide-specific phospholipase C (PI-PLC), which is a ubiquitous enzyme catalyzing the cleavage of the sn3-phosphodiester bond in the membrane phosphoinositides (phosphatidylinositol, PI; Phosphatidylinositol-4-phosphate, PIP; phosphatidylinositol 4,5-bisphosphate, PIP2) to yield inositol phosphates (inositol monosphosphate, InsP; inositol diphosphate, InsP2; inositol trisphosphate, InsP3) and diacylglycerol (DAG). The higher eukaryotic PI-PLCs (EC 3.1.4.11) have a multidomain organization that consists of a PLC catalytic core domain, and various regulatory domains. They play a critical role in most signal transduction pathways, controlling numerous cellular events, such as cell growth, proliferation, excitation and secretion. These PI-PLCs strictly require Ca2+ for their catalytic activity. They display a clear preference towards the hydrolysis of the more highly phosphorylated PI-analogues, PIP2 and PIP, to generate two important second messengers, InsP3 and DAG. InsP3 triggers inflow of calcium from intracellular stores, while DAG, together with calcium, activates protein kinase C, which then phosphorylates other molecules, leading to altered cellular activity. In contrast, bacterial PI-PLCs contain a single catalytic domain. Although their precise physiological function remains unclear, bacterial PI-PLCs may function as virulence factors in some pathogenic bacteria. They participate in Ca2+-independent PI metabolism. They are characterized as phosphatidylinositol-specific phospholipase C (EC 4.6.1.13) that selectively hydrolyze PI, not PIP or PIP2. The TIM-barrel type catalytic domain in bacterial PI-PLCs is very similar to the one in eukaryotic PI-PLCs, in which the catalytic domain is assembled from two highly conserved X- and Y-regions split by a divergent linker sequence. The catalytic mechanism of both prokaryotic and eukaryotic PI-PLCs is based on general base and acid catalysis utilizing two well conserved histidines, and consists of two steps, a phosphotransfer and a phosphodiesterase reaction. This superfamily also includes a distinctly different type of eukaryotic PLC, glycosylphosphatidylinositol-specific phospholipase C (GPI-PLC), an integral membrane protein characterized in the protozoan parasite Trypanosoma brucei. T. brucei GPI-PLC hydrolyzes the GPI-anchor on the variant specific glycoprotein (VSG), releasing dimyristyl glycerol (DMG), which may facilitate the evasion of the protozoan to the host#s immune system. It does not require Ca2+ for its activity and is more closely related to bacterial PI-PLCs, but not mammalian PI-PLCs.

Pssm-ID: 176497 [Multi-domain] Cd Length: 274 Bit Score: 157.81 E-value: 7.92e-43

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    312 QDMNNPLSHYWISSSHNTYLTGDQL-----RSESSPEAYIRCLRMGCRCIELDCWDGPDGKPVIYHGWTrTTKIKFDDVV 386
Cdd:cd00137    2 HPDTQPLAHYSIPGTHDTYLTAGQFtikqvWGLTQTEMYRQQLLSGCRCVDIRCWDGKPEEPIIYHGPT-FLDIFLKEVI 80

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 190036    387 QAIKDHAFVTSSFPVILSIEEHCSV--EQQRHMAKAFKEVFGDLLLTKPTEASaDQLPSPSQLREKIIIKHKKLG 459
Cdd:cd00137   81 EAIAQFLKKNPPETIIMSLKNEVDSmdSFQAKMAEYCRTIFGDMLLTPPLKPT-VPLPSLEDLRGKILLLNKKNG 154

PI-PLCc_beta1

cd08623

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-beta1; This subfamily ...

312-458

8.19e-43

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-beta1; This subfamily corresponds to the catalytic domain present in metazoan phosphoinositide-specific phospholipase C (PI-PLC, EC 3.1.4.11)-beta isozyme 1. PI-PLC is a signaling enzyme that hydrolyzes the membrane phospholipids phosphatidylinositol-4,5-bisphosphate (PIP2) to generate two important second messengers in eukaryotic signal transduction cascades, Inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG). InsP3 triggers inflow of calcium from intracellular stores, while DAG, together with calcium, activates protein kinase C, which goes on to phosphorylate other molecules, leading to altered cellular activity. Calcium is required for the catalysis. PLC-beta represents a class of mammalian PI-PLC that has an N-terminal pleckstrin homology (PH) domain, an array of EF hands, a PLC catalytic core domain, a C2 domain, and a unique C-terminal coiled-coil (CT) domain necessary for homodimerization. The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. PI-PLC-beta1 is expressed at highest levels in specific regions of the brain. It is activated by the heterotrimeric G protein alpha q subunits through their C2 domain and long C-terminal extension.

Pssm-ID: 176560 [Multi-domain] Cd Length: 258 Bit Score: 157.17 E-value: 8.19e-43

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    312 QDMNNPLSHYWISSSHNTYLTGDQLRSESSPEAYIRCLRMGCRCIELDCWDG--PDGKPVIYHGWTRTTKIKFDDVVQAI 389
Cdd:cd08623    2 EDMSQPLSHYFINSSHNTYLTAGQLAGNSSVEMYRQVLLSGCRCVELDCWKGrtAEEEPVITHGFTMTTEISFKEVIEAI 81

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 190036    390 KDHAFVTSSFPVILSIEEHC-SVEQQRHMAKAFKEVFGDLLLTKPTE----ASADQLPSPSQLREKIIIKHKKL 458
Cdd:cd08623   82 AECAFKTSPFPILLSFENHVdSPKQQAKMAEYCRLIFGDALLMEPLEkyplESGVPLPSPMDLMYKILVKNKKM 155

EFh_PI-PLCgamma1

cd16214

EF-hand motif found in phosphoinositide phospholipase C gamma 1 (PI-PLC-gamma1); PI-PLC-gamma1, ...

145-298

2.14e-38

EF-hand motif found in phosphoinositide phospholipase C gamma 1 (PI-PLC-gamma1); PI-PLC-gamma1, also termed 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1, or PLC-148, or phospholipase C-II (PLC-II), or phospholipase C-gamma-1 (PLC-gamma-1), is abundantly expressed in embryonal cortical structures, neurons, oligodendrocytes and astrocytes, and is involved in various cellular events, including proliferation, differentiation, migration, survival, and cell death. It also associates with many diseases, including epilepsy, Huntington's disease (HD), depression, Alzheimer's disease (AD) and bipolar disorder. PI-PLC-gamma1 plays a critical role in cell migration and tumor cell invasiveness and metastasis. It can mediate the cell motility effects of growth factors, including platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin-like growth factor (IGF) and hepatocyte growth factor (HGF), as well as adhesion receptors. Moreover, PI-PLC-gamma1 can modulate neurite outgrowth, neuronal cell migration and synaptic plasticity through the Trk receptor. PI-PLC-gamma1 contains an N-terminal pleckstrin homology (PH) domain, an array of EF hands, a PLC catalytic core domain, and a C2 domain. The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. Besides, PI-PLC-gamma1 has a second PH domain, two SH2 (Src homology 2) regions, and one SH3 (Src homology 3) region, which are present within this linker. PI-PLC-gamma1 is activated by receptor and non-receptor tyrosine kinases via its two SH2 and a single SH3 domain.

Pssm-ID: 320044 Cd Length: 146 Bit Score: 140.35 E-value: 2.14e-38

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    145 WLRKQIYSVDQTRRNSISLRELKTILPLINFKVSSAKFLKDKFVEIGAHKDELSFEQFHLFYKKLMFEQQKSIldefkkd 224
Cdd:cd16214    1 WLRKQFYSVDRNREDRISVKDLKNMLSQVNYRVPNMKFLREKLTDLELRSGDITYGQFAQLYRSLMFDAQKTM------- 73

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 190036    225 sSVFILGNTDRPDASAVYLHDFQRFLIHEQQEHWAQDLNKVRERMTKFIDDTMRETAEPFLFVDEFLTYLFSRE 298
Cdd:cd16214   74 -EVPFLERFEEREECKISLEDFQKFLLDYQKELWATDTNQVQEFMFNFLRDPLREIEEPYFSLDEFLTFLFSKE 146

PI-PLCc_eukaryota

cd08558

Catalytic domain of eukaryotic phosphoinositide-specific phospholipase C and similar proteins; ...

954-1031

1.42e-37

Pssm-ID: 176501 [Multi-domain] Cd Length: 226 Bit Score: 141.05 E-value: 1.42e-37

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 190036    954 EIRSFVETKADSIIRQKPVDLLKYNQKGLTRVYPKGQRVDSSNYDPFRLWLCGSQMVALNFQTADKYMQMNHALFSLN 1031
Cdd:cd08558  149 HMSSFSETKALKLLKESPEEFVKYNKRQLSRVYPKGTRVDSSNYNPQPFWNAGCQMVALNYQTPDLPMQLNQGKFEQN 226

PI-PLCc_delta

cd08593

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-delta; This subfamily ...

922-1031

2.90e-35

Pssm-ID: 176535 [Multi-domain] Cd Length: 257 Bit Score: 135.54 E-value: 2.90e-35

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    922 KNQSIAIELSDLVVYCK--PTSKTKDNLENPDFREIRSFVETKADSIIRQKPVDLLKYNQKGLTRVYPKGQRVDSSNYDP 999
Cdd:cd08593  146 KKLKLAKELSDLVIYCKsvHFKSFEHSKENYHFYEMSSFSESKALKLAQESGNEFVRHNKRQLSRIYPAGLRTDSSNYDP 225

                         90       100       110
                 ....*....|....*....|....*....|..
gi 190036   1000 FRLWLCGSQMVALNFQTADKYMQMNHALFSLN 1031
Cdd:cd08593  226 QEMWNVGCQIVALNFQTPGEEMDLNDGLFRQN 257

PHsplit_PLC_gamma

Phospholipase C-gamma Split pleckstrin homology (PH) domain; PLC-gamma (PLCgamma) is activated ...

840-910

3.15e-35

Pssm-ID: 270054 Cd Length: 105 Bit Score: 129.90 E-value: 3.15e-35

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 190036    840 IEDNPLGSLCRGILDLNTYNVVKAPQGKNQKSFVFILEPKEQGDPPVEFATDRVEELFEWFQSIREITWKI 910
Cdd:cd13234   35 TENSPLGSLLRGILDVPSCHVVKRPEGKNSRPFVFILSPKSLSDPPLDVAADSQEELQDWVQKIREVAQTA 105

SH3_PLCgamma2

cd11969

Src homology 3 domain of Phospholipase C (PLC) gamma 2; PLCgamma2 is primarily expressed in ...

773-827

1.56e-33

Pssm-ID: 212902 Cd Length: 55 Bit Score: 123.03 E-value: 1.56e-33

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 190036    773 TVKALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRIQQYFPSNYVEDI 827
Cdd:cd11969    1 TVKALYDYRAKRSDELSFCKGALIHNVSKETGGWWKGDYGGKVQHYFPSNYVEDV 55

PLN02222

phosphoinositide phospholipase C 2

248-528

2.58e-33

phosphoinositide phospholipase C 2

Pssm-ID: 177868 [Multi-domain] Cd Length: 581 Bit Score: 137.08 E-value: 2.58e-33

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036     248 RFLIHEQQEHWAqdlnkVRERMTKFIDDTMRETAEPFLFVDEFLTYLFSRENS-IWDEKYDavdmQDMNNPLSHYWISSS 326
Cdd:PLN02222   47 RFLIDVQKQDKA-----TREDAQSIINSASSLLHRNGLHLDAFFKYLFGDNNPpLALHEVH----HDMDAPISHYFIFTG 117

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036     327 HNTYLTGDQLRSESSPEAYIRCLRMGCRCIELDCWDGPDGKPV-IYHGWTRTTKIKFDDVVQAIKDHAFVTSSFPVILSI 405
Cdd:PLN02222  118 HNSYLTGNQLSSDCSEVPIIDALKKGVRVIELDIWPNSDKDDIdVLHGMTLTTPVGLIKCLKAIRAHAFDVSDYPVVVTL 197

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036     406 EEHCSVEQQRHMAKAFKEVFGDLLLTKPTEASADQLPSPSQLREKIIIKHKKlgPRGDVDVNMEDKKDEHKQQGELYMWD 485
Cdd:PLN02222  198 EDHLTPDLQSKVAEMVTEIFGEILFTPPVGESLKEFPSPNSLKKRIIISTKP--PKEYKEGKDDEVVQKGKDLGDEEVWG 275

                         250       260       270       280
                  ....*....|....*....|....*....|....*....|....
gi 190036     486 SIDQKWTRHYCAIADAKLSFS-DDIEQTMEEEVPQDIPPTELHF 528
Cdd:PLN02222  276 REVPSFIQRNKSVDKNDSNGDdDDDDDDGEDKSKKNAPPQYKHL 319

PLN02228

Phosphoinositide phospholipase C

248-456

1.14e-32

Phosphoinositide phospholipase C

Pssm-ID: 177873 [Multi-domain] Cd Length: 567 Bit Score: 135.16 E-value: 1.14e-32

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036     248 RFLIHEQQEHWAqDLNKVRERMTKFIDDTMREtAEPFLFVDEFLTYLFSRENS-------IWdekydavdmQDMNNPLSH 320
Cdd:PLN02228   46 RFVSEVQGERHA-GLDYVQDIFHSVKHHNVFH-HHGLVHLNAFYRYLFSDTNSplpmsgqVH---------HDMKAPLSH 114

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036     321 YWISSSHNTYLTGDQLRSESSPEAYIRCLRMGCRCIELDCWDGPDGKPV-IYHGWTRTTKIKFDDVVQAIKDHAFVTSSF 399
Cdd:PLN02228  115 YFVYTGHNSYLTGNQVNSRSSVEPIVQALRKGVKVIELDLWPNPSGNAAeVRHGRTLTSHEDLQKCLNAIKDNAFQVSDY 194

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 190036     400 PVILSIEEHCSVEQQRHMAKAFKEVFGDLLLtKPTEASADQLPSPSQLREKIIIKHK 456
Cdd:PLN02228  195 PVVITLEDHLPPNLQAQVAKMLTKTFRGMLF-RCTSESTKHFPSPEELKNKILISTK 250

PLN02228

Phosphoinositide phospholipase C

903-1188

2.06e-31

Phosphoinositide phospholipase C

Pssm-ID: 177873 [Multi-domain] Cd Length: 567 Bit Score: 131.31 E-value: 2.06e-31

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036     903 IREITWK--IDSKENNMKYWEKNQSIAIELSDLVVYCKPTSK--TKDNLENPDFREIR-SFVETKADSIIRQKPVDLLKY 977
Cdd:PLN02228  269 VKETSWKrvADAENKILEEYKDEESEAVGYRDLIAIHAANCKdpLKDCLSDDPEKPIRvSMDEQWLETMVRTRGTDLVRF 348

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036     978 NQKGLTRVYPKGQRVDSSNYDPFRLWLCGSQMVALNFQTADKYMQMNHALFSLNGRTGYVLQPESMRTEK--YDPMppeS 1055
Cdd:PLN02228  349 TQRNLVRIYPKGTRVDSSNYDPHVGWTHGAQMVAFNMQGHGKQLWIMQGMFRANGGCGYVKKPRILLDEHtlFDPC---K 425

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    1056 QRKILMTLTVKVLGAR------HLPKLGR-SIACPFVEVEICGAEYGNNKFKTTVVNDNGLsPIWapTQEKVTFEIYDPN 1128
Cdd:PLN02228  426 RLPIKTTLKVKIYTGEgwdldfHLTHFDQySPPDFFVKIGIAGVPRDTVSYRTETAVDQWF-PIW--GNDEFLFQLRVPE 502

                         250       260       270       280       290       300
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    1129 LAFLRFVVYEEDMFSDPNFLAHATYPIKAVKSGFRSVPLKNGYSEDIELASLLVFCEMRP 1188
Cdd:PLN02228  503 LALLWFKVQDYDNDTQNDFAGQTCLPLPELKSGVRAVRLHDRAGKAYKNTRLLVSFALDP 562

PLN02952

phosphoinositide phospholipase C

198-456

2.19e-31

phosphoinositide phospholipase C

Pssm-ID: 178538 [Multi-domain] Cd Length: 599 Bit Score: 131.66 E-value: 2.19e-31

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036     198 SFEQFHLFYKKLMF---EQQKSILDEFKKdssvFILGntdrpdASAVYLHDFQRFLIHEQQEhwaqdLNKVRERMTKFID 274
Cdd:PLN02952   18 NYKMFNLFNRKFKIteaEPPDDVKDVFCK----FSVG------GGHMGADQLRRFLVLHQDE-----LDCTLAEAQRIVE 82

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036     275 DTMRET------AEPFLFVDEFLTYLFsrensiwdekYDAVD-------MQDMNNPLSHYWISSSHNTYLTGDQLRSESS 341
Cdd:PLN02952   83 EVINRRhhvtryTRHGLNLDDFFHFLL----------YDDLNgpitpqvHHDMTAPLSHYFIYTGHNSYLTGNQLSSDCS 152

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036     342 PEAYIRCLRMGCRCIELDCWDGPDGKPV-IYHGWTRTTKIKFDDVVQAIKDHAFVTSSFPVILSIEEHCSVEQQRHMAKA 420
Cdd:PLN02952  153 EVPIVKALQRGVRVIELDLWPGSTKDEIlVLHGRTLTTPVPLIKCLKSIRDYAFSSSPYPVIITLEDHLTPDLQAKVAEM 232

                         250       260       270
                  ....*....|....*....|....*....|....*.
gi 190036     421 FKEVFGDLLLTkPTEASADQLPSPSQLREKIIIKHK 456
Cdd:PLN02952  233 ATQIFGQMLYY-PESDSLVQFPSPESLKHRIIISTK 267

PI-PLCc_gamma1

cd08627

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-gamma1; This subfamily ...

938-1031

2.64e-31

Pssm-ID: 176564 [Multi-domain] Cd Length: 229 Bit Score: 123.21 E-value: 2.64e-31

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    938 KPTSKTKDNLENPD-------------FREIRSFVETKADSII-RQKPVDLLKYNQKGLTRVYPKGQRVDSSNYDPFRLW 1003
Cdd:cd08627  122 KPVDINADGLPSPNqlkrkilikhkklYRDMSSFPETKAEKYVnRSKGKKFLQYNRRQLSRIYPKGQRLDSSNYDPLPMW 201

                         90       100
                 ....*....|....*....|....*...
gi 190036   1004 LCGSQMVALNFQTADKYMQMNHALFSLN 1031
Cdd:cd08627  202 ICGSQLVALNFQTPDKPMQMNQALFMLG 229

PLN02230

phosphoinositide phospholipase C 4

253-473

5.82e-31

phosphoinositide phospholipase C 4

Pssm-ID: 177875 [Multi-domain] Cd Length: 598 Bit Score: 130.21 E-value: 5.82e-31

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036     253 EQQEHWAQDLNKVRERMTKFiddTMREtaepfLFVDEFLTYLFSRENS--IWDEKYdavdmQDMNNPLSHYWISSSHNTY 330
Cdd:PLN02230   67 EEAERIVDEVLRRKHHIAKF---TRRN-----LTLDDFNYYLFSTDLNppIADQVH-----QNMDAPLSHYFIFTGHNSY 133

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036     331 LTGDQLRSESSPEAYIRCLRMGCRCIELDCWDGPDGKPVIYHGWTRTTKIKFDDVVQAIKDHAFVTSSFPVILSIEEHCS 410
Cdd:PLN02230  134 LTGNQLSSNCSELPIADALRRGVRVVELDLWPRGTDDVCVKHGRTLTKEVKLGKCLDSIKANAFAISKYPVIITLEDHLT 213

                         170       180       190       200       210       220
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 190036     411 VEQQRHMAKAFKEVFGDLLLTKPTEaSADQLPSPSQLREKIIIKHKKlgPRGDVDVNMEDKKD 473
Cdd:PLN02230  214 PKLQFKVAKMITQTFGDMLYYHDSE-GCQEFPSPEELKEKILISTKP--PKEYLEANDAKEKD 273

SH3_PLCgamma

cd11825

Src homology 3 domain of Phospholipase C (PLC) gamma; PLC catalyzes the hydrolysis of ...

773-826

1.18e-29

Src homology 3 domain of Phospholipase C (PLC) gamma; PLC catalyzes the hydrolysis of phosphatidylinositol (4,5)-bisphosphate [PtdIns(4,5)P2] to produce Ins(1,4,5)P3 and diacylglycerol (DAG) in response to various receptors. Ins(1,4,5)P3 initiates the calcium signaling cascade while DAG functions as an activator of PKC. PLCgamma catalyzes this reaction in tyrosine kinase-dependent signaling pathways. It is activated and recruited to its substrate at the membrane. Vertebrates contain two forms of PLCgamma, PLCgamma1, which is widely expressed, and PLCgamma2, which is primarily found in haematopoietic cells. PLCgamma contains a Pleckstrin homology (PH) domain followed by an elongation factor (EF) domain, two catalytic regions of PLC domains that flank two tandem SH2 domains, followed by a SH3 domain and C2 domain. The SH3 domain of PLCgamma1 directly interacts with dynamin-1 and can serve as a guanine nucleotide exchange factor (GEF). It also interacts with Cbl, inhibiting its phosphorylation and activity. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212759 [Multi-domain] Cd Length: 54 Bit Score: 112.04 E-value: 1.18e-29

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....
gi 190036    773 TVKALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRIQQYFPSNYVED 826
Cdd:cd11825    1 TVKALYDYRAQRPDELSFCKHAIITNVEKEDGGWWRGDYGGKKQKWFPANYVEE 54

PI-PLCc_beta

cd08591

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-beta; This subfamily ...

930-1031

2.19e-29

Pssm-ID: 176533 [Multi-domain] Cd Length: 257 Bit Score: 118.21 E-value: 2.19e-29

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    930 LSDLVVYCKPTS-KTKDNLE--NPDFrEIRSFVETKADSIIRQKPVDLLKYNQKGLTRVYPKGQRVDSSNYDPFRLWLCG 1006
Cdd:cd08591  154 LSSLVNYIQPVKfQGFEVAEkrNKHY-EMSSFNESKGLGYLKKSPIEFVNYNKRQLSRIYPKGTRVDSSNYMPQIFWNAG 232

                         90       100
                 ....*....|....*....|....*
gi 190036   1007 SQMVALNFQTADKYMQMNHALFSLN 1031
Cdd:cd08591  233 CQMVALNFQTPDLPMQLNQGKFEYN 257

PLN02952

phosphoinositide phospholipase C

862-1182

2.49e-29

phosphoinositide phospholipase C

Pssm-ID: 178538 [Multi-domain] Cd Length: 599 Bit Score: 125.11 E-value: 2.49e-29

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036     862 KAPQGKNQKSFVFILEPKEQGDPPVEFATDRVEE-------LFEWFQSIREITWKIDSKENNMKYWEKNQSIAIELSdlv 934
Cdd:PLN02952  267 KPPKEYLESSGPIVIKKKNNVSPSGRNSSEETEEaqtlesmLFEQEADSRSDSDQDDNKSGELQKPAYKRLITIHAG--- 343

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036     935 vycKPTSKTKDNLENPDFREIR-SFVETKADSIIRQKPVDLLKYNQKGLTRVYPKGQRVDSSNYDPFRLWLCGSQMVALN 1013
Cdd:PLN02952  344 ---KPKGTLKDAMKVAVDKVRRlSLSEQELEKAATTNGQDVVRFTQRNILRIYPKGTRITSSNYKPLIGWMHGAQMIAFN 420

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    1014 FQTADKYMQMNHALFSLNGRTGYVLQPESMRTEKYDP--MPPESQRKILMTLTVKV-------LGARHLPKLGRSIACPF 1084
Cdd:PLN02952  421 MQGYGKSLWLMHGMFRANGGCGYLKKPDFLMKKGFHDevFDPKKKLPVKKTLKVKVylgdgwrLDFSHTHFDSYSPPDFY 500

                         250       260       270       280       290       300       310       320
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    1085 VEVEICGAEYGNNKFKTTVVNDNgLSPIWaptQEKVTFEIYDPNLAFLRFVVYEEDMFSDPNFLAHATYPIKAVKSGFRS 1164
Cdd:PLN02952  501 TKMYIVGVPADNAKKKTKIIEDN-WYPAW---NEEFSFPLTVPELALLRIEVREYDMSEKDDFGGQTCLPVSELRPGIRS 576

                         330
                  ....*....|....*...
gi 190036    1165 VPLKNGYSEDIELASLLV 1182
Cdd:PLN02952  577 VPLHDKKGEKLKNVRLLM 594

SH2

SH2 domain;

532-617

1.74e-26

SH2 domain;

Pssm-ID: 425423 [Multi-domain] Cd Length: 77 Bit Score: 103.83 E-value: 1.74e-26

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036      532 WFHKKVEkRTSAEKLLQEycmetGGKDGTFLVRESETFPNDYTLSFWRSGRVQHCRIRSTMEGgtlKYYLTDNLRFRRMY 611
Cdd:pfam00017    1 WYHGKIS-RQEAERLLLN-----GKPDGTFLVRESESTPGGYTLSVRDDGKVKHYKIQSTDNG---GYYISGGVKFSSLA 71


                   ....*.
gi 190036      612 ALIQHY 617
Cdd:pfam00017   72 ELVEHY 77

PI-PLCc_eta2

cd08633

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-eta2; This subfamily ...

922-1031

7.05e-26

Pssm-ID: 176570 [Multi-domain] Cd Length: 254 Bit Score: 108.20 E-value: 7.05e-26

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    922 KNQSIAIELSDLVVYCKPTSKTKDNLENPDFREIRSFVETKADSIIRQKPVDLLKYNQKGLTRVYPKGQRVDSSNYDPFR 1001
Cdd:cd08633  145 KGKKLSRALSDLVKYTKSVRVHDIETEATSSWQVSSFSETKAHQILQQKPAQYLRFNQRQLSRIYPSSYRVDSSNYNPQP 224

                         90       100       110
                 ....*....|....*....|....*....|
gi 190036   1002 LWLCGSQMVALNFQTADKYMQMNHALFSLN 1031
Cdd:cd08633  225 FWNAGCQMVALNYQSEGRMLQLNRAKFSAN 254

PI-PLC1c_yeast

cd08598

Catalytic domain of putative yeast phosphatidylinositide-specific phospholipases C; This ...

921-1031

1.58e-25

Pssm-ID: 176540 [Multi-domain] Cd Length: 231 Bit Score: 106.56 E-value: 1.58e-25

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    921 EKNQSIAIELSDL----VVYCKPTSKTkdnlenpdFREIRSFVETKADSIIRQKPVDLLKYNQKGLTRVYPKGQRVDSSN 996
Cdd:cd08598  125 DGLEDELPSPEELrgkiLIKVKKESKT--------PNHIFSLSERSLLKLLKDKRAALDKHNRRHLMRVYPSGTRISSSN 196

                         90       100       110
                 ....*....|....*....|....*....|....*
gi 190036    997 YDPFRLWLCGSQMVALNFQTADKYMQMNHALFSLN 1031
Cdd:cd08598  197 FNPLPFWRAGVQMVALNWQTYDLGMQLNEAMFAGS 231

PI-PLCc_delta4

cd08631

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-delta4; This subfamily ...

929-1031

2.25e-25

Pssm-ID: 176568 [Multi-domain] Cd Length: 258 Bit Score: 106.96 E-value: 2.25e-25

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    929 ELSDLVVYCK--PTSKTKDNLENPDFREIRSFVETKADSIIRQKPVDLLKYNQKGLTRVYPKGQRVDSSNYDPFRLWLCG 1006
Cdd:cd08631  154 ELSDCVIYCKsvSFRSFTHSREHYHFYEISSFTETKARKLIREAGNEFVQHNTWQLSRVYPSGLRTDSSNYNPQEMWNAG 233

                         90       100
                 ....*....|....*....|....*
gi 190036   1007 SQMVALNFQTADKYMQMNHALFSLN 1031
Cdd:cd08631  234 CQMVALNFQTAGLEMDLNDGLFRQN 258

PI-PLCc_beta2

cd08624

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-beta2; This subfamily ...

929-1031

5.89e-25

Pssm-ID: 176561 [Multi-domain] Cd Length: 261 Bit Score: 105.52 E-value: 5.89e-25

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    929 ELSDLVVYCKPTSKtkDNLENPDFRE----IRSFVETKADSIIRQKPVDLLKYNQKGLTRVYPKGQRVDSSNYDPFRLWL 1004
Cdd:cd08624  157 EMSSLVNYIQPTKF--VSFEFSAQKNrsyvISSFTELKAYDLLSKASVQFVEYNKRQMSRIYPKGTRMDSSNYMPQMFWN 234

                         90       100
                 ....*....|....*....|....*..
gi 190036   1005 CGSQMVALNFQTADKYMQMNHALFSLN 1031
Cdd:cd08624  235 VGCQMVALNFQTMDLPMQQNMALFEFN 261

PLN02223

phosphoinositide phospholipase C

256-479

3.75e-24

phosphoinositide phospholipase C

Pssm-ID: 165867 [Multi-domain] Cd Length: 537 Bit Score: 108.57 E-value: 3.75e-24

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036     256 EHWAQDLNKVRERMTKFIDDTMREtaepflfVDEFLTYLFSREnsIWDEKYDAVDMQDMNNPLSHYWISSSHNTYLTGDQ 335
Cdd:PLN02223   59 EKIAAELKRRKCDILAFRNLRCLE-------LDHLNEFLFSTE--LNPPIGDQVRHHDMHAPLSHYFIHTSLKSYFTGNN 129

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036     336 LRSES-SPEAYIRCLRMGCRCIELDCWdgPDGKPVI--YHGWTRTTKIKFDDVVQAIKDHAFV-TSSFPVILSIEEHCSV 411
Cdd:PLN02223  130 VFGKLySIEPIIDALEQGVRVVELDLL--PDGKDGIcvRPKWNFEKPLELQECLDAIKEHAFTkCRSYPLIITFKDGLKP 207

                         170       180       190       200       210       220       230
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 190036     412 EQQRHMAKAFKEVFGDLLLTKPTEASADQLPSPSQLREKIIIKH---KKLGPRGDVDVNMEDKKDEHKQQG 479
Cdd:PLN02223  208 DLQSKATQMIDQTFGDMVYHEDPQHSLEEFPSPAELQNKILISRrppKELLYAKADDGGVGVRNELEIQEG 278

SH2

SH2 domain;

646-720

4.59e-24

SH2 domain;

Pssm-ID: 425423 [Multi-domain] Cd Length: 77 Bit Score: 96.90 E-value: 4.59e-24

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 190036      646 WYYDSLSRGEAEDMLMRIPRDGAFLIRKREGSD-SYAITFRARGKVKHCRINRDGR-HFVLGTSAYFESLVELVSYY 720
Cdd:pfam00017    1 WYHGKISRQEAERLLLNGKPDGTFLVRESESTPgGYTLSVRDDGKVKHYKIQSTDNgGYYISGGVKFSSLAELVEHY 77

PI-PLCc_beta3

cd08625

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-beta3; This subfamily ...

929-1031

5.68e-24

Pssm-ID: 176562 [Multi-domain] Cd Length: 258 Bit Score: 102.83 E-value: 5.68e-24

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    929 ELSDLVVYCKPTS-KTKDNLENPD-FREIRSFVETKADSIIRQKPVDLLKYNQKGLTRVYPKGQRVDSSNYDPFRLWLCG 1006
Cdd:cd08625  154 KMSTLVNYIEPVKfKSFEAAAKRNkFFEMSSFVETKAMEQLTKSPMEFVEYNKKQLSRIYPKGTRVDSSNYMPQLFWNVG 233

                         90       100
                 ....*....|....*....|....*
gi 190036   1007 SQMVALNFQTADKYMQMNHALFSLN 1031
Cdd:cd08625  234 CQMVALNFQTLDLAMQLNMGVFEYN 258

PI-PLCc_eta

cd08594

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-eta; This family ...

954-1031

9.33e-24

Pssm-ID: 176536 [Multi-domain] Cd Length: 227 Bit Score: 101.03 E-value: 9.33e-24

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 190036    954 EIRSFVETKADSIIRQKPVDLLKYNQKGLTRVYPKGQRVDSSNYDPFRLWLCGSQMVALNFQTADKYMQMNHALFSLN 1031
Cdd:cd08594  150 QVSSFSETRAHQIVQQKAAQFLRFNQRQLSRIYPSAYRIDSSNFNPQPYWNAGCQLVALNYQTEGRMLQLNRAKFRAN 227

PI-PLCc_eta1

cd08632

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-eta1; This subfamily ...

922-1031

1.33e-23

Pssm-ID: 176569 [Multi-domain] Cd Length: 253 Bit Score: 101.65 E-value: 1.33e-23

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    922 KNQSIAIELSDLVVYCKPTSkTKDNLENPDFREIRSFVETKADSIIRQKPVDLLKYNQKGLTRVYPKGQRVDSSNYDPFR 1001
Cdd:cd08632  145 KGKKLCRDLSDLVVYTNSVA-AQDIVDDGSTGNVLSFSETRAHQLVQQKAEQFMTYNQKQLTRIYPSAYRIDSSNFNPLP 223

                         90       100       110
                 ....*....|....*....|....*....|
gi 190036   1002 LWLCGSQMVALNFQTADKYMQMNHALFSLN 1031
Cdd:cd08632  224 YWNVGCQLVALNYQSEGRMMQLNRAKFMVN 253

PI-PLCc_delta1

cd08629

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-delta1; This subfamily ...

922-1031

4.41e-23

Pssm-ID: 176566 [Multi-domain] Cd Length: 258 Bit Score: 100.11 E-value: 4.41e-23

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    922 KNQSIAIELSDLVVYCK--PTSKTKDNLENP-DFREIRSFVETKADSIIRQKPVDLLKYNQKGLTRVYPKGQRVDSSNYD 998
Cdd:cd08629  146 KKLKLVPELSDMIIYCKsvHFGGFSSPGTSGqAFYEMASFSESRALRLLQESGNGFVRHNVSCLSRIYPAGWRTDSSNYS 225

                         90       100       110
                 ....*....|....*....|....*....|...
gi 190036    999 PFRLWLCGSQMVALNFQTADKYMQMNHALFSLN 1031
Cdd:cd08629  226 PVEMWNGGCQIVALNFQTPGPEMDVYLGCFQDN 258

EFh_PI-PLC

cd15898

EF-hand motif found in eukaryotic phosphoinositide-specific phospholipase C (PI-PLC, EC 3.1.4. ...

145-298

7.06e-23

EF-hand motif found in eukaryotic phosphoinositide-specific phospholipase C (PI-PLC, EC 3.1.4.11) isozymes; PI-PLC isozymes are signaling enzymes that hydrolyze the membrane phospholipids phosphatidylinositol-4,5-bisphosphate (PIP2) to generate two important second messengers in eukaryotic signal transduction cascades, Inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG). InsP3 triggers inflow of calcium from intracellular stores, while DAG, together with calcium, activates protein kinase C, which goes on to phosphorylate other molecules, leading to altered cellular activity. Calcium is required for the catalysis. This family corresponds to the four EF-hand motifs containing PI-PLC isozymes, including PI-PLC-beta (1-4), -gamma (1-2), -delta (1,3,4), -epsilon (1), -zeta (1), eta (1-2). Lower eukaryotes such as yeast and slime molds contain only delta-type isozymes. In contrast, other types of isoforms present in higher eukaryotes. This family also includes 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase 1 (PLC1) from fungi. Some homologs from plants contain only two atypical EF-hand motifs and they are not included. All PI-PLC isozymes except sperm-specific PI-PLC-zeta share a core set of domains, including an N-terminal pleckstrin homology (PH) domain, four atypical EF-hand motifs, a PLC catalytic core, and a single C2 domain. PI-PLC-zeta lacks the PH domain. The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. Most of EF-hand motifs found in PI-PLCs consist of a helix-loop-helix structure, but lack residues critical to metal binding. Moreover, the EF-hand region of most of PI-PLCs may have an important regulatory function, but it has yet to be identified. However, PI-PLC-zeta is a key exception. It is responsible for Ca2+ oscillations in fertilized oocytes and exhibits a high sensitivity to Ca2+ mediated through its EF-hand domain. In addition, PI-PLC-eta2 shows a canonical EF-loop directing Ca2+-sensitivity and thus can amplify transient Ca2+ signals. Also it appears that PI-PLC-delta1 can regulate the binding of PH domain to PIP2 in a Ca2+-dependent manner through its functionally important EF-hand domains. PI-PLCs can be activated by a variety of extracellular ligands, such as growth factors, hormones, cytokines and lipids. Their activation has been implicated in tumorigenesis and/or metastasis linked to migration, proliferation, growth, inflammation, angiogenesis and actin cytoskeleton reorganization. PI-PLC-beta isozymes are activated by G-protein coupled receptor (GPCR) through different mechanisms. However, PI-PLC-gamma isozymes are activated by receptor tyrosine kinase (RTK), such as Rho and Ras GTPases. In contrast, PI-PLC-epsilon are activated by both GPCR and RTK. PI-PLC-delta1 and PLC-eta 1 are activated by GPCR-mediated calcium mobilization. The activation mechanism for PI-PLC-zeta remains unclear.

Pssm-ID: 320029 [Multi-domain] Cd Length: 137 Bit Score: 95.81 E-value: 7.06e-23

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    145 WLRKQIYSVDQTRRNSISLRELKTILPLINFKVSSaKFLKDKFVEIG-AHKDELSFEQFHLFYKKLMFeqQKSILDEFKK 223
Cdd:cd15898    1 WLRRQWIKADKDGDGKLSLKEIKKLLKRLNIRVSE-KELKKLFKEVDtNGDGTLTFDEFEELYKSLTE--RPELEPIFKK 77

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 190036    224 DSSvfilgntdrPDASAVYLHDFQRFLIHEQQEHWaqDLNKVRERMTKFIDdtmrETAEPFLFVDEFLTYLFSRE 298
Cdd:cd15898   78 YAG---------TNRDYMTLEEFIRFLREEQGENV--SEEECEELIEKYEP----ERENRQLSFEGFTNFLLSPE 137

SH2

Src homology 2 domains; Src homology 2 domains bind phosphotyrosine-containing polypeptides ...

530-623

1.69e-22

Pssm-ID: 214585 [Multi-domain] Cd Length: 84 Bit Score: 92.68 E-value: 1.69e-22

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036       530 EKWFHKKVEkRTSAEKLLQeycmetGGKDGTFLVRESETFPNDYTLSFWRSGRVQHCRIRSTMEGgtlKYYLTDNLRFRR 609
Cdd:smart00252    1 QPWYHGFIS-REEAEKLLK------NEGDGDFLVRDSESSPGDYVLSVRVKGKVKHYRIRRNEDG---KFYLEGGRKFPS 70

                            90
                    ....*....|....
gi 190036       610 MYALIQHYRETHLP 623
Cdd:smart00252   71 LVELVEHYQKNSLG 84

PI-PLCc_delta3

cd08630

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-delta3; This subfamily ...

922-1031

2.49e-22

Pssm-ID: 176567 [Multi-domain] Cd Length: 258 Bit Score: 97.78 E-value: 2.49e-22

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    922 KNQSIAIELSDLVVYCKPTS----KTKDNLENPDfrEIRSFVETKADSIIRQKPVDLLKYNQKGLTRVYPKGQRVDSSNY 997
Cdd:cd08630  147 KKLQISPELSALAVYCQATRlrtlEPAPVQPQPC--QVSSLSERKAKKLIREAGNSFVRHNARQLTRVYPLGLRMNSANY 224

                         90       100       110
                 ....*....|....*....|....*....|....
gi 190036    998 DPFRLWLCGSQMVALNFQTADKYMQMNHALFSLN 1031
Cdd:cd08630  225 SPQEMWNSGCQLVALNFQTPGYEMDLNAGRFLVN 258

SH3_PLCgamma1

cd11970

Src homology 3 domain of Phospholipase C (PLC) gamma 1; PLCgamma1 is widely expressed and is ...

773-828

3.42e-22

Src homology 3 domain of Phospholipase C (PLC) gamma 1; PLCgamma1 is widely expressed and is essential in growth and development. It is activated by the TrkA receptor tyrosine kinase and functions as a key regulator of cell differentiation. It is also the predominant PLCgamma in T cells and is required for T cell and NK cell function. PLCs catalyze the hydrolysis of phosphatidylinositol (4,5)-bisphosphate [PtdIns(4,5)P2] to produce Ins(1,4,5)P3 and diacylglycerol (DAG). Ins(1,4,5)P3 initiates the calcium signaling cascade while DAG functions as an activator of PKC. PLCgamma contains a Pleckstrin homology (PH) domain followed by an elongation factor (EF) domain, two catalytic regions of PLC domains that flank two tandem SH2 domains, followed by a SH3 domain and C2 domain. The SH3 domain of PLCgamma1 directly interacts with dynamin-1 and can serve as a guanine nucleotide exchange factor (GEF). It also interacts with Cbl, inhibiting its phosphorylation and activity. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212903 Cd Length: 60 Bit Score: 90.82 E-value: 3.42e-22

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 190036    773 TVKALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRIQQYFPSNYVEDIS 828
Cdd:cd11970    5 AVKALFDYKAQREDELTFTKNAIIQNVEKQEGGWWRGDYGGKKQLWFPSNYVEEIS 60

PLN02222

phosphoinositide phospholipase C 2

938-1185

3.91e-22

phosphoinositide phospholipase C 2

Pssm-ID: 177868 [Multi-domain] Cd Length: 581 Bit Score: 102.42 E-value: 3.91e-22

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036     938 KPTSKTKDNLE-NPDFREIRSFVETKADSIIRQKPVDLLKYNQKGLTRVYPKGQRVDSSNYDPFRLWLCGSQMVALNFQT 1016
Cdd:PLN02222  326 KPKGGITECLKvDPDKVRRLSLSEEQLEKAAEKYAKQIVRFTQHNLLRIYPKGTRVTSSNYNPLVGWSHGAQMVAFNMQG 405

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    1017 ADKYMQMNHALFSLNGRTGYVLQPESMRTEKYDP--MPPESQRKILMTLTVKV-LGA------RHLPKLGRSIACPFVEV 1087
Cdd:PLN02222  406 YGRSLWLMQGMFRANGGCGYIKKPDLLLKSGSDSdiFDPKATLPVKTTLRVTIyMGEgwyfdfRHTHFDQYSPPDFYTRV 485

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    1088 EICGAEYGNNKFKTTVVNDNglspiWAPTQEKV-TFEIYDPNLAFLRFVVYEEDMFSDPNFLAHATYPIKAVKSGFRSVP 1166
Cdd:PLN02222  486 GIAGVPGDTVMKKTKTLEDN-----WIPAWDEVfEFPLTVPELALLRLEVHEYDMSEKDDFGGQTCLPVWELSQGIRAFP 560

                         250
                  ....*....|....*....
gi 190036    1167 LKNGYSEDIELASLLVFCE 1185
Cdd:PLN02222  561 LHSRKGEKYKSVKLLVKVE 579

PI-PLCc_PRIP_metazoa

cd08597

Catalytic domain of metazoan phospholipase C related, but catalytically inactive protein; This ...

929-1031

4.22e-22

Pssm-ID: 176539 [Multi-domain] Cd Length: 260 Bit Score: 97.11 E-value: 4.22e-22

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    929 ELSDLVVYCK-------PTSKtkdnlENPDFREIRSFVETKADSIIRQKPVDLLKYNQKGLTRVYPKGQRVDSSNYDPFR 1001
Cdd:cd08597  156 ELSDLVSLCKsvrfqdfPTSA-----QNQKYWEVCSFSENLARRLANEFPEDFVNYNKKFLSRVYPSPMRVDSSNYNPQD 230

                         90       100       110
                 ....*....|....*....|....*....|
gi 190036   1002 LWLCGSQMVALNFQTADKYMQMNHALFSLN 1031
Cdd:cd08597  231 FWNCGCQIVAMNYQTPGLMMDLNTGKFLEN 260

PI-PLCc_epsilon

cd08596

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-epsilon; This family ...

922-1031

8.11e-22

Pssm-ID: 176538 [Multi-domain] Cd Length: 254 Bit Score: 96.46 E-value: 8.11e-22

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    922 KNQSiAIELSDLVVYCKPTsKTKdNLENPDFREIRSFVETKADSIIRQKPVDLLKYNQKGLTRVYPKGQRVDSSNYDPFR 1001
Cdd:cd08596  148 KNKK-APELSDLVIYCQAV-KFP-GLSTPKCYHISSLNENAAKRLCRRYPQKLVQHTRCQLLRTYPAATRIDSSNPNPLI 224

                         90       100       110
                 ....*....|....*....|....*....|
gi 190036   1002 LWLCGSQMVALNFQTADKYMQMNHALFSLN 1031
Cdd:cd08596  225 FWLHGLQLVALNYQTDDLPMHLNAAMFEAN 254

PI-PLCc_beta1

cd08623

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-beta1; This subfamily ...

929-1031

2.11e-21

Pssm-ID: 176560 [Multi-domain] Cd Length: 258 Bit Score: 95.15 E-value: 2.11e-21

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    929 ELSDLVVYCKPT---SKTKDNLENPDFrEIRSFVETKADSIIRQKPVDLLKYNQKGLTRVYPKGQRVDSSNYDPFRLWLC 1005
Cdd:cd08623  154 KMSNLVNYIQPVkfeSFEASKKRNKSF-EMSSFVETKGLEQLTKSPVEFVEYNKMQLSRIYPKGTRVDSSNYMPQLFWNA 232

                         90       100
                 ....*....|....*....|....*.
gi 190036   1006 GSQMVALNFQTADKYMQMNHALFSLN 1031
Cdd:cd08623  233 GCQMVALNFQTVDLSMQINMGMYEYN 258

SH2

Src homology 2 domains; Src homology 2 domains bind phosphotyrosine-containing polypeptides ...

645-726

2.37e-21

Pssm-ID: 214585 [Multi-domain] Cd Length: 84 Bit Score: 89.21 E-value: 2.37e-21

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036       645 PWYYDSLSRGEAEDMLMRIPrDGAFLIRKREGS-DSYAITFRARGKVKHCRINRDGRH-FVLGTSAYFESLVELVSYYEK 722
Cdd:smart00252    2 PWYHGFISREEAEKLLKNEG-DGDFLVRDSESSpGDYVLSVRVKGKVKHYRIRRNEDGkFYLEGGRKFPSLVELVEHYQK 80


                    ....
gi 190036       723 HSLY 726
Cdd:smart00252   81 NSLG 84

PI-PLCc_beta4

cd08626

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-beta4; This subfamily ...

930-1031

2.51e-20

Pssm-ID: 176563 [Multi-domain] Cd Length: 257 Bit Score: 92.13 E-value: 2.51e-20

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    930 LSDLVVYCKPTS-----KTKDNleNPDFrEIRSFVETKADSIIRQKPVDLLKYNQKGLTRVYPKGQRVDSSNYDPFRLWL 1004
Cdd:cd08626  154 LSSLVNYAQPVKfqgfdVAEER--NIHF-NMSSFNESVGLGYLKTSAIEFVNYNKRQMSRIYPKGTRVDSSNYMPQIFWN 230

                         90       100
                 ....*....|....*....|....*..
gi 190036   1005 CGSQMVALNFQTADKYMQMNHALFSLN 1031
Cdd:cd08626  231 AGCQMVSLNFQTPDLGMQLNQGKFEYN 257

PLN02230

phosphoinositide phospholipase C 4

973-1169

3.95e-20

phosphoinositide phospholipase C 4

Pssm-ID: 177875 [Multi-domain] Cd Length: 598 Bit Score: 96.31 E-value: 3.95e-20

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036     973 DLLKYNQKGLTRVYPKGQRVDSSNYDPFRLWLCGSQMVALNFQTADKYMQMNHALFSLNGRTGYVLQPESM-----RTEK 1047
Cdd:PLN02230  379 DVIRFTQKNFLRIYPKGTRFNSSNYKPQIGWMSGAQMIAFNMQGYGRALWLMEGMFRANGGCGYVKKPDFLmdagpNGQD 458

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    1048 YDPMPPESQRKilmTLTVKVL-GARHLPKLGR----SIACP--FVEVEICGAEYGNNKFKTTVVNDNgLSPIWaptQEKV 1120
Cdd:PLN02230  459 FYPKDNSCPKK---TLKVKVCmGDGWLLDFKKthfdSYSPPdfFVRVGIAGAPVDEVMEKTKIEYDT-WTPIW---NKEF 531

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|....*....
gi 190036    1121 TFEIYDPNLAFLRFVVYEEDMFSDPNFLAHATYPIKAVKSGFRSVPLKN 1169
Cdd:PLN02230  532 IFPLAVPELALLRVEVHEHDINEKDDFGGQTCLPVSEIRQGIHAVPLFN 580

PI-PLCc_zeta

cd08595

Catalytic domain of metazoan phosphoinositide-specific phospholipase C-zeta; This family ...

922-1031

1.04e-19

Pssm-ID: 176537 [Multi-domain] Cd Length: 257 Bit Score: 90.38 E-value: 1.04e-19

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    922 KNQS-IAIELSDLVVYCKPTS--KTKDNLENPDFREIRSFVETKADSIIRQKPVDLLKYNQKGLTRVYPKGQRVDSSNYD 998
Cdd:cd08595  145 KNKKkIAKALSDLVIYTKSEKfcSFTHSRDNQHSYENNSIGENKARKLLKSSGADFVGHTQRFITRIYPKGTRASSSNYN 224

                         90       100       110
                 ....*....|....*....|....*....|...
gi 190036    999 PFRLWLCGSQMVALNFQTADKYMQMNHALFSLN 1031
Cdd:cd08595  225 PQEFWNVGCQMVALNFQTLGAPMDLQNGKFLDN 257

SH2_Src_family

cd09933

Src homology 2 (SH2) domain found in the Src family of non-receptor tyrosine kinases; The Src ...

530-620

1.40e-18

Src homology 2 (SH2) domain found in the Src family of non-receptor tyrosine kinases; The Src family kinases are nonreceptor tyrosine kinases that have been implicated in pathways regulating proliferation, angiogenesis, invasion and metastasis, and bone metabolism. It is thought that transforming ability of Src is linked to its ability to activate key signaling molecules in these pathways, rather than through direct activity. As such blocking Src activation has been a target for drug companies. Src family members can be divided into 3 groups based on their expression pattern: 1) Src, Fyn, and Yes; 2) Blk, Fgr, Hck, Lck, and Lyn; and 3) Frk-related kinases Frk/Rak and Iyk/Bsk Of these, cellular c-Src is the best studied and most frequently implicated in oncogenesis. The c-Src contains five distinct regions: a unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail, as do the other members of the family. Src exists in both active and inactive conformations. Negative regulation occurs through phosphorylation of Tyr, resulting in an intramolecular association between phosphorylated Tyr and the SH2 domain of SRC, which locks the protein in a closed conformation. Further stabilization of the inactive state occurs through interactions between the SH3 domain and a proline-rich stretch of residues within the kinase domain. Conversely, dephosphorylation of Tyr allows SRC to assume an open conformation. Full activity requires additional autophosphorylation of a Tyr residue within the catalytic domain. Loss of the negative-regulatory C-terminal segment has been shown to result in increased activity and transforming potential. Phosphorylation of the C-terminal Tyr residue by C-terminal Src kinase (Csk) and Csk homology kinase results in increased intramolecular interactions and consequent Src inactivation. Specific phosphatases, protein tyrosine phosphatase a (PTPa) and the SH-containing phosphatases SHP1/SHP2, have also been shown to take a part in Src activation. Src is also activated by direct binding of focal adhesion kinase (Fak) and Crk-associated substrate (Cas) to the SH2 domain. SRC activity can also be regulated by numerous receptor tyrosine kinases (RTKs), such as Her2, epidermal growth factor receptor (EGFR), fibroblast growth factor receptor, platelet-derived growth factor receptor (PDGFR), and vascular endothelial growth factor receptor (VEGFR). In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 199827 Cd Length: 101 Bit Score: 82.24 E-value: 1.40e-18

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    530 EKWFHKKVeKRTSAEKLLqeycMETGGKDGTFLVRESETFPNDYTLS-----FWRSGRVQHCRIRSTMEGGtlkYYLTDN 604
Cdd:cd09933    3 EEWFFGKI-KRKDAEKLL----LAPGNPRGTFLIRESETTPGAYSLSvrdgdDARGDTVKHYRIRKLDNGG---YYITTR 74

                         90
                 ....*....|....*.
gi 190036    605 LRFRRMYALIQHYRET 620
Cdd:cd09933   75 ATFPTLQELVQHYSKD 90

PI-PLCc_plant

cd08599

Catalytic domain of plant phosphatidylinositide-specific phospholipases C; This family ...

957-1031

2.38e-18

Pssm-ID: 176541 [Multi-domain] Cd Length: 228 Bit Score: 85.50 E-value: 2.38e-18

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 190036    957 SFVETKADSIIRQK-PVDLLKYNQKGLTRVYPKGQRVDSSNYDPFRLWLCGSQMVALNFQTADKYMQMNHALFSLN 1031
Cdd:cd08599  153 SLSETQLKKVIEGEhPTDLIEFTQKNLLRVYPAGLRITSSNYDPMLAWMHGAQMVALNMQGYDRPLWLNRGKFRAN 228

SH3

smart00326

Src homology 3 domains; Src homology 3 (SH3) domains bind to target proteins through sequences ...

770-825

3.17e-18

Pssm-ID: 214620 [Multi-domain] Cd Length: 56 Bit Score: 79.50 E-value: 3.17e-18

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|....*.
gi 190036       770 PQRTVKALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRIQQYFPSNYVE 825
Cdd:smart00326    1 EGPQVRALYDYTAQDPDELSFKKGDIITVLEKSDDGWWKGRLGRGKEGLFPSNYVE 56

PH_PLC_ELMO1

cd01248

Phospholipase C and Engulfment and cell motility protein 1 pleckstrin homology domain; The ...

22-129

3.87e-18

Phospholipase C and Engulfment and cell motility protein 1 pleckstrin homology domain; The C-terminal region of ELMO1, the PH domain and Pro-rich sequences, binds the SH3-containing region of DOCK2 forming a intermolecular five-helix bundle allowing for DOCK mediated Rac1 activation. ELMO1, a mammalian homolog of C. elegans CED-12, contains an N-terminal RhoG-binding region, a ELMO domain, a PH domain, and a C-terminal sequence with three PxxP motifs. Specificaly, PLCs catalyze the cleavage of phosphatidylinositol-4,5-bisphosphate (PIP2) and result in the release of 1,2-diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3). These products trigger the activation of protein kinase C (PKC) and the release of Ca2+ from intracellular stores. There are fourteen kinds of mammalian phospholipase C which are are classified into six isotypes (beta, gamma, delta, epsilon, zeta, eta). All PLCs, except for PLCzeta, have a PH domain which is for most part N-terminally located, though lipid binding specificity is not conserved between them. In addition PLC gamma contains a split PH domain within its catalytic domain that is separated by 2 SH2 domains and a single SH3 domain. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

Pssm-ID: 269952 Cd Length: 108 Bit Score: 81.21 E-value: 3.87e-18

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036     22 LELGTVMTVFSfRKSTPERRTVQVIMETRQVAW-SKTADKIEGFLDIMEIKEIRPGKNSKDFERAKAVRQ-KEDCCFTIL 99
Cdd:cd01248    1 LQQGTLLLKYR-EGSKPKERTFYLDPDGTRITWeSSKKKSEKKSIDISDIKEIRPGKDTDGFKRKKKSNKpKEERCFSII 79

                         90       100       110
                 ....*....|....*....|....*....|
gi 190036    100 YGTQFvlSTLSLAADSKEDAVNWLSGLKIL 129
Cdd:cd01248   80 YGSNN--KTLDLVAPSEDEANLWVEGLRAL 107

smart00239

Protein kinase C conserved region 2 (CalB); Ca2+-binding motif present in phospholipases, ...

1062-1167

5.01e-18

Pssm-ID: 214577 [Multi-domain] Cd Length: 101 Bit Score: 80.61 E-value: 5.01e-18

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036      1062 TLTVKVLGARHLPKLGRSIAC-PFVEVEICGAeyGNNKFKTTVVNDNgLSPIWaptQEKVTFEIYDPNLAFLRFVVYEED 1140
Cdd:smart00239    1 TLTVKIISARNLPPKDKGGKSdPYVKVSLDGD--PKEKKKTKVVKNT-LNPVW---NETFEFEVPPPELAELEIEVYDKD 74

                            90       100
                    ....*....|....*....|....*..
gi 190036      1141 MFSDPNFLAHATYPIKAVKSGFRSVPL 1167
Cdd:smart00239   75 RFGRDDFIGQVTIPLSDLLLGGRHEKL 101

PI-PLCc_GDPD_SF

cd08555

Catalytic domain of phosphoinositide-specific phospholipase C-like phosphodiesterases ...

325-432

1.10e-17

Pssm-ID: 176498 [Multi-domain] Cd Length: 179 Bit Score: 82.10 E-value: 1.10e-17

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    325 SSHNTYLTGDQlrsESSPEAYIRCLRMGCRCIELDCWDGPDGKPVIYHGWT------RTTKIKFDDVVQAIKDHAFvTSS 398
Cdd:cd08555    2 LSHRGYSQNGQ---ENTLEAFYRALDAGARGLELDVRLTKDGELVVYHGPTldrttaGILPPTLEEVLELIADYLK-NPD 77

                         90       100       110
                 ....*....|....*....|....*....|....*...
gi 190036    399 FPVILSIEEHCSV----EQQRHMAKAFKEVFGDLLLTK 432
Cdd:cd08555   78 YTIILSLEIKQDSpeydEFLAKVLKELRVYFDYDLRGK 115

SH2

cd00173

Src homology 2 (SH2) domain; In general, SH2 domains are involved in signal transduction; they ...

532-617

2.13e-17

Src homology 2 (SH2) domain; In general, SH2 domains are involved in signal transduction; they bind pTyr-containing polypeptide ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites. They are present in a wide array of proteins including: adaptor proteins (Nck1, Crk, Grb2), scaffolds (Slp76, Shc, Dapp1), kinases (Src, Syk, Fps, Tec), phosphatases (Shp-1, Shp-2), transcription factors (STAT1), Ras signaling molecules (Ras-Gap), ubiquitination factors (c-Cbl), cytoskeleton regulators (Tensin), signal regulators (SAP), and phospholipid second messengers (PLCgamma), amongst others.

Pssm-ID: 198173 [Multi-domain] Cd Length: 79 Bit Score: 77.88 E-value: 2.13e-17

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    532 WFHKKVEkRTSAEKLLQeycmetGGKDGTFLVRESETFPNDYTLSFW-RSGRVQHCRIRSTMEGGTLKYYltDNLRFRRM 610
Cdd:cd00173    2 WFHGSIS-REEAERLLR------GKPDGTFLVRESSSEPGDYVLSVRsGDGKVKHYLIERNEGGYYLLGG--SGRTFPSL 72


                 ....*..
gi 190036    611 YALIQHY 617
Cdd:cd00173   73 PELVEHY 79

PLN02223

phosphoinositide phospholipase C

962-1167

2.94e-17

phosphoinositide phospholipase C

Pssm-ID: 165867 [Multi-domain] Cd Length: 537 Bit Score: 86.62 E-value: 2.94e-17

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036     962 KADSIirQKP----VDLLKYNQKGLTRVYPKGQRVDS-SNYDPFRLWLCGSQMVALNFQTADKYMQMNHALFSLNGRTGY 1036
Cdd:PLN02223  306 KADDI--QQPgwyeRDIISFTQKKFLRTRPKKKNLLInAPYKPQRAWMHGAQLIALSRKDDKEKLWLMQGMFRANGGCGY 383

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    1037 VLQPES-MRTEKYDPMPPESQRKILMTLTVKV-LGARHL----PKLGRsIACP--FVEVEICGAEYGNNKFKTTVVNdNG 1108
Cdd:PLN02223  384 VKKPDFlLNAGPSGVFYPTENPVVVKILKVKIyMGDGWIvdfkKRIGR-LSKPdlYVRISIAGVPHDEKIMKTTVKN-NE 461

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 190036    1109 LSPIWAptqEKVTFEIYDPNLAFLRFVVYEEDMFSDPNFLAHATYPIKAVKSGFRSVPL 1167
Cdd:PLN02223  462 WKPTWG---EEFTFPLTYPDLALISFEVYDYEVSTADAFCGQTCLPVSELIEGIRAVPL 517

SH2

cd00173

Src homology 2 (SH2) domain; In general, SH2 domains are involved in signal transduction; they ...

645-720

3.67e-17

Pssm-ID: 198173 [Multi-domain] Cd Length: 79 Bit Score: 77.11 E-value: 3.67e-17

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    645 PWYYDSLSRGEAEDMLMRiPRDGAFLIRKRE-GSDSYAITFRAR-GKVKHCRINR--DGRHFVLGTSAYFESLVELVSYY 720
Cdd:cd00173    1 PWFHGSISREEAERLLRG-KPDGTFLVRESSsEPGDYVLSVRSGdGKVKHYLIERneGGYYLLGGSGRTFPSLPELVEHY 79

pfam00168

C2 domain;

1062-1161

3.93e-17

C2 domain;

Pssm-ID: 425499 [Multi-domain] Cd Length: 104 Bit Score: 78.13 E-value: 3.93e-17

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036     1062 TLTVKVLGARHLPKLGRSIAC-PFVEVEICGaeyGNNKFKTTVVNdNGLSPIWaptQEKVTFEIYDPNLAFLRFVVYEED 1140
Cdd:pfam00168    2 RLTVTVIEAKNLPPKDGNGTSdPYVKVYLLD---GKQKKKTKVVK-NTLNPVW---NETFTFSVPDPENAVLEIEVYDYD 74

                           90       100
                   ....*....|....*....|.
gi 190036     1141 MFSDPNFLAHATYPIKAVKSG 1161
Cdd:pfam00168   75 RFGRDDFIGEVRIPLSELDSG 95

SH3_1

pfam00018

SH3 domain; SH3 (Src homology 3) domains are often indicative of a protein involved in signal ...

775-821

2.06e-15

Pssm-ID: 394975 [Multi-domain] Cd Length: 47 Bit Score: 71.08 E-value: 2.06e-15

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*..
gi 190036      775 KALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRIQQYFPS 821
Cdd:pfam00018    1 VALYDYTAQEPDELSFKKGDIIIVLEKSEDGWWKGRNKGGKEGLIPS 47

SH2_Vav_family

cd09940

Src homology 2 (SH2) domain found in the Vav family; Vav proteins are involved in several ...

644-725

2.53e-15

Src homology 2 (SH2) domain found in the Vav family; Vav proteins are involved in several processes that require cytoskeletal reorganization, such as the formation of the immunological synapse (IS), phagocytosis, platelet aggregation, spreading, and transformation. Vavs function as guanine nucleotide exchange factors (GEFs) for the Rho/Rac family of GTPases. Vav family members have several conserved motifs/domains including: a leucine-rich region, a leucine-zipper, a calponin homology (CH) domain, an acidic domain, a Dbl-homology (DH) domain, a pleckstrin homology (PH) domain, a cysteine-rich domain, 2 SH3 domains, a proline-rich region, and a SH2 domain. Vavs are the only known Rho GEFs that have both the DH/PH motifs and SH2/SH3 domains in the same protein. The leucine-rich helix-loop-helix (HLH) domain is thought to be involved in protein heterodimerization with other HLH proteins and it may function as a negative regulator by forming inactive heterodimers. The CH domain is usually involved in the association with filamentous actin, but in Vav it controls NFAT stimulation, Ca2+ mobilization, and its transforming activity. Acidic domains are involved in protein-protein interactions and contain regulatory tyrosines. The DH domain is a GDP-GTP exchange factor on Rho/Rac GTPases. The PH domain in involved in interactions with GTP-binding proteins, lipids and/or phosphorylated serine/threonine residues. The SH3 domain is involved in localization of proteins to specific sites within the cell interacting with protein with proline-rich sequences. The SH2 domain mediates a high affinity interaction with tyrosine phosphorylated proteins. There are three Vav mammalian family members: Vav1 which is expressed in the hematopoietic system, Vav2 and Vav3 are more ubiquitously expressed. The members here include insect and amphibian Vavs. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198193 Cd Length: 102 Bit Score: 72.71 E-value: 2.53e-15

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    644 KPWYYDSLSRGEAEDMLMRIPrDGAFLIRKR-EGSDSYAITFRARGKVKHCRINRDGRHFV-LGTSAYFESLVELVSYYE 721
Cdd:cd09940    5 FLWFVGEMERDTAENRLENRP-DGTYLVRVRpQGETQYALSIKYNGDVKHMKIEQRSDGLYyLSESRHFKSLVELVNYYE 83


                 ....
gi 190036    722 KHSL 725
Cdd:cd09940   84 RNSL 87

SH2_cSH2_p85_like

cd09930

C-terminal Src homology 2 (cSH2) domain found in p85; Phosphoinositide 3-kinases (PI3Ks) are ...

641-735

3.17e-15

C-terminal Src homology 2 (cSH2) domain found in p85; Phosphoinositide 3-kinases (PI3Ks) are essential for cell growth, migration, and survival. p110, the catalytic subunit, is composed of an adaptor-binding domain, a Ras-binding domain, a C2 domain, a helical domain, and a kinase domain. The regulatory unit is called p85 and is composed of an SH3 domain, a RhoGap domain, a N-terminal SH2 (nSH2) domain, a inter SH2 (iSH2) domain, and C-terminal (cSH2) domain. There are 2 inhibitory interactions between p110alpha and p85 of P13K: 1) p85 nSH2 domain with the C2, helical, and kinase domains of p110alpha and 2) p85 iSH2 domain with C2 domain of p110alpha. There are 3 inhibitory interactions between p110beta and p85 of P13K: 1) p85 nSH2 domain with the C2, helical, and kinase domains of p110beta, 2) p85 iSH2 domain with C2 domain of p110alpha, and 3) p85 cSH2 domain with the kinase domain of p110alpha. It is interesting to note that p110beta is oncogenic as a wild type protein while p110alpha lacks this ability. One explanation is the idea that the regulation of p110beta by p85 is unique because of the addition of inhibitory contacts from the cSH2 domain and the loss of contacts in the iSH2 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198184 Cd Length: 104 Bit Score: 72.45 E-value: 3.17e-15

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    641 HESKPWYYDSLSRGEAEDMLmRIPRDGAFLIRKREGSDSYAITFRARGKVKHCRINRDGRHFvlGTSAYF---ESLVELV 717
Cdd:cd09930    3 HDERTWLVGDINRTQAEELL-RGKPDGTFLIRESSTQGCYACSVVCNGEVKHCVIYKTETGY--GFAEPYnlyESLKELV 79

                         90       100
                 ....*....|....*....|...
gi 190036    718 SYYEKHSLYR-----KMRLRYPV 735
Cdd:cd09930   80 LHYAHNSLEQhndslTVTLAYPV 102

SH2_ABL

cd09935

Src homology 2 (SH2) domain found in Abelson murine lymphosarcoma virus (ABL) proteins; ...

532-621

3.35e-15

Src homology 2 (SH2) domain found in Abelson murine lymphosarcoma virus (ABL) proteins; ABL-family proteins are highly conserved tyrosine kinases. Each ABL protein contains an SH3-SH2-TK (Src homology 3-Src homology 2-tyrosine kinase) domain cassette, which confers autoregulated kinase activity and is common among nonreceptor tyrosine kinases. Several types of posttranslational modifications control ABL catalytic activity, subcellular localization, and stability, with consequences for both cytoplasmic and nuclear ABL functions. Binding partners provide additional regulation of ABL catalytic activity, substrate specificity, and downstream signaling. By combining this cassette with actin-binding and -bundling domain, ABL proteins are capable of connecting phosphoregulation with actin-filament reorganization. Vertebrate paralogs, ABL1 and ABL2, have evolved to perform specialized functions. ABL1 includes nuclear localization signals and a DNA binding domain which is used to mediate DNA damage-repair functions, while ABL2 has additional binding capacity for actin and for microtubules to enhance its cytoskeletal remodeling functions. SH2 is involved in several autoinhibitory mechanism that constrain the enzymatic activity of the ABL-family kinases. In one mechanism SH2 and SH3 cradle the kinase domain while a cap sequence stabilizes the inactive conformation resulting in a locked inactive state. Another involves phosphatidylinositol 4,5-bisphosphate (PIP2) which binds the SH2 domain through residues normally required for phosphotyrosine binding in the linker segment between the SH2 and kinase domains. The SH2 domain contributes to ABL catalytic activity and target site specificity. It is thought that the ABL catalytic site and SH2 pocket have coevolved to recognize the same sequences. Recent work now supports a hierarchical processivity model in which the substrate target site most compatible with ABL kinase domain preferences is phosphorylated with greatest efficiency. If this site is compatible with the ABL SH2 domain specificity, it will then reposition and dock in the SH2 pocket. This mechanism also explains how ABL kinases phosphorylates poor targets on the same substrate if they are properly positioned and how relatively poor substrate proteins might be recruited to ABL through a complex with strong substrates that can also dock with the SH2 pocket. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198189 Cd Length: 94 Bit Score: 72.04 E-value: 3.35e-15

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    532 WFHKKVeKRTSAEKLLQEycmetgGKDGTFLVRESETFPNDYTLSFWRSGRVQHCRIRSTMEGgtlKYYLTDNLRFRRMY 611
Cdd:cd09935    5 WYHGPI-SRNAAEYLLSS------GINGSFLVRESESSPGQYSISLRYDGRVYHYRISEDSDG---KVYVTQEHRFNTLA 74

                         90
                 ....*....|
gi 190036    612 ALIQHYRETH 621
Cdd:cd09935   75 ELVHHHSKNA 84

SH2_BLNK_SLP-76

cd09929

Src homology 2 (SH2) domain found in B-cell linker (BLNK) protein and SH2 domain-containing ...

643-735

1.17e-14

Src homology 2 (SH2) domain found in B-cell linker (BLNK) protein and SH2 domain-containing leukocyte protein of 76 kDa (SLP-76); BLNK (also known as SLP-65 or BASH) is an important adaptor protein expressed in B-lineage cells. BLNK consists of a N-terminal sterile alpha motif (SAM) domain and a C-terminal SH2 domain. BLNK is a cytoplasmic protein, but a part of it is bound to the plasma membrane through an N-terminal leucine zipper motif and transiently bound to a cytoplasmic domain of Iga through its C-terminal SH2 domain upon B cell antigen receptor (BCR)-stimulation. A non-ITAM phosphotyrosine in Iga is necessary for the binding with the BLNK SH2 domain and/or for normal BLNK function in signaling and B cell activation. Upon phosphorylation BLNK binds Btk and PLCgamma2 through their SH2 domains and mediates PLCgamma2 activation by Btk. BLNK also binds other signaling molecules such as Vav, Grb2, Syk, and HPK1. BLNK has been shown to be necessary for BCR-mediated Ca2+ mobilization, for the activation of mitogen-activated protein kinases such as ERK, JNK, and p38 in a chicken B cell line DT40, and for activation of transcription factors such as NF-AT and NF-kappaB in human or mouse B cells. BLNK is involved in B cell development, B cell survival, activation, proliferation, and T-independent immune responses. BLNK is structurally homologous to SLP-76. SLP-76 and (linker for activation of T cells) LAT are adaptor/linker proteins in T cell antigen receptor activation and T cell development. BLNK interacts with many downstream signaling proteins that interact directly with both SLP-76 and LAT. New data suggest functional complementation of SLP-76 and LAT in T cell antigen receptor function with BLNK in BCR function. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198183 Cd Length: 121 Bit Score: 71.58 E-value: 1.17e-14

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    643 SKPWYYDSLSRGEAEDMLMRIPRDGAFLIRKREGSDS---YAITFRARGKVKHCRINRD--GRHFVLGT----SAYFESL 713
Cdd:cd09929   10 PKEWYAGNIDRKEAEEALRRSNKDGTFLVRDSSGKDSsqpYTLMVLYNDKVYNIQIRFLenTRQYALGTglrgEETFSSV 89

                         90       100       110
                 ....*....|....*....|....*....|.
gi 190036    714 VELVSYYEKHSLY---------RKMRLRYPV 735
Cdd:cd09929   90 AEIIEHHQKTPLLlidgkdntkDSTCLLYAA 120

SH3

cd00174

Src Homology 3 domain superfamily; Src Homology 3 (SH3) domains are protein interaction ...

773-823

1.55e-14

Src Homology 3 domain superfamily; Src Homology 3 (SH3) domains are protein interaction domains that bind proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. Thus, they are referred to as proline-recognition domains (PRDs). SH3 domains are less selective and show more diverse specificity compared to other PRDs. They have been shown to bind peptide sequences that lack the PxxP motif; examples include the PxxDY motif of Eps8 and the RKxxYxxY sequence in SKAP55. SH3 domain containing proteins play versatile and diverse roles in the cell, including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies, among others. Many members of this superfamily are adaptor proteins that associate with a number of protein partners, facilitating complex formation and signal transduction.

Pssm-ID: 212690 [Multi-domain] Cd Length: 51 Bit Score: 68.64 E-value: 1.55e-14

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 190036    773 TVKALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRIQQYFPSNY 823
Cdd:cd00174    1 YARALYDYEAQDDDELSFKKGDIITVLEKDDDGWWEGELNGGREGLFPANY 51

SH3_PIX

cd11877

Src Homology 3 domain of Pak Interactive eXchange factors; PIX proteins are Rho guanine ...

773-826

5.93e-14

Src Homology 3 domain of Pak Interactive eXchange factors; PIX proteins are Rho guanine nucleotide exchange factors (GEFs), which activate small GTPases by exchanging bound GDP for free GTP. They act as GEFs for both Cdc42 and Rac 1, and have been implicated in cell motility, adhesion, neurite outgrowth, and cell polarity. Vertebrates contain two proteins from the PIX subfamily, alpha-PIX and beta-PIX. Alpha-PIX, also called ARHGEF6, is localized in dendritic spines where it regulates spine morphogenesis. Mutations in the ARHGEF6 gene cause X-linked intellectual disability in humans. Beta-PIX play roles in regulating neuroendocrine exocytosis, focal adhesion maturation, cell migration, synaptic vesicle localization, and insulin secretion. PIX proteins contain an N-terminal SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains, and a C-terminal leucine-zipper domain for dimerization. The SH3 domain of PIX binds to an atypical PxxxPR motif in p21-activated kinases (PAKs) with high affinity. The binding of PAKs to PIX facilitate the localization of PAKs to focal complexes and also localizes PAKs to PIX targets Cdc43 and Rac, leading to the activation of PAKs. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212810 [Multi-domain] Cd Length: 53 Bit Score: 67.34 E-value: 5.93e-14

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....
gi 190036    773 TVKALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRIqQYFPSNYVED 826
Cdd:cd11877    1 LVRAKFNFEGTNEDELSFDKGDIITVTQVVEGGWWEGTLNGKT-GWFPSNYVKE 53

SH2_csk_like

cd09937

Src homology 2 (SH2) domain found in Carboxyl-Terminal Src Kinase (Csk); Both the C-terminal ...

532-619

1.43e-13

Src homology 2 (SH2) domain found in Carboxyl-Terminal Src Kinase (Csk); Both the C-terminal Src kinase (CSK) and CSK-homologous kinase (CHK) are members of the CSK-family of protein tyrosine kinases. These proteins suppress activity of Src-family kinases (SFK) by selectively phosphorylating the conserved C-terminal tail regulatory tyrosine by a similar mechanism. CHK is also capable of inhibiting SFKs by a non-catalytic mechanism that involves binding of CHK to SFKs to form stable protein complexes. The unphosphorylated form of SFKs is inhibited by CSK and CHK by a two-step mechanism. The first step involves the formation of a complex of SFKs with CSK/CHK with the SFKs in the complex are inactive. The second step, involves the phosphorylation of the C-terminal tail tyrosine of SFKs, which then dissociates and adopt an inactive conformation. The structural basis of how the phosphorylated SFKs dissociate from CSK/CHK to adopt the inactive conformation is not known. The inactive conformation of SFKs is stabilized by two intramolecular inhibitory interactions: (a) the pYT:SH2 interaction in which the phosphorylated C-terminal tail tyrosine (YT) binds to the SH2 domain, and (b) the linker:SH3 interaction of which the SH2-kinase domain linker binds to the SH3 domain. SFKs are activated by multiple mechanisms including binding of the ligands to the SH2 and SH3 domains to displace the two inhibitory intramolecular interactions, autophosphorylation, and dephosphorylation of YT. By selective phosphorylation and the non-catalytic inhibitory mechanism CSK and CHK are able to inhibit the active forms of SFKs. CSK and CHK are regulated by phosphorylation and inter-domain interactions. They both contain SH3, SH2, and kinase domains separated by the SH3-SH2 connector and SH2 kinase linker, intervening segments separating the three domains. They lack a conserved tyrosine phosphorylation site in the kinase domain and the C-terminal tail regulatory tyrosine phosphorylation site. The CSK SH2 domain is crucial for stabilizing the kinase domain in the active conformation. A disulfide bond here regulates CSK kinase activity. The subcellular localization and activity of CSK are regulated by its SH2 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198190 Cd Length: 98 Bit Score: 67.70 E-value: 1.43e-13

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    532 WFHKKVeKRTSAEKLLQEYcmetggKDGTFLVRESETFPNDYTLSFWRSGRVQHCRIRSTmeGGTLKyylTDNLR-FRRM 610
Cdd:cd09937    5 WFHGKI-SREEAERLLQPP------EDGLFLVRESTNYPGDYTLCVSFEGKVEHYRVIYR--NGKLT---IDEEEyFENL 72


                 ....*....
gi 190036    611 YALIQHYRE 619
Cdd:cd09937   73 IQLVEHYTK 81

SH2_Src_family

cd09933

Src homology 2 (SH2) domain found in the Src family of non-receptor tyrosine kinases; The Src ...

642-724

2.83e-13

Pssm-ID: 199827 Cd Length: 101 Bit Score: 66.84 E-value: 2.83e-13

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    642 ESKPWYYDSLSRGEAEDMLM--RIPRdGAFLIRKREGS-DSYAITFR----ARG-KVKHCRINR-DGRHFVLGTSAYFES 712
Cdd:cd09933    1 EAEEWFFGKIKRKDAEKLLLapGNPR-GTFLIRESETTpGAYSLSVRdgddARGdTVKHYRIRKlDNGGYYITTRATFPT 79

                         90
                 ....*....|..
gi 190036    713 LVELVSYYEKHS 724
Cdd:cd09933   80 LQELVQHYSKDA 91

SH2_ABL

cd09935

Src homology 2 (SH2) domain found in Abelson murine lymphosarcoma virus (ABL) proteins; ...

642-734

7.32e-13

Pssm-ID: 198189 Cd Length: 94 Bit Score: 65.49 E-value: 7.32e-13

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    642 ESKPWYYDSLSRGEAEdMLMRIPRDGAFLIRKREGS-DSYAITFRARGKVKHCRINRDGRHFVLGTSAY-FESLVELVSY 719
Cdd:cd09935    1 EKHSWYHGPISRNAAE-YLLSSGINGSFLVRESESSpGQYSISLRYDGRVYHYRISEDSDGKVYVTQEHrFNTLAELVHH 79

                         90
                 ....*....|....*
gi 190036    720 YEKHSLYRKMRLRYP 734
Cdd:cd09935   80 HSKNADGLITTLRYP 94

SH3_Intersectin_5

cd11840

Fifth Src homology 3 domain (or SH3E) of Intersectin; Intersectins (ITSNs) are adaptor ...

774-825

8.59e-13

Fifth Src homology 3 domain (or SH3E) of Intersectin; Intersectins (ITSNs) are adaptor proteins that function in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. They are essential for initiating clathrin-coated pit formation. They bind to many proteins through their multidomain structure and facilitate the assembly of multimeric complexes. Vertebrates contain two ITSN proteins, ITSN1 and ITSN2, which exist in alternatively spliced short and long isoforms. The short isoforms contain two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoforms, in addition, contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. ITSN1 and ITSN2 are both widely expressed, with variations depending on tissue type and stage of development. The fifth SH3 domain (or SH3E) of ITSN1 has been shown to bind many protein partners including SGIP1, Sos1, dynamin1/2, CIN85, c-Cbl, SHIP2, N-WASP, and synaptojanin-1, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212774 [Multi-domain] Cd Length: 53 Bit Score: 63.97 E-value: 8.59e-13

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 190036    774 VKALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRIqQYFPSNYVE 825
Cdd:cd11840    2 VIALFPYTAQNEDELSFQKGDIINVLSKDDPDWWRGELNGQT-GLFPSNYVE 52

SH3_AHI-1

cd11812

Src Homology 3 domain of Abelson helper integration site-1 (AHI-1); AHI-1, also called ...

773-824

9.08e-13

Src Homology 3 domain of Abelson helper integration site-1 (AHI-1); AHI-1, also called Jouberin, is expressed in high levels in the brain, gonad tissues, and skeletal muscle. It is an adaptor protein that interacts with the small GTPase Rab8a and regulates it distribution and function, affecting cilium formation and vesicle transport. Mutations in the AHI-1 gene can cause Joubert syndrome, a disorder characterized by brainstem malformations, cerebellar aplasia/hypoplasia, and retinal dystrophy. AHI-1 variation is also associated with susceptibility to schizophrenia and type 2 diabetes mellitus progression. AHI-1 contains WD40 and SH3 domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212746 [Multi-domain] Cd Length: 52 Bit Score: 64.07 E-value: 9.08e-13

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 190036    773 TVKALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRIQQYFPSNYV 824
Cdd:cd11812    1 TVVALYDYTANRSDELTIHRGDIIRVLYKDNDNWWFGSLVNGQQGYFPANYV 52

SH3_CD2AP-like_1

cd11873

First Src Homology 3 domain (SH3A) of CD2-associated protein and similar proteins; This ...

773-825

1.45e-12

First Src Homology 3 domain (SH3A) of CD2-associated protein and similar proteins; This subfamily is composed of the first SH3 domain (SH3A) of CD2AP, CIN85 (Cbl-interacting protein of 85 kDa), and similar domains. CD2AP and CIN85 are adaptor proteins that bind to protein partners and assemble complexes that have been implicated in T cell activation, kidney function, and apoptosis of neuronal cells. They also associate with endocytic proteins, actin cytoskeleton components, and other adaptor proteins involved in receptor tyrosine kinase (RTK) signaling. CD2AP and the main isoform of CIN85 contain three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP and CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. SH3A of both proteins bind to an atypical PXXXPR motif at the C-terminus of Cbl and the cytoplasmic domain of the cell adhesion protein CD2. CIN85 SH3A binds to internal proline-rich motifs within the proline-rich region; this intramolecular interaction serves as a regulatory mechanism to keep CIN85 in a closed conformation, preventing the recruitment of other proteins. CIN85 SH3A has also been shown to bind ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212806 [Multi-domain] Cd Length: 53 Bit Score: 63.44 E-value: 1.45e-12

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 190036    773 TVKALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRiQQYFPSNYVE 825
Cdd:cd11873    1 EVIVEFDYDAEEPDELTLKVGDIITNVKKMEEGWWEGTLNGK-RGMFPDNFVK 52

SH2_Grb2_like

cd09941

Src homology 2 domain found in Growth factor receptor-bound protein 2 (Grb2) and similar ...

645-727

1.45e-12

Src homology 2 domain found in Growth factor receptor-bound protein 2 (Grb2) and similar proteins; The adaptor proteins here include homologs Grb2 in humans, Sex muscle abnormal protein 5 (Sem-5) in Caenorhabditis elegans, and Downstream of receptor kinase (drk) in Drosophila melanogaster. They are composed of one SH2 and two SH3 domains. Grb2/Sem-5/drk regulates the Ras pathway by linking the tyrosine kinases to the Ras guanine nucleotide releasing protein Sos, which converts Ras to the active GTP-bound state. The SH2 domain of Grb2/Sem-5/drk binds class II phosphotyrosyl peptides while its SH3 domain binds to Sos and Sos-derived, proline-rich peptides. Besides it function in Ras signaling, Grb2 is also thought to play a role in apoptosis. Unlike most SH2 structures in which the peptide binds in an extended conformation (such that the +3 peptide residue occupies a hydrophobic pocket in the protein, conferring a modest degree of selectivity), Grb2 forms several hydrogen bonds via main chain atoms with the side chain of +2 Asn. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 199828 Cd Length: 95 Bit Score: 64.60 E-value: 1.45e-12

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    645 PWYYDSLSRGEAEDMLMRIPRDGAFLIRKREGSDS-YAITFRARGKVKHCRINRDGR-HFVLGTSAyFESLVELVSYYEK 722
Cdd:cd09941    4 PWFHGKISRAEAEEILMNQRPDGAFLIRESESSPGdFSLSVKFGNDVQHFKVLRDGAgKYFLWVVK-FNSLNELVDYHRT 82


                 ....*
gi 190036    723 HSLYR 727
Cdd:cd09941   83 TSVSR 87

SH2_Nterm_shark_like

cd10347

N-terminal Src homology 2 (SH2) domain found in SH2 domains, ANK, and kinase domain (shark) ...

530-617

1.67e-12

N-terminal Src homology 2 (SH2) domain found in SH2 domains, ANK, and kinase domain (shark) proteins; These non-receptor protein-tyrosine kinases contain two SH2 domains, five ankyrin (ANK)-like repeats, and a potential tyrosine phosphorylation site in the carboxyl-terminal tail which resembles the phosphorylation site in members of the src family. Like, mammalian non-receptor protein-tyrosine kinases, ZAP-70 and syk proteins, they do not have SH3 domains. However, the presence of ANK makes these unique among protein-tyrosine kinases. Both tyrosine kinases and ANK repeats have been shown to transduce developmental signals, and SH2 domains are known to participate intimately in tyrosine kinase signaling. These tyrosine kinases are believed to be involved in epithelial cell polarity. The members of this family include the shark (SH2 domains, ANK, and kinase domain) gene in Drosophila and yellow fever mosquitos, as well as the hydra protein HTK16. Drosophila Shark is proposed to transduce intracellularly the Crumbs, a protein necessary for proper organization of ectodermal epithelia, intercellular signal. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198210 Cd Length: 81 Bit Score: 63.94 E-value: 1.67e-12

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    530 EKWFHKKVEKRTSAEKLLQEycmetGGKDGTFLVRESETFPNDYTLSFWRSGRVQHCRIRStmEGGTLKYYLTDNLRFRR 609
Cdd:cd10347    1 LRWYHGKISREVAEALLLRE-----GGRDGLFLVRESTSAPGDYVLSLLAQGEVLHYQIRR--HGEDAFFSDDGPLIFHG 73


                 ....*...
gi 190036    610 MYALIQHY 617
Cdd:cd10347   74 LDTLIEHY 81

SH2_Grb7_family

cd09944

Src homology 2 (SH2) domain found in the growth factor receptor bound, subclass 7 (Grb7) ...

526-637

2.14e-12

Src homology 2 (SH2) domain found in the growth factor receptor bound, subclass 7 (Grb7) proteins; The Grb family binds to the epidermal growth factor receptor (EGFR, erbB1) via their SH2 domains. There are 3 members of the Grb7 family of proteins: Grb7, Grb10, and Grb14. They are composed of an N-terminal Proline-rich domain, a Ras Associating-like (RA) domain, a Pleckstrin Homology (PH) domain, a phosphotyrosine interaction region (PIR, BPS) and a C-terminal SH2 domain. The SH2 domains of Grb7, Grb10 and Grb14 preferentially bind to a different RTK. Grb7 binds strongly to the erbB2 receptor, unlike Grb10 and Grb14 which bind weakly to it. Grb14 binds to Fibroblast Growth Factor Receptor (FGFR). Grb10 has been shown to interact with many different proteins, including the insulin and IGF1 receptors, platelet-derived growth factor (PDGF) receptor-beta, Ret, Kit, Raf1 and MEK1, and Nedd4. Grb7 family proteins are phosphorylated on serine/threonine as well as tyrosine residues. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198197 [Multi-domain] Cd Length: 108 Bit Score: 64.75 E-value: 2.14e-12

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    526 LHFGEKWFHKKVeKRTSAEKLLQEYcmetGGKDGTFLVRESETFPNDYTLSFWRSGRVQHCRIRSTMEGGTLKYYLTD-N 604
Cdd:cd09944    1 IHRSQPWFHGGI-SRDEAARLIRQQ----GLVDGVFLVRESQSNPGAFVLSLKHGQKIKHYQIIPIEDEGQWYFTLDDgV 75

                         90       100       110
                 ....*....|....*....|....*....|....*
gi 190036    605 LRFRRMYALIQHYR--ETHLPCaefelRLTDPVPN 637
Cdd:cd09944   76 TKFYDLLQLVEFYQlnAGSLPT-----RLKHYCTR 105

SH2_Nck_family

cd09943

Src homology 2 (SH2) domain found in the Nck family; Nck proteins are adaptors that modulate ...

644-726

2.81e-12

Src homology 2 (SH2) domain found in the Nck family; Nck proteins are adaptors that modulate actin cytoskeleton dynamics by linking proline-rich effector molecules to tyrosine kinases or phosphorylated signaling intermediates. There are two members known in this family: Nck1 (Nckalpha) and Nck2 (Nckbeta and Growth factor receptor-bound protein 4 (Grb4)). They are characterized by having 3 SH3 domains and a C-terminal SH2 domain. Nck1 and Nck2 have overlapping functions as determined by gene knockouts. Both bind receptor tyrosine kinases and other tyrosine-phosphorylated proteins through their SH2 domains. In addition they also bind distinct targets. Neuronal signaling proteins: EphrinB1, EphrinB2, and Disabled-1 (Dab-1) all bind to Nck-2 exclusively. And in the case of PDGFR, Tyr(P)751 binds to Nck1 while Tyr(P)1009 binds to Nck2. Nck1 and Nck2 have a role in the infection process of enteropathogenic Escherichia coli (EPEC). Their SH3 domains are involved in recruiting and activating the N-WASP/Arp2/3 complex inducing actin polymerization resulting in the production of pedestals, dynamic bacteria-presenting protrusions of the plasma membrane. A similar thing occurs in the vaccinia virus where motile plasma membrane projections are formed beneath the virus. Recently it has been shown that the SH2 domains of both Nck1 and Nck2 bind the G-protein coupled receptor kinase-interacting protein 1 (GIT1) in a phosphorylation-dependent manner. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198196 Cd Length: 93 Bit Score: 63.69 E-value: 2.81e-12

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    644 KPWYYDSLSRGEAEDMLMRIPRDGAFLIRKREGSDS-YAITFRARGKVKHCRINRDGRHFVLGTSAyFESLVELVSYYEK 722
Cdd:cd09943    1 QPWYYGRITRHQAETLLNEHGHEGDFLIRDSESNPGdYSVSLKAPGRNKHFKVQVVDNVYCIGQRK-FHTMDELVEHYKK 79


                 ....
gi 190036    723 HSLY 726
Cdd:cd09943   80 APIF 83

cd00030

C2 domain; The C2 domain was first identified in PKC. C2 domains fold into an 8-standed ...

1063-1160

3.51e-12

C2 domain; The C2 domain was first identified in PKC. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions.

Pssm-ID: 175973 [Multi-domain] Cd Length: 102 Bit Score: 64.01 E-value: 3.51e-12

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036   1063 LTVKVLGARHLPKLGRSIAC-PFVEVEICGAEygnnKFKTTVVNDNgLSPIWaptQEKVTFEIYDPNLAFLRFVVYEEDM 1141
Cdd:cd00030    1 LRVTVIEARNLPAKDLNGKSdPYVKVSLGGKQ----KFKTKVVKNT-LNPVW---NETFEFPVLDPESDTLTVEVWDKDR 72

                         90
                 ....*....|....*....
gi 190036   1142 FSDPNFLAHATYPIKAVKS 1160
Cdd:cd00030   73 FSKDDFLGEVEIPLSELLD 91

SH2_C-SH2_SHP_like

cd09931

C-terminal Src homology 2 (C-SH2) domain found in SH2 domain Phosphatases (SHP) proteins; The ...

531-620

4.22e-12

C-terminal Src homology 2 (C-SH2) domain found in SH2 domain Phosphatases (SHP) proteins; The SH2 domain phosphatases (SHP-1, SHP-2/Syp, Drosophila corkscrew (csw), and Caenorhabditis elegans Protein Tyrosine Phosphatase (Ptp-2)) are cytoplasmic signaling enzymes. They are both targeted and regulated by interactions of their SH2 domains with phosphotyrosine docking sites. These proteins contain two SH2 domains (N-SH2, C-SH2) followed by a tyrosine phosphatase (PTP) domain, and a C-terminal extension. Shp1 and Shp2 have two tyrosyl phosphorylation sites in their C-tails, which are phosphorylated differentially by receptor and nonreceptor PTKs. Csw retains the proximal tyrosine and Ptp-2 lacks both sites. Shp-binding proteins include receptors, scaffolding adapters, and inhibitory receptors. Some of these bind both Shp1 and Shp2 while others bind only one. Most proteins that bind a Shp SH2 domain contain one or more immuno-receptor tyrosine-based inhibitory motifs (ITIMs): [SIVL]xpYxx[IVL]. Shp1 N-SH2 domain blocks the catalytic domain and keeps the enzyme in the inactive conformation, and is thus believed to regulate the phosphatase activity of SHP-1. Its C-SH2 domain is thought to be involved in searching for phosphotyrosine activators. The SHP2 N-SH2 domain is a conformational switch; it either binds and inhibits the phosphatase, or it binds phosphoproteins and activates the enzyme. The C-SH2 domain contributes binding energy and specificity, but it does not have a direct role in activation. Csw SH2 domain function is essential, but either SH2 domain can fulfill this requirement. The role of the csw SH2 domains during Sevenless receptor tyrosine kinase (SEV) signaling is to bind Daughter of Sevenless rather than activated SEV. Ptp-2 acts in oocytes downstream of sheath/oocyte gap junctions to promote major sperm protein (MSP)-induced MAP Kinase (MPK-1) phosphorylation. Ptp-2 functions in the oocyte cytoplasm, not at the cell surface to inhibit multiple RasGAPs, resulting in sustained Ras activation. It is thought that MSP triggers PTP-2/Ras activation and ROS production to stimulate MPK-1 activity essential for oocyte maturation and that secreted MSP domains and Cu/Zn superoxide dismutases function antagonistically to control ROS and MAPK signaling. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198185 Cd Length: 99 Bit Score: 63.45 E-value: 4.22e-12

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    531 KWFHKKVEKRtSAEKLLQEycmetGGKDGTFLVRESETFPNDYTLSFwRSG--RVQHCRIRSTMEggtlKYYLTDNLRFR 608
Cdd:cd09931    1 RWFHGHLSGK-EAEKLLLE-----KGKPGSFLVRESQSKPGDFVLSV-RTDddKVTHIMIRCQGG----KYDVGGGEEFD 69

                         90
                 ....*....|..
gi 190036    609 RMYALIQHYRET 620
Cdd:cd09931   70 SLTDLVEHYKKN 81

SH2_Src_Src42

cd10370

Src homology 2 (SH2) domain found in the Src oncogene at 42A (Src42); Src42 is a member of the ...

530-617

5.68e-12

Src homology 2 (SH2) domain found in the Src oncogene at 42A (Src42); Src42 is a member of the Src non-receptor type tyrosine kinase family of proteins. The integration of receptor tyrosine kinase-induced RAS and Src42 signals by Connector eNhancer of KSR (CNK) as a two-component input is essential for RAF activation in Drosophila. Src42 is present in a wide variety of organisms including: California sea hare, pea aphid, yellow fever mosquito, honey bee, Panamanian leafcutter ant, and sea urchin. Src42 has a unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail, as do the other members of the family. Like the other members of the Src family the SH2 domain in addition to binding the target, also plays an autoinhibitory role by binding to its C-terminal tail. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198233 Cd Length: 96 Bit Score: 63.29 E-value: 5.68e-12

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    530 EKWFHKKVeKRTSAEKLLqeycMETGGKDGTFLVRESETFPNDYTLSFWRSGRVQHCRIRSTMEGGtlkYYLTDNLRFRR 609
Cdd:cd10370    3 EPWYFGKI-KRIEAEKKL----LLPENEHGAFLIRDSESRHNDYSLSVRDGDTVKHYRIRQLDEGG---FFIARRTTFRT 74


                 ....*...
gi 190036    610 MYALIQHY 617
Cdd:cd10370   75 LQELVEHY 82

SH2_Src_Fyn

cd10368

Src homology 2 (SH2) domain found in Fyn; Fyn is a member of the Src non-receptor type ...

529-620

1.15e-11

Src homology 2 (SH2) domain found in Fyn; Fyn is a member of the Src non-receptor type tyrosine kinase family of proteins. Fyn is involved in the control of cell growth and is required in the following pathways: T and B cell receptor signaling, integrin-mediated signaling, growth factor and cytokine receptor signaling, platelet activation, ion channel function, cell adhesion, axon guidance, fertilization, entry into mitosis, and differentiation of natural killer cells, oligodendrocytes and keratinocytes. The protein associates with the p85 subunit of phosphatidylinositol 3-kinase and interacts with the Fyn-binding protein. Alternatively spliced transcript variants encoding distinct isoforms exist. Fyn is primarily localized to the cytoplasmic leaflet of the plasma membrane. Tyrosine phosphorylation of target proteins by Fyn serves to either regulate target protein activity, and/or to generate a binding site on the target protein that recruits other signaling molecules. FYN has been shown to interact with a number of proteins including: BCAR1, Cbl, Janus kinase, nephrin, Sky, tyrosine kinase, Wiskott-Aldrich syndrome protein, and Zap-70. Fyn has a unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail, as do the other members of the family. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198231 [Multi-domain] Cd Length: 101 Bit Score: 62.35 E-value: 1.15e-11

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    529 GEKWFHKKVEKRTSAEKLLQeycmeTGGKDGTFLVRESETFPNDYTLSF--W---RSGRVQHCRIRSTMEGGtlkYYLTD 603
Cdd:cd10368    2 AEEWYFGKLGRKDAERQLLS-----FGNPRGTFLIRESETTKGAYSLSIrdWddmKGDHVKHYKIRKLDNGG---YYITT 73

                         90
                 ....*....|....*..
gi 190036    604 NLRFRRMYALIQHYRET 620
Cdd:cd10368   74 RAQFETLQQLVQHYSET 90

SH3_MyoIe_If_like

cd11827

Src homology 3 domain of Myosins Ie, If, and similar proteins; Myosins Ie (MyoIe) and If ...

773-825

1.80e-11

Src homology 3 domain of Myosins Ie, If, and similar proteins; Myosins Ie (MyoIe) and If (MyoIf) are nonmuscle, unconventional, long tailed, class I myosins containing an N-terminal motor domain and a myosin tail with TH1, TH2, and SH3 domains. MyoIe interacts with the endocytic proteins, dynamin and synaptojanin-1, through its SH3 domain; it may play a role in clathrin-dependent endocytosis. In the kidney, MyoIe is critical for podocyte function and normal glomerular filtration. Mutations in MyoIe is associated with focal segmental glomerulosclerosis, a disease characterized by massive proteinuria and progression to end-stage kidney disease. MyoIf is predominantly expressed in the immune system; it plays a role in immune cell motility and innate immunity. Mutations in MyoIf may be associated with the loss of hearing. The MyoIf gene has also been found to be fused to the MLL (Mixed lineage leukemia) gene in infant acute myeloid leukemias (AML). SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212761 [Multi-domain] Cd Length: 53 Bit Score: 60.12 E-value: 1.80e-11

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 190036    773 TVKALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRiQQYFPSNYVE 825
Cdd:cd11827    1 QCKALYAYDAQDTDELSFNEGDIIEILKEDPSGWWTGRLRGK-EGLFPGNYVE 52

SH2_Src_Fyn_isoform_a_like

cd10418

Src homology 2 (SH2) domain found in Fyn isoform a like proteins; Fyn is a member of the Src ...

529-619

1.93e-11

Src homology 2 (SH2) domain found in Fyn isoform a like proteins; Fyn is a member of the Src non-receptor type tyrosine kinase family of proteins. This cd contains the SH2 domain found in Fyn isoform a type proteins. Fyn is involved in the control of cell growth and is required in the following pathways: T and B cell receptor signaling, integrin-mediated signaling, growth factor and cytokine receptor signaling, platelet activation, ion channel function, cell adhesion, axon guidance, fertilization, entry into mitosis, and differentiation of natural killer cells, oligodendrocytes and keratinocytes. The protein associates with the p85 subunit of phosphatidylinositol 3-kinase and interacts with the Fyn-binding protein. Alternatively spliced transcript variants encoding distinct isoforms exist. Fyn is primarily localized to the cytoplasmic leaflet of the plasma membrane. Tyrosine phosphorylation of target proteins by Fyn serves to either regulate target protein activity, and/or to generate a binding site on the target protein that recruits other signaling molecules. FYN has been shown to interact with a number of proteins including: BCAR1, Cbl, Janus kinase, nephrin, Sky, tyrosine kinase, Wiskott-Aldrich syndrome protein, and Zap-70. Fyn has a unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail, as do the other members of the family. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198281 Cd Length: 101 Bit Score: 61.94 E-value: 1.93e-11

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    529 GEKWFHKKVEKRTSAEKLLQeycmeTGGKDGTFLVRESETFPNDYTLSF--W---RSGRVQHCRIRSTMEGGtlkYYLTD 603
Cdd:cd10418    2 AEEWYFGKLGRKDAERQLLS-----FGNPRGTFLIRESETTKGAYSLSIrdWddmKGDHVKHYKIRKLDNGG---YYITT 73

                         90
                 ....*....|....*.
gi 190036    604 NLRFRRMYALIQHYRE 619
Cdd:cd10418   74 RAQFETLQQLVQHYSE 89

SH3_Nck_2

cd11766

Second Src Homology 3 domain of Nck adaptor proteins; Nck adaptor proteins regulate actin ...

778-826

2.03e-11

Second Src Homology 3 domain of Nck adaptor proteins; Nck adaptor proteins regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates. They contain three SH3 domains and a C-terminal SH2 domain. They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics. Vertebrates contain two Nck adaptor proteins: Nck1 (also called Nckalpha) and Nck2 (also called Nckbeta or Growth factor receptor-bound protein 4, Grb4), which show partly overlapping functions but also bind distinct targets. Their SH3 domains are involved in recruiting downstream effector molecules, such as the N-WASP/Arp2/3 complex, which when activated induces actin polymerization that results in the production of pedestals, or protrusions of the plasma membrane. The second SH3 domain of Nck appears to prefer ligands containing the APxxPxR motif. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity, preferentially a PxxP motif. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212700 [Multi-domain] Cd Length: 53 Bit Score: 59.97 E-value: 2.03e-11

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*....
gi 190036    778 YDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRIqQYFPSNYVED 826
Cdd:cd11766    6 FNYEAQREDELSLRKGDRVLVLEKSSDGWWRGECNGQV-GWFPSNYVTE 53

SH3_alphaPIX

cd12060

Src Homology 3 domain of alpha-Pak Interactive eXchange factor; Alpha-PIX, also called Rho ...

771-829

2.28e-11

Src Homology 3 domain of alpha-Pak Interactive eXchange factor; Alpha-PIX, also called Rho guanine nucleotide exchange factor 6 (ARHGEF6) or Cool (Cloned out of Library)-2, activates small GTPases by exchanging bound GDP for free GTP. It acts as a GEF for both Cdc42 and Rac 1, and is localized in dendritic spines where it regulates spine morphogenesis. It controls dendritic length and spine density in the hippocampus. Mutations in the ARHGEF6 gene cause X-linked intellectual disability in humans. PIX proteins contain an N-terminal SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains, and a C-terminal leucine-zipper domain for dimerization. The SH3 domain of PIX binds to an atypical PxxxPR motif in p21-activated kinases (PAKs) with high affinity. The binding of PAKs to PIX facilitate the localization of PAKs to focal complexes and also localizes PAKs to PIX targets Cdc43 and Rac, leading to the activation of PAKs. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212993 Cd Length: 58 Bit Score: 60.02 E-value: 2.28e-11

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 190036    771 QRTVKALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRiQQYFPSNYVEDIST 829
Cdd:cd12060    1 QLVVKARFNFKQTNEDELSVCKGDIIYVTRVEEGGWWEGTLNGK-TGWFPSNYVREIKS 58

SH2_Cterm_RasGAP

cd10354

C-terminal Src homology 2 (SH2) domain found in Ras GTPase-activating protein 1 (GAP); RasGAP ...

531-617

4.01e-11

C-terminal Src homology 2 (SH2) domain found in Ras GTPase-activating protein 1 (GAP); RasGAP is part of the GAP1 family of GTPase-activating proteins. The protein is located in the cytoplasm and stimulates the GTPase activity of normal RAS p21, but not its oncogenic counterpart. Acting as a suppressor of RAS function, the protein enhances the weak intrinsic GTPase activity of RAS proteins resulting in RAS inactivation, thereby allowing control of cellular proliferation and differentiation. Mutations leading to changes in the binding sites of either protein are associated with basal cell carcinomas. Alternative splicing results in two isoforms. The shorter isoform which lacks the N-terminal hydrophobic region, has the same activity, and is expressed in placental tissues. In general longer isoform contains 2 SH2 domains, a SH3 domain, a pleckstrin homology (PH) domain, and a calcium-dependent phospholipid-binding C2 domain. The C-terminus contains the catalytic domain of RasGap which catalyzes the activation of Ras by hydrolyzing GTP-bound active Ras into an inactive GDP-bound form of Ras. This model contains the C-terminal SH2 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198217 Cd Length: 77 Bit Score: 60.13 E-value: 4.01e-11

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    531 KWFHKKVEKRtSAEKLLQeycmeTGGKDGTFLVRESETFPNDYTLSFWRSGRVQHCRIRSTmegGTLKYYLTDnLRFRRM 610
Cdd:cd10354    1 IWFHGKISRE-EAYNMLV-----KVGGPGSFLVRESDNTPGDYSLSFRVNEGIKHFKIIPT---GNNQFMMGG-RYFSSL 70


                 ....*..
gi 190036    611 YALIQHY 617
Cdd:cd10354   71 DDVIDRY 77

PH_PLC_eta

cd13364

Phospholipase C-eta (PLC-eta) pleckstrin homology (PH) domain; PLC-eta (PLCeta) consists of ...

55-129

4.29e-11

Phospholipase C-eta (PLC-eta) pleckstrin homology (PH) domain; PLC-eta (PLCeta) consists of two enzymes, PLCeta1 and PLCeta2. They hydrolyze phosphatidylinositol 4,5-bisphosphate, are more sensitive to Ca2+ than other PLC isozymes, and involved in PKC activation in the brain and neuroendocrine systems. PLC-eta consists of an N-terminal PH domain, a EF hand domain, a catalytic domain split into X and Y halves by a variable linker, a C2 domain, and a C-terminal PDZ domain. PLCs (EC 3.1.4.3) play a role in the initiation of cellular activation, proliferation, differentiation and apoptosis. They are central to inositol lipid signalling pathways, facilitating intracellular Ca2+ release and protein kinase C (PKC) activation. Specificaly, PLCs catalyze the cleavage of phosphatidylinositol-4,5-bisphosphate (PIP2) and result in the release of 1,2-diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3). These products trigger the activation of protein kinase C (PKC) and the release of Ca2+ from intracellular stores. There are fourteen kinds of mammalian phospholipase C proteins which are are classified into six isotypes (beta, gamma, delta, epsilon, zeta, eta). PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.involved in targeting proteins to the plasma membrane, but only a few (less than 10%) display strong specificity in binding inositol phosphates. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinases, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, cytoskeletal associated molecules, and in lipid associated enzymes.

Pssm-ID: 270170 Cd Length: 109 Bit Score: 61.14 E-value: 4.29e-11

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 190036     55 SKTADKieGFLDIMEIKEIRPGKNSKDFERAKAVRQ-KEDCCFTILYGTQFvlSTLSLAADSKEDAVNWLSGLKIL 129
Cdd:cd13364   36 KKKSEK--AKIPISSIREVREGKTTDIFRSCDISGDfPEECCFSIIYGEEY--ETLDLVASSPDEANIWITGLRYL 107

SH3_Abi

cd11826

Src homology 3 domain of Abl Interactor proteins; Abl interactor (Abi) proteins are adaptor ...

774-825

5.69e-11

Src homology 3 domain of Abl Interactor proteins; Abl interactor (Abi) proteins are adaptor proteins serving as binding partners and substrates of Abl tyrosine kinases. They are involved in regulating actin cytoskeletal reorganization and play important roles in membrane-ruffling, endocytosis, cell motility, and cell migration. They localize to sites of actin polymerization in epithelial adherens junction and immune synapses, as well as to the leading edge of lamellipodia. Vertebrates contain two Abi proteins, Abi1 and Abi2. Abi1 displays a wide expression pattern while Abi2 is highly expressed in the eye and brain. Abi proteins contain a homeobox homology domain, a proline-rich region, and a SH3 domain. The SH3 domain of Abi binds to a PxxP motif in Abl. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212760 [Multi-domain] Cd Length: 52 Bit Score: 58.87 E-value: 5.69e-11

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 190036    774 VKALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYgTRIQQYFPSNYVE 825
Cdd:cd11826    2 VVALYDYTADKDDELSFQEGDIIYVTKKNDDGWYEGVL-NGVTGLFPGNYVE 52

SH2_Srm

cd10360

Src homology 2 (SH2) domain found in Src-related kinase lacking C-terminal regulatory tyrosine ...

645-720

6.32e-11

Src homology 2 (SH2) domain found in Src-related kinase lacking C-terminal regulatory tyrosine and N-terminal myristoylation sites (srm); Srm is a nonreceptor protein kinase that has two SH2 domains, a SH3 domain, and a kinase domain with a tyrosine residue for autophosphorylation. However it lacks an N-terminal glycine for myristoylation and a C-terminal tyrosine which suppresses kinase activity when phosphorylated. Srm is most similar to members of the Tec family who other members include: Tec, Btk/Emb, and Itk/Tsk/Emt. However Srm differs in its N-terminal unique domain it being much smaller than in the Tec family and is closer to Src. Srm is thought to be a new family of nonreceptor tyrosine kinases that may be redundant in function. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198223 Cd Length: 79 Bit Score: 59.58 E-value: 6.32e-11

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    645 PWYYDSLSRGEAEDMLMRIPRD-GAFLIRKREGS-DSYAITFRARGKVKHCRINR--DGRHFvLGTSAYFESLVELVSYY 720
Cdd:cd10360    1 PWYFSGISRTQAQQLLLSPPNEpGAFLIRPSESSlGGYSLSVRAQAKVCHYRICMapSGSLY-LQKGRLFPGLEELLAYY 79

PHsplit_PLC_gamma

Phospholipase C-gamma Split pleckstrin homology (PH) domain; PLC-gamma (PLCgamma) is activated ...

475-510

6.84e-11

Pssm-ID: 270054 Cd Length: 105 Bit Score: 60.17 E-value: 6.84e-11

                         10        20        30
                 ....*....|....*....|....*....|....*.
gi 190036    475 HKQQGELYMWDSIDQKWTRHYCAIADAKLSFSDDIE 510
Cdd:cd13234    1 SIKNGILYLEDPINHEWYPHFFVLTSNKIYYSEETE 36

SH2_SHIP

cd10343

Src homology 2 (SH2) domain found in SH2-containing inositol-5'-phosphatase (SHIP) and ...

643-735

9.29e-11

Src homology 2 (SH2) domain found in SH2-containing inositol-5'-phosphatase (SHIP) and SLAM-associated protein (SAP); The SH2-containing inositol-5'-phosphatase, SHIP (also called SHIP1/SHIP1a), is a hematopoietic-restricted phosphatidylinositide phosphatase that translocates to the plasma membrane after extracellular stimulation and hydrolyzes the phosphatidylinositol-3-kinase (PI3K)-generated second messenger PI-3,4,5-P3 (PIP3) to PI-3,4-P2. As a result, SHIP dampens down PIP3 mediated signaling and represses the proliferation, differentiation, survival, activation, and migration of hematopoietic cells. PIP3 recruits lipid-binding pleckstrin homology(PH) domain-containing proteins to the inner wall of the plasma membrane and activates them. PH domain-containing downstream effectors include the survival/proliferation enhancing serine/threonine kinase, Akt (protein kinase B), the tyrosine kinase, Btk, the regulator of protein translation, S6K, and the Rac and cdc42 guanine nucleotide exchange factor, Vav. SHIP is believed to act as a tumor suppressor during leukemogenesis and lymphomagenesis, and may play a role in activating the immune system to combat cancer. SHIP contains an N-terminal SH2 domain, a centrally located phosphatase domain that specifically hydrolyzes the 5'-phosphate from PIP3, PI-4,5-P2 and inositol-1,3,4,5- tetrakisphosphate (IP4), a C2 domain, that is an allosteric activating site when bound by SHIP's enzymatic product, PI-3,4-P2; 2 NPXY motifs that bind proteins with a phosphotyrosine binding (Shc, Dok 1, Dok 2) or an SH2 (p85a, SHIP2) domain; and a proline-rich domain consisting of four PxxP motifs that bind a subset of SH3-containing proteins including Grb2, Src, Lyn, Hck, Abl, PLCg1, and PIAS1. The SH2 domain of SHIP binds to the tyrosine phosphorylated forms of Shc, SHP-2, Doks, Gabs, CD150, platelet-endothelial cell adhesion molecule, Cas, c-Cbl, immunoreceptor tyrosine-based inhibitory motifs (ITIMs), and immunoreceptor tyrosine-based activation motifs (ITAMs). The X-linked lymphoproliferative syndrome (XLP) gene encodes SAP (also called SH2D1A/DSHP) a protein that consists of a 5 residue N-terminus, a single SH2 domain, and a short 25 residue C-terminal tail. XLP is characterized by an extreme sensitivity to Epstein-Barr virus. Both T and natural killer (NK) cell dysfunctions have been seen in XLP patients. SAP binds the cytoplasmic tail of Signaling lymphocytic activation molecule (SLAM), 2B4, Ly-9, and CD84. SAP is believed to function as a signaling inhibitor, by blocking or regulating binding of other signaling proteins. SAP and the SAP-like protein EAT-2 recognize the sequence motif TIpYXX(V/I), which is found in the cytoplasmic domains of a restricted number of T, B, and NK cell surface receptors and are proposed to be natural inhibitors or regulators of the physiological role of a small family of receptors on the surface of these cells. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198206 Cd Length: 103 Bit Score: 59.76 E-value: 9.29e-11

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    643 SKPWYYDSLSRGEAEDMLMRIPRDGAFLIRKREG-SDSYAITFRARGKVKHCRINRDGRHF-VLGTSA-----YFESLVE 715
Cdd:cd10343    2 APPWYHGNITRSKAEELLSKAGKDGSFLVRDSESvSGAYALCVLYQNCVHTYRILPNAEDKlSVQASEgvpvrFFTTLPE 81

                         90       100
                 ....*....|....*....|
gi 190036    716 LVSYYEKHSLYRKMRLRYPV 735
Cdd:cd10343   82 LIEFYQKENMGLVTHLLYPV 101

SH2_Cterm_RasGAP

cd10354

C-terminal Src homology 2 (SH2) domain found in Ras GTPase-activating protein 1 (GAP); RasGAP ...

645-720

1.03e-10

Pssm-ID: 198217 Cd Length: 77 Bit Score: 58.97 E-value: 1.03e-10

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 190036    645 PWYYDSLSRGEAEDMLMRIPRDGAFLIRKREGS-DSYAITFRARGKVKHCRINRDGRHFVLGTSAYFESLVELVSYY 720
Cdd:cd10354    1 IWFHGKISREEAYNMLVKVGGPGSFLVRESDNTpGDYSLSFRVNEGIKHFKIIPTGNNQFMMGGRYFSSLDDVIDRY 77

SH3_FCHSD_2

cd11762

Second Src Homology 3 domain of FCH and double SH3 domains proteins; This group is composed of ...

774-826

1.44e-10

Second Src Homology 3 domain of FCH and double SH3 domains proteins; This group is composed of FCH and double SH3 domains protein 1 (FCHSD1) and FCHSD2. These proteins have a common domain structure consisting of an N-terminal F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs), two SH3, and C-terminal proline-rich domains. They have only been characterized in silico and their functions remain unknown. This group also includes the insect protein, nervous wreck, which acts as a regulator of synaptic growth signaling. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212696 [Multi-domain] Cd Length: 57 Bit Score: 57.79 E-value: 1.44e-10

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 190036    774 VKALYDYKAKRSDELSFCRGALIHNVSKEPG----GWWKGDYGTRIqQYFPSNYVED 826
Cdd:cd11762    2 VRALYDYEAQSDEELSFPEGAIIRILRKDDNgvddGWWEGEFNGRV-GVFPSLVVEE 57

SH3_OSTF1

cd11772

Src Homology 3 domain of metazoan osteoclast stimulating factor 1; OSTF1, also named OSF or ...

774-825

1.53e-10

Src Homology 3 domain of metazoan osteoclast stimulating factor 1; OSTF1, also named OSF or SH3P2, is a signaling protein containing SH3 and ankyrin-repeat domains. It acts through a Src-related pathway to enhance the formation of osteoclasts and bone resorption. It also acts as a negative regulator of cell motility. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212706 [Multi-domain] Cd Length: 53 Bit Score: 57.69 E-value: 1.53e-10

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 190036    774 VKALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRiQQYFPSNYVE 825
Cdd:cd11772    2 FRALYDYEAQHPDELSFEEGDLLYISDKSDPNWWKATCGGK-TGLIPSNYVE 52

SH2_Src_Blk

cd10371

Src homology 2 (SH2) domain found in B lymphoid kinase (Blk); Blk is a member of the Src ...

530-617

1.76e-10

Src homology 2 (SH2) domain found in B lymphoid kinase (Blk); Blk is a member of the Src non-receptor type tyrosine kinase family of proteins. Blk is expressed in the B-cells. Unlike most other Src members Blk lacks cysteine residues in the SH4 domain that undergo palmitylation. Blk is required for the development of IL-17-producing gamma-delta T cells. Furthermore, Blk is expressed in lymphoid precursors and, in this capacity, plays a role in regulating thymus cellularity during ontogeny. Blk has a unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail, as do the other members of the family. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198234 [Multi-domain] Cd Length: 100 Bit Score: 58.88 E-value: 1.76e-10

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    530 EKWFHKKVEKRTSAEKLLQEYcmetgGKDGTFLVRESETFPNDYTLSF----WRSGRVQHCRIRSTMEGGtlkYYLTDNL 605
Cdd:cd10371    3 EKWFFRTISRKDAERQLLAPM-----NKAGSFLIRESESNKGAFSLSVkdvtTQGEVVKHYKIRSLDNGG---YYISPRI 74

                         90
                 ....*....|..
gi 190036    606 RFRRMYALIQHY 617
Cdd:cd10371   75 TFPTLQALVQHY 86

SH2_Src_Fgr

cd10367

Src homology 2 (SH2) domain found in Gardner-Rasheed feline sarcoma viral (v-fgr) oncogene ...

530-619

2.24e-10

Src homology 2 (SH2) domain found in Gardner-Rasheed feline sarcoma viral (v-fgr) oncogene homolog, Fgr; Fgr is a member of the Src non-receptor type tyrosine kinase family of proteins. The protein contains N-terminal sites for myristoylation and palmitoylation, a PTK domain, and SH2 and SH3 domains which are involved in mediating protein-protein interactions with phosphotyrosine-containing and proline-rich motifs, respectively. Fgr is expressed in B-cells and myeloid cells, localizes to plasma membrane ruffles, and functions as a negative regulator of cell migration and adhesion triggered by the beta-2 integrin signal transduction pathway. Multiple alternatively spliced variants, encoding the same protein, have been identified Fgr has been shown to interact with Wiskott-Aldrich syndrome protein. Fgr has a unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail, as do the other members of the family. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198230 Cd Length: 101 Bit Score: 58.76 E-value: 2.24e-10

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    530 EKWFHKKVEKRTSAEKLLQEycmetGGKDGTFLVRESETFPNDYTLSF--W---RSGRVQHCRIRSTMEGGtlkYYLTDN 604
Cdd:cd10367    3 EEWYFGKIGRKDAERQLLSP-----GNPRGAFLIRESETTKGAYSLSIrdWdqnRGDHVKHYKIRKLDTGG---YYITTR 74

                         90
                 ....*....|....*
gi 190036    605 LRFRRMYALIQHYRE 619
Cdd:cd10367   75 AQFDTVQELVQHYME 89

SH2_Tec_family

cd09934

Src homology 2 (SH2) domain found in Tec-like proteins; The Tec protein tyrosine kinase is the ...

646-737

2.38e-10

Src homology 2 (SH2) domain found in Tec-like proteins; The Tec protein tyrosine kinase is the founding member of a family that includes Btk, Itk, Bmx, and Txk. The members have a PH domain, a zinc-binding motif, a SH3 domain, a SH2 domain, and a protein kinase catalytic domain. Btk is involved in B-cell receptor signaling with mutations in Btk responsible for X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (xid) in mice. Itk is involved in T-cell receptor signaling. Tec is expressed in both T and B cells, and is thought to function in activated and effector T lymphocytes to induce the expression of genes regulated by NFAT transcription factors. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198188 Cd Length: 104 Bit Score: 58.57 E-value: 2.38e-10

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    646 WYYDSLSRGEAEDMLMRIPRDGAFLIRKREGSDSYAITFRAR----GKVKHCRINRDGR-HFVLGTSAYFESLVELVSYY 720
Cdd:cd09934    8 WYVGDMSRQRAESLLKQEDKEGCFVVRNSSTKGLYTVSLFTKvpgsPHVKHYHIKQNARsEFYLAEKHCFETIPELINYH 87

                         90
                 ....*....|....*..
gi 190036    721 EKHSLYRKMRLRYPVTP 737
Cdd:cd09934   88 QHNSGGLATRLKYPVCD 104

SH2_Vav2

cd10406

Src homology 2 (SH2) domain found in the Vav2 proteins; Proto-oncogene vav is a member of the ...

645-734

2.56e-10

Src homology 2 (SH2) domain found in the Vav2 proteins; Proto-oncogene vav is a member of the Dbl family of guanine nucleotide exchange factors (GEF) for the Rho family of GTP binding proteins. All vavs are activated by tyrosine phosphorylation leading to their activation. There are three Vav mammalian family members: Vav1 which is expressed in the hematopoietic system, and Vav2 and Vav3 are more ubiquitously expressed. Vav2 is a GEF for RhoA, RhoB and RhoG and may activate Rac1 and Cdc42. Vav2 has been shown to interact with CD19 and Grb2. Alternatively spliced transcript variants encoding different isoforms have been found for Vav2. Vav proteins are involved in several processes that require cytoskeletal reorganization, such as the formation of the immunological synapse (IS), phagocytosis, platelet aggregation, spreading, and transformation. Vavs function as guanine nucleotide exchange factors (GEFs) for the Rho/Rac family of GTPases. Vav family members have several conserved motifs/domains including: a leucine-rich region, a leucine-zipper, a calponin homology (CH) domain, an acidic domain, a Dbl-homology (DH) domain, a pleckstrin homology (PH) domain, a cysteine-rich domain, 2 SH3 domains, a proline-rich region, and a SH2 domain. Vavs are the only known Rho GEFs that have both the DH/PH motifs and SH2/SH3 domains in the same protein. The leucine-rich helix-loop-helix (HLH) domain is thought to be involved in protein heterodimerization with other HLH proteins and it may function as a negative regulator by forming inactive heterodimers. The CH domain is usually involved in the association with filamentous actin, but in Vav it controls NFAT stimulation, Ca2+ mobilization, and its transforming activity. Acidic domains are involved in protein-protein interactions and contain regulatory tyrosines. The DH domain is a GDP-GTP exchange factor on Rho/Rac GTPases. The PH domain in involved in interactions with GTP-binding proteins, lipids and/or phosphorylated serine/threonine residues. The SH3 domain is involved in localization of proteins to specific sites within the cell interacting with protein with proline-rich sequences. The SH2 domain mediates a high affinity interaction with tyrosine phosphorylated proteins. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198269 Cd Length: 103 Bit Score: 58.54 E-value: 2.56e-10

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    645 PWYYDSLSRGEAeDMLMRIPRDGAFLIRKREG-SDSYAITFRARGKVKHCRINRDGRHFVLGTSAYFESLVELVSYYEKH 723
Cdd:cd10406    6 PWFAGNMERQQT-DNLLKSHASGTYLIRERPAeAERFAISIKFNDEVKHIKVVEKDNWIHITEAKKFESLLELVEYYQCH 84

                         90
                 ....*....|....*.
gi 190036    724 SLYRKMR-----LRYP 734
Cdd:cd10406   85 SLKESFKqldttLKYP 100

SH2_SHB_SHD_SHE_SHF_like

cd09945

Src homology 2 domain found in SH2 domain-containing adapter proteins B, D, E, and F (SHB, SHD, ...

644-735

2.83e-10

Src homology 2 domain found in SH2 domain-containing adapter proteins B, D, E, and F (SHB, SHD, SHE, SHF); SHB, SHD, SHE, and SHF are SH2 domain-containing proteins that play various roles throughout the cell. SHB functions in generating signaling compounds in response to tyrosine kinase activation. SHB contains proline-rich motifs, a phosphotyrosine binding (PTB) domain, tyrosine phosphorylation sites, and a SH2 domain. SHB mediates certain aspects of platelet-derived growth factor (PDGF) receptor-, fibroblast growth factor (FGF) receptor-, neural growth factor (NGF) receptor TRKA-, T cell receptor-, interleukin-2 (IL-2) receptor- and focal adhesion kinase- (FAK) signaling. SRC-like FYN-Related Kinase FRK/RAK (also named BSK/IYK or GTK) and SHB regulate apoptosis, proliferation and differentiation. SHB promotes apoptosis and is also required for proper mitogenicity, spreading and tubular morphogenesis in endothelial cells. SHB also plays a role in preventing early cavitation of embryoid bodies and reduces differentiation to cells expressing albumin, amylase, insulin and glucagon. SHB is a multifunctional protein that has difference responses in different cells under various conditions. SHE is expressed in heart, lung, brain, and skeletal muscle, while expression of SHD is restricted to the brain. SHF is mainly expressed in skeletal muscle, brain, liver, prostate, testis, ovary, small intestine, and colon. SHD may be a physiological substrate of c-Abl and may function as an adapter protein in the central nervous system. It is also thought to be involved in apoptotic regulation. SHD contains five YXXP motifs, a substrate sequence preferred by Abl tyrosine kinases, in addition to a poly-proline rich region and a C-terminal SH2 domain. SHE contains two pTry protein binding domains, protein interaction domain (PID) and a SH2 domain, followed by a glycine-proline rich region, all of which are N-terminal to the phosphotyrosine binding (PTB) domain. SHF contains four putative tyrosine phosphorylation sites and an SH2 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198198 Cd Length: 98 Bit Score: 58.21 E-value: 2.83e-10

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    644 KPWYYDSLSRGEAEDMLmRIPRDGAFLIRKREGS-DSYAITFRARGKVKHCRI--NRDGRhFVLG-TSAYFESLVELVSY 719
Cdd:cd09945    1 QGWYHGAITRIEAESLL-RPCKEGSYLVRNSESTkQDYSLSLKSAKGFMHMRIqrNETGQ-YILGqFSRPFETIPEMIRH 78

                         90       100
                 ....*....|....*....|
gi 190036    720 YEKHSLYRK----MRLRYPV 735
Cdd:cd09945   79 YCLNKLPVRgaehMCLLEPV 98

SH3_betaPIX

cd12061

Src Homology 3 domain of beta-Pak Interactive eXchange factor; Beta-PIX, also called Rho ...

774-827

2.86e-10

Src Homology 3 domain of beta-Pak Interactive eXchange factor; Beta-PIX, also called Rho guanine nucleotide exchange factor 7 (ARHGEF7) or Cool (Cloned out of Library)-1, activates small GTPases by exchanging bound GDP for free GTP. It acts as a GEF for both Cdc42 and Rac 1, and plays important roles in regulating neuroendocrine exocytosis, focal adhesion maturation, cell migration, synaptic vesicle localization, and insulin secretion. PIX proteins contain an N-terminal SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains, and a C-terminal leucine-zipper domain for dimerization. The SH3 domain of PIX binds to an atypical PxxxPR motif in p21-activated kinases (PAKs) with high affinity. The binding of PAKs to PIX facilitate the localization of PAKs to focal complexes and also localizes PAKs to PIX targets Cdc43 and Rac, leading to the activation of PAKs. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212994 [Multi-domain] Cd Length: 54 Bit Score: 57.00 E-value: 2.86e-10

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....
gi 190036    774 VKALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRiQQYFPSNYVEDI 827
Cdd:cd12061    2 VRAKFNFQQTNEDELSFSKGDVIHVTRVEEGGWWEGTHNGR-TGWFPSNYVREI 54

SH3_9

pfam14604

Variant SH3 domain;

776-825

2.88e-10

Variant SH3 domain;

Pssm-ID: 434066 [Multi-domain] Cd Length: 49 Bit Score: 56.86 E-value: 2.88e-10

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|
gi 190036      776 ALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRiQQYFPSNYVE 825
Cdd:pfam14604    1 ALYPYEPKDDDELSLQRGDVITVIEESEDGWWEGINTGR-TGLVPANYVE 49

SH2_nSH2_p85_like

cd09942

N-terminal Src homology 2 (nSH2) domain found in p85; Phosphoinositide 3-kinases (PI3Ks) are ...

640-757

3.11e-10

N-terminal Src homology 2 (nSH2) domain found in p85; Phosphoinositide 3-kinases (PI3Ks) are essential for cell growth, migration, and survival. p110, the catalytic subunit, is composed of an adaptor-binding domain, a Ras-binding domain, a C2 domain, a helical domain, and a kinase domain. The regulatory unit is called p85 and is composed of an SH3 domain, a RhoGap domain, a N-terminal SH2 (nSH2) domain, an internal SH2 (iSH2) domain, and C-terminal (cSH2) domain. There are 2 inhibitory interactions between p110alpha and p85 of P13K: (1) p85 nSH2 domain with the C2, helical, and kinase domains of p110alpha and (2) p85 iSH2 domain with C2 domain of p110alpha. There are 3 inhibitory interactions between p110beta and p85 of P13K: (1) p85 nSH2 domain with the C2, helical, and kinase domains of p110beta, (2) p85 iSH2 domain with C2 domain of p110alpha, and (3) p85 cSH2 domain with the kinase domain of p110alpha. It is interesting to note that p110beta is oncogenic as a wild type protein while p110alpha lacks this ability. One explanation is the idea that the regulation of p110beta by p85 is unique because of the addition of inhibitory contacts from the cSH2 domain and the loss of contacts in the iSH2 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198195 Cd Length: 110 Bit Score: 58.49 E-value: 3.11e-10

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    640 PHESK--PWYYDSLSRGEAEDMLMRIPrDGAFLIRK-REGSDSYAITFRARGKVKHCRINRDGRHFVLGTSAYFESLVEL 716
Cdd:cd09942    1 PHSLQeaEWYWGDISREEVNEKMRDTP-DGTFLVRDaSTMKGDYTLTLRKGGNNKLIKIFHRDGKYGFSDPLTFNSVVEL 79

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|.
gi 190036    717 VSYYEKHSlyrkmrlrypvtpelLERYNTERDINSLYDVSR 757
Cdd:cd09942   80 INYYRNNS---------------LAEYNRKLDVKLLYPVSR 105

SH2_Src_Frk

cd10369

Src homology 2 (SH2) domain found in the Fyn-related kinase (Frk); Frk is a member of the Src ...

642-724

4.57e-10

Src homology 2 (SH2) domain found in the Fyn-related kinase (Frk); Frk is a member of the Src non-receptor type tyrosine kinase family of proteins. The Frk subfamily is composed of Frk/Rak and Iyk/Bsk/Gst. It is expressed primarily epithelial cells. Frk is a nuclear protein and may function during G1 and S phase of the cell cycle and suppress growth. Unlike the other Src members it lacks a glycine at position 2 of SH4 which is important for addition of a myristic acid moiety that is involved in targeting Src PTKs to cellular membranes. FRK and SHB exert similar effects when overexpressed in rat phaeochromocytoma (PC12) and beta-cells, where both induce PC12 cell differentiation and beta-cell proliferation. Under conditions that cause beta-cell degeneration these proteins augment beta-cell apoptosis. The FRK-SHB responses involve FAK and insulin receptor substrates (IRS) -1 and -2. Frk has been demonstrated to interact with retinoblastoma protein. Frk regulates PTEN protein stability by phosphorylating PTEN, which in turn prevents PTEN degradation. Frk also plays a role in regulation of embryonal pancreatic beta cell formation. Frk has a unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail, as do the other members of the family. Like the other members of the Src family the SH2 domain in addition to binding the target, also plays an autoinhibitory role by binding to its activation loop. The tryosine involved is at the same site as the tyrosine involved in the autophosphorylation of Src. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 199831 Cd Length: 96 Bit Score: 57.58 E-value: 4.57e-10

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    642 ESKPWYYDSLSRGEAEDMLMRIP-RDGAFLIRKREGSDS-YAITFRARGKVKHCRINR-DGRHFVLGTSAYFESLVELVS 718
Cdd:cd10369    1 QAEPWFFGAIKRADAEKQLLYSEnQTGAFLIRESESQKGeFSLSVLDGGVVKHYRIRRlDEGGFFLTRRKTFSTLNEFVN 80


                 ....*.
gi 190036    719 YYEKHS 724
Cdd:cd10369   81 YYTTTS 86

SH3_GRAF-like

cd11882

Src Homology 3 domain of GTPase Regulator Associated with Focal adhesion kinase and similar ...

773-826

5.10e-10

Src Homology 3 domain of GTPase Regulator Associated with Focal adhesion kinase and similar proteins; This subfamily is composed of Rho GTPase activating proteins (GAPs) with similarity to GRAF. Members contain an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, a Rho GAP domain, and a C-terminal SH3 domain. Although vertebrates harbor four Rho GAPs in the GRAF subfamily including GRAF, GRAF2, GRAF3, and Oligophrenin-1 (OPHN1), only three are included in this model. OPHN1 contains the BAR, PH and GAP domains, but not the C-terminal SH3 domain. GRAF and GRAF2 show GAP activity towards RhoA and Cdc42. GRAF influences Rho-mediated cytoskeletal rearrangements and binds focal adhesion kinase. GRAF2 regulates caspase-activated p21-activated protein kinase-2. The SH3 domain of GRAF and GRAF2 binds PKNbeta, a target of the small GTPase Rho. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212815 [Multi-domain] Cd Length: 54 Bit Score: 56.15 E-value: 5.10e-10

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 190036    773 TVKALYDYKAKRSDELSFCRGALIHNV--SKEPgGWWKGDYGTRiQQYFPSNYVED 826
Cdd:cd11882    1 RARALYACKAEDESELSFEPGQIITNVqpSDEP-GWLEGTLNGR-TGLIPENYVEF 54

SH2_DAPP1_BAM32_like

cd10355

Src homology 2 domain found in dual adaptor for phosphotyrosine and 3-phosphoinositides ( ...

642-720

5.92e-10

Src homology 2 domain found in dual adaptor for phosphotyrosine and 3-phosphoinositides ( DAPP1)/B lymphocyte adaptor molecule of 32 kDa (Bam32)-like proteins; DAPP1/Bam32 contains a putative myristoylation site at its N-terminus, followed by a SH2 domain, and a pleckstrin homology (PH) domain at its C-terminus. DAPP1 could potentially be recruited to the cell membrane by any of these domains. Its putative myristoylation site could facilitate the interaction of DAPP1 with the lipid bilayer. Its SH2 domain may also interact with phosphotyrosine residues on membrane-associated proteins such as activated tyrosine kinase receptors. And finally its PH domain exhibits a high-affinity interaction with the PtdIns(3,4,5)P(3) PtdIns(3,4)P(2) second messengers produced at the cell membrane following the activation of PI 3-kinases. DAPP1 is thought to interact with both tyrosine phosphorylated proteins and 3-phosphoinositides and therefore may play a role in regulating the location and/or activity of such proteins(s) in response to agonists that elevate PtdIns(3,4,5)P(3) and PtdIns(3,4)P(2). This protein is likely to play an important role in triggering signal transduction pathways that lie downstream from receptor tyrosine kinases and PI 3-kinase. It is likely that DAPP1 functions as an adaptor to recruit other proteins to the plasma membrane in response to extracellular signals. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198218 Cd Length: 92 Bit Score: 57.10 E-value: 5.92e-10

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    642 ESKPWYYDSLSRGEAEDMLMRIPRDGAFLIRK-REGSDSYAITFRARGKVKHCRINRDGRHFVLGTSAyFESLVELVSYY 720
Cdd:cd10355    4 QSLGWYHGNLTRHAAEALLLSNGVDGSYLLRNsNEGTGLFSLSVRAKDSVKHFHVEYTGYSFKFGFNE-FSSLQDFVKHF 82

SH2_Src_Lyn

cd10364

Src homology 2 (SH2) domain found in Lyn; Lyn is a member of the Src non-receptor type ...

530-619

7.09e-10

Src homology 2 (SH2) domain found in Lyn; Lyn is a member of the Src non-receptor type tyrosine kinase family of proteins and is expressed in the hematopoietic cells, in neural tissues, liver, and adipose tissue. There are two alternatively spliced forms of Lyn. Lyn plays an inhibitory role in myeloid lineage proliferation. Following engagement of the B cell receptors, Lyn undergoes rapid phosphorylation and activation, triggering a cascade of signaling events mediated by Lyn phosphorylation of tyrosine residues within the immunoreceptor tyrosine-based activation motifs (ITAM) of the receptor proteins, and subsequent recruitment and activation of other kinases including Syk, phospholipase C2 (PLC2) and phosphatidyl inositol-3 kinase. These kinases play critical roles in proliferation, Ca2+ mobilization and cell differentiation. Lyn plays an essential role in the transmission of inhibitory signals through phosphorylation of tyrosine residues within the immunoreceptor tyrosine-based inhibitory motifs (ITIM) in regulatory proteins such as CD22, PIR-B and FC RIIb1. Their ITIM phosphorylation subsequently leads to recruitment and activation of phosphatases such as SHIP-1 and SHP-1 which further down modulate signaling pathways, attenuate cell activation and can mediate tolerance. Lyn also plays a role in the insulin signaling pathway. Activated Lyn phosphorylates insulin receptor substrate 1 (IRS1) leading to an increase in translocation of Glut-4 to the cell membrane and increased glucose utilization. It is the primary Src family member involved in signaling downstream of the B cell receptor. Lyn plays an unusual, 2-fold role in B cell receptor signaling; it is essential for initiation of signaling but is also later involved in negative regulation of the signal. Lyn has a unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail, as do the other members of the family. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198227 Cd Length: 101 Bit Score: 57.30 E-value: 7.09e-10

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    530 EKWFHKKVEKRTSAEKLLQeycmeTGGKDGTFLVRESETFPNDYTLSF-----WRSGRVQHCRIRSTMEGGtlkYYLTDN 604
Cdd:cd10364    3 EEWFFKDITRKDAERQLLA-----PGNSAGAFLIRESETLKGSYSLSVrdydpQHGDVIKHYKIRSLDNGG---YYISPR 74

                         90
                 ....*....|....*
gi 190036    605 LRFRRMYALIQHYRE 619
Cdd:cd10364   75 ITFPCISDMIKHYQK 89

PI-PLCc_bacteria_like

cd08557

Catalytic domain of bacterial phosphatidylinositol-specific phospholipase C and similar ...

317-453

7.25e-10

Catalytic domain of bacterial phosphatidylinositol-specific phospholipase C and similar proteins; This subfamily corresponds to the catalytic domain present in bacterial phosphatidylinositol-specific phospholipase C (PI-PLC, EC 4.6.1.13) and their sequence homologs found in eukaryota. Bacterial PI-PLCs participate in Ca2+-independent PI metabolism, hydrolyzing the membrane lipid phosphatidylinositol (PI) to produce phosphorylated myo-inositol and diacylglycerol (DAG). Although their precise physiological function remains unclear, bacterial PI-PLCs may function as virulence factors in some pathogenic bacteria. Bacterial PI-PLCs contain a single TIM-barrel type catalytic domain. Its catalytic mechanism is based on general base and acid catalysis utilizing two well conserved histidines, and consists of two steps, a phosphotransfer and a phosphodiesterase reaction. Eukaryotic homologs in this family are named as phosphatidylinositol-specific phospholipase C X domain containing proteins (PI-PLCXD). They are distinct from the typical eukaryotic phosphoinositide-specific phospholipases C (PI-PLC, EC 3.1.4.11), which have a multidomain organization that consists of a PLC catalytic core domain, and various regulatory domains. The catalytic core domain is assembled from two highly conserved X- and Y-regions split by a divergent linker sequence. In contrast, eukaryotic PI-PLCXDs contain a single TIM-barrel type catalytic domain, X domain, which is closely related to that of bacterial PI-PLCs. Although the biological function of eukaryotic PI-PLCXDs still remains unclear, it may be distinct from that of typical eukaryotic PI-PLCs. This family also includes a distinctly different type of eukaryotic PLC, glycosylphosphatidylinositol-specific phospholipase C (GPI-PLC), an integral membrane protein characterized in the protozoan parasite Trypanosoma brucei. T. brucei GPI-PLC hydrolyzes the GPI-anchor on the variant specific glycoprotein (VSG), releasing dimyristyl glycerol (DMG), which may facilitate the evasion of the protozoan to the host's immune system. It does not require Ca2+ for its activity and is more closely related to bacterial PI-PLCs, but not mammalian PI-PLCs.

Pssm-ID: 176500 [Multi-domain] Cd Length: 271 Bit Score: 61.34 E-value: 7.25e-10

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    317 PLSHYWISSSHNTY-LTGDQLRSESSPeaYIRC--------LRMGCRCIELDCW-DGPDGKPVIYHGWTRTTKIKFDDVV 386
Cdd:cd08557    8 PLSQLSIPGTHNSYaYTIDGNSPIVSK--WSKTqdlsitdqLDAGVRYLDLRVAyDPDDGDLYVCHGLFLLNGQTLEDVL 85

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 190036    387 QAIKDhaFVTS--SFPVILSIEEHCSVEQQRHMAK---AFKEVFGDLLLTKPTEASADqlPSPSQLRE-KIII 453
Cdd:cd08557   86 NEVKD--FLDAhpSEVVILDLEHEYGGDNGEDHDEldaLLRDVLGDPLYRPPVRAGGW--PTLGELRAgKRVL 154

SH3_Cortactin_like

cd11819

Src homology 3 domain of Cortactin and related proteins; This subfamily includes cortactin, ...

773-825

1.60e-09

Src homology 3 domain of Cortactin and related proteins; This subfamily includes cortactin, Abp1 (actin-binding protein 1), hematopoietic lineage cell-specific protein 1 (HS1), and similar proteins. These proteins are involved in regulating actin dynamics through direct or indirect interaction with the Arp2/3 complex, which is required to initiate actin polymerization. They all contain at least one C-terminal SH3 domain. Cortactin and HS1 bind Arp2/3 and actin through an N-terminal region that contains an acidic domain and several copies of a repeat domain found in cortactin and HS1. Abp1 binds actin via an N-terminal actin-depolymerizing factor (ADF) homology domain. Yeast Abp1 binds Arp2/3 directly through two acidic domains. Mammalian Abp1 does not directly interact with Arp2/3; instead, it regulates actin dynamics indirectly by interacting with dynamin and WASP family proteins. The C-terminal region of these proteins acts as an adaptor or scaffold that can connect membrane trafficking and signaling proteins that bind the SH3 domain within the actin network. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212753 [Multi-domain] Cd Length: 54 Bit Score: 54.63 E-value: 1.60e-09

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 190036    773 TVKALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRIQQYFPSNYVE 825
Cdd:cd11819    1 RAKALYDYQAAEDNEISFVEGDIITQIEQIDEGWWLGVNAKGQKGLFPANYVE 53

SH2_Nck1

cd10408

Src homology 2 (SH2) domain found in Nck; Nck proteins are adaptors that modulate actin ...

644-726

1.62e-09

Src homology 2 (SH2) domain found in Nck; Nck proteins are adaptors that modulate actin cytoskeleton dynamics by linking proline-rich effector molecules to tyrosine kinases or phosphorylated signaling intermediates. There are two members known in this family: Nck1 (Nckalpha) and Nck2 (Nckbeta and Growth factor receptor-bound protein 4 (Grb4)). They are characterized by having 3 SH3 domains and a C-terminal SH2 domain. Nck1 and Nck2 have overlapping functions as determined by gene knockouts. Both bind receptor tyrosine kinases and other tyrosine-phosphorylated proteins through their SH2 domains. In addition they also bind distinct targets. Neuronal signaling proteins: EphrinB1, EphrinB2, and Disabled-1 (Dab-1) all bind to Nck-2 exclusively. And in the case of PDGFR, Tyr(P)751 binds to Nck1 while Tyr(P)1009 binds to Nck2. Nck1 and Nck2 have a role in the infection process of enteropathogenic Escherichia coli (EPEC). Their SH3 domains are involved in recruiting and activating the N-WASP/Arp2/3 complex inducing actin polymerization resulting in the production of pedestals, dynamic bacteria-presenting protrusions of the plasma membrane. A similar thing occurs in the vaccinia virus where motile plasma membrane projections are formed beneath the virus. Recently it has been shown that the SH2 domains of both Nck1 and Nck2 bind the G-protein coupled receptor kinase-interacting protein 1 (GIT1) in a phosphorylation-dependent manner. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198271 Cd Length: 97 Bit Score: 56.19 E-value: 1.62e-09

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    644 KPWYYDSLSRGEAEDMLMRIPRDGAFLIRKREGS-DSYAITFRARGKVKHCRINRDGRHFVLGTSAyFESLVELVSYYEK 722
Cdd:cd10408    1 NPWYYGKVTRHQAEMALNERGNEGDFLIRDSESSpNDFSVSLKAQGKNKHFKVQLKECVYCIGQRK-FSSMEELVEHYKK 79


                 ....
gi 190036    723 HSLY 726
Cdd:cd10408   80 APIF 83

SH2_Src_Fyn_isoform_b_like

cd10419

Src homology 2 (SH2) domain found in Fyn isoform b like proteins; Fyn is a member of the Src ...

529-619

1.87e-09

Src homology 2 (SH2) domain found in Fyn isoform b like proteins; Fyn is a member of the Src non-receptor type tyrosine kinase family of proteins. This cd contains the SH2 domain found in Fyn isoform b type proteins. Fyn is involved in the control of cell growth and is required in the following pathways: T and B cell receptor signaling, integrin-mediated signaling, growth factor and cytokine receptor signaling, platelet activation, ion channel function, cell adhesion, axon guidance, fertilization, entry into mitosis, and differentiation of natural killer cells, oligodendrocytes and keratinocytes. The protein associates with the p85 subunit of phosphatidylinositol 3-kinase and interacts with the Fyn-binding protein. Alternatively spliced transcript variants encoding distinct isoforms exist. Fyn is primarily localized to the cytoplasmic leaflet of the plasma membrane. Tyrosine phosphorylation of target proteins by Fyn serves to either regulate target protein activity, and/or to generate a binding site on the target protein that recruits other signaling molecules. FYN has been shown to interact with a number of proteins including: BCAR1, Cbl, Janus kinase, nephrin, Sky, tyrosine kinase, Wiskott-Aldrich syndrome protein, and Zap-70. Fyn has a unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail, as do the other members of the family. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198282 Cd Length: 101 Bit Score: 56.22 E-value: 1.87e-09

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    529 GEKWFHKKVEKRTSAEKLLQeycmeTGGKDGTFLVRESETFPNDYTLSF--W---RSGRVQHCRIRSTMEGGtlkYYLTD 603
Cdd:cd10419    2 AEEWYFGKLGRKDAERQLLS-----FGNPRGTFLIRESETTKGAYSLSIrdWddmKGDHVKHYKIRKLDNGG---YYITT 73

                         90
                 ....*....|....*.
gi 190036    604 NLRFRRMYALIQHYRE 619
Cdd:cd10419   74 RAQFETLQQLVQHYSE 89

SH3_Nostrin

cd11823

Src homology 3 domain of Nitric Oxide Synthase TRaffic INducer; Nostrin is expressed in ...

775-825

1.97e-09

Src homology 3 domain of Nitric Oxide Synthase TRaffic INducer; Nostrin is expressed in endothelial and epithelial cells and is involved in the regulation, trafficking and targeting of endothelial NOS (eNOS). It facilitates the endocytosis of eNOS by coordinating the functions of dynamin and the Wiskott-Aldrich syndrome protein (WASP). Increased expression of Nostrin may be correlated to preeclampsia. Nostrin contains an N-terminal F-BAR domain and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212757 [Multi-domain] Cd Length: 53 Bit Score: 54.27 E-value: 1.97e-09

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 190036    775 KALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDY-GTRiqQYFPSNYVE 825
Cdd:cd11823    3 KALYSYTANREDELSLQPGDIIEVHEKQDDGWWLGELnGKK--GIFPATYVE 52

SH2_SH2D2A_SH2D7

cd10349

Src homology 2 domain found in the SH2 domain containing protein 2A and 7 (SH2D2A and SH2D7); ...

645-720

2.03e-09

Src homology 2 domain found in the SH2 domain containing protein 2A and 7 (SH2D2A and SH2D7); SH2D2A and SH7 both contain a single SH2 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 199830 Cd Length: 77 Bit Score: 55.22 E-value: 2.03e-09

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 190036    645 PWYYDSLSRGEAEDMLMRIPRdGAFLIRKREGSDSYAITFRARGKVKHCRIN--RDGRHFVLGTSAYFESLVELVSYY 720
Cdd:cd10349    1 AWFHGFITRREAERLLEPKPQ-GCYLVRFSESAVTFVLSYRSRTCCRHFLLAqlRDGRHVVLGEDSAHARLQDLLLHY 77

SH3_Bbc1

cd11887

Src Homology 3 domain of Bbc1 and similar domains; This subfamily is composed of Saccharomyces ...

773-825

2.05e-09

Src Homology 3 domain of Bbc1 and similar domains; This subfamily is composed of Saccharomyces cerevisiae Bbc1p, also called Mti1p (Myosin tail region-interacting protein), and similar proteins. Bbc1p interacts with and regulates type I myosins in yeast, Myo3p and Myo5p, which are involved in actin cytoskeletal reorganization. It also binds and inhibits Las17, a WASp family protein that functions as an activator of the Arp2/3 complex. Bbc1p contains an N-terminal SH3 domain. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212820 [Multi-domain] Cd Length: 60 Bit Score: 54.66 E-value: 2.05e-09

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 190036    773 TVKALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDY----GTRIQQYFPSNYVE 825
Cdd:cd11887    3 KVKALYPYESDHEDDLNFDVGQLITVTEEEDADWYFGEYvdsnGNTKEGIFPKNFVE 59

SH2_N-SH2_SHP_like

cd10340

N-terminal Src homology 2 (N-SH2) domain found in SH2 domain Phosphatases (SHP) proteins; The ...

532-621

2.12e-09

N-terminal Src homology 2 (N-SH2) domain found in SH2 domain Phosphatases (SHP) proteins; The SH2 domain phosphatases (SHP-1, SHP-2/Syp, Drosophila corkscrew (csw), and Caenorhabditis elegans Protein Tyrosine Phosphatase (Ptp-2)) are cytoplasmic signaling enzymes. They are both targeted and regulated by interactions of their SH2 domains with phosphotyrosine docking sites. These proteins contain two SH2 domains (N-SH2, C-SH2) followed by a tyrosine phosphatase (PTP) domain, and a C-terminal extension. Shp1 and Shp2 have two tyrosyl phosphorylation sites in their C-tails, which are phosphorylated differentially by receptor and nonreceptor PTKs. Csw retains the proximal tyrosine and Ptp-2 lacks both sites. Shp-binding proteins include receptors, scaffolding adapters, and inhibitory receptors. Some of these bind both Shp1 and Shp2 while others bind only one. Most proteins that bind a Shp SH2 domain contain one or more immuno-receptor tyrosine-based inhibitory motifs (ITIMs): [IVL]xpYxx[IVL]. Shp1 N-SH2 domain blocks the catalytic domain and keeps the enzyme in the inactive conformation, and is thus believed to regulate the phosphatase activity of SHP-1. Its C-SH2 domain is thought to be involved in searching for phosphotyrosine activators. The SHP2 N-SH2 domain is a conformational switch; it either binds and inhibits the phosphatase, or it binds phosphoproteins and activates the enzyme. The C-SH2 domain contributes binding energy and specificity, but it does not have a direct role in activation. Csw SH2 domain function is essential, but either SH2 domain can fulfill this requirement. The role of the csw SH2 domains during Sevenless receptor tyrosine kinase (SEV) signaling is to bind Daughter of Sevenless rather than activated SEV. Ptp-2 acts in oocytes downstream of sheath/oocyte gap junctions to promote major sperm protein (MSP)-induced MAP Kinase (MPK-1) phosphorylation. Ptp-2 functions in the oocyte cytoplasm, not at the cell surface to inhibit multiple RasGAPs, resulting in sustained Ras activation. It is thought that MSP triggers PTP-2/Ras activation and ROS production to stimulate MPK-1 activity essential for oocyte maturation and that secreted MSP domains and Cu/Zn superoxide dismutases function antagonistically to control ROS and MAPK signaling. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198203 Cd Length: 99 Bit Score: 55.87 E-value: 2.12e-09

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    532 WFHKkVEKRTSAEKLLQEYcmetgGKDGTFLVRESETFPNDYTLSFWRSGRVQHCRIRSTMEggtlKYYLTDNLRFRRMY 611
Cdd:cd10340    2 WFHP-VISGIEAENLLKTR-----GVDGSFLARPSKSNPGDFTLSVRRGDEVTHIKIQNTGD----YYDLYGGEKFATLS 71

                         90
                 ....*....|
gi 190036    612 ALIQHYRETH 621
Cdd:cd10340   72 ELVQYYMEQH 81

SH2_Grb14

cd10414

Src homology 2 (SH2) domain found in the growth factor receptor bound, subclass 14 (Grb14) ...

526-624

2.18e-09

Src homology 2 (SH2) domain found in the growth factor receptor bound, subclass 14 (Grb14) proteins; The Grb family binds to the epidermal growth factor receptor (EGFR, erbB1) via their SH2 domains. Grb14 is part of the Grb7 family of proteins which also includes Grb7, and Grb14. They are composed of an N-terminal Proline-rich domain, a Ras Associating-like (RA) domain, a Pleckstrin Homology (PH) domain, a phosphotyrosine interaction region (PIR, BPS) and a C-terminal SH2 domain. The SH2 domains of Grb7, Grb10 and Grb14 preferentially bind to a different RTK. Grb14 binds to Fibroblast Growth Factor Receptor (FGFR) and weakly to the erbB2 receptor. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198277 Cd Length: 108 Bit Score: 56.09 E-value: 2.18e-09

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    526 LHFGEKWFHKKVEkRTSAEKLLqeycMETGGKDGTFLVRESETFPNDYTLSFWRSGRVQHCRIRSTMEGGTLKYYLTD-N 604
Cdd:cd10414    1 IHRSQPWFHHKIS-RDEAQRLI----IQQGLVDGVFLVRDSQSNPRTFVLSMSHGQKIKHFQIIPVEDDGELFHTLDDgH 75

                         90       100
                 ....*....|....*....|..
gi 190036    605 LRFRRMYALIQHYRETH--LPC 624
Cdd:cd10414   76 TRFTDLIQLVEFYQLNKgvLPC 97

SH2_Vav3

cd10407

Src homology 2 (SH2) domain found in the Vav3 proteins; Proto-oncogene vav is a member of the ...

641-730

2.37e-09

Src homology 2 (SH2) domain found in the Vav3 proteins; Proto-oncogene vav is a member of the Dbl family of guanine nucleotide exchange factors (GEF) for the Rho family of GTP binding proteins. All vavs are activated by tyrosine phosphorylation leading to their activation. There are three Vav mammalian family members: Vav1 which is expressed in the hematopoietic system, and Vav2 and Vav3 are more ubiquitously expressed. Vav3 preferentially activates RhoA, RhoG and, to a lesser extent, Rac1. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. VAV3 has been shown to interact with Grb2. Vav proteins are involved in several processes that require cytoskeletal reorganization, such as the formation of the immunological synapse (IS), phagocytosis, platelet aggregation, spreading, and transformation. Vavs function as guanine nucleotide exchange factors (GEFs) for the Rho/Rac family of GTPases. Vav family members have several conserved motifs/domains including: a leucine-rich region, a leucine-zipper, a calponin homology (CH) domain, an acidic domain, a Dbl-homology (DH) domain, a pleckstrin homology (PH) domain, a cysteine-rich domain, 2 SH3 domains, a proline-rich region, and a SH2 domain. Vavs are the only known Rho GEFs that have both the DH/PH motifs and SH2/SH3 domains in the same protein. The leucine-rich helix-loop-helix (HLH) domain is thought to be involved in protein heterodimerization with other HLH proteins and it may function as a negative regulator by forming inactive heterodimers. The CH domain is usually involved in the association with filamentous actin, but in Vav it controls NFAT stimulation, Ca2+ mobilization, and its transforming activity. Acidic domains are involved in protein-protein interactions and contain regulatory tyrosines. The DH domain is a GDP-GTP exchange factor on Rho/Rac GTPases. The PH domain in involved in interactions with GTP-binding proteins, lipids and/or phosphorylated serine/threonine residues. The SH3 domain is involved in localization of proteins to specific sites within the cell interacting with protein with proline-rich sequences. The SH2 domain mediates a high affinity interaction with tyrosine phosphorylated proteins. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198270 Cd Length: 103 Bit Score: 55.78 E-value: 2.37e-09

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    641 HESKPWYYDSLSRGEAEDMLmrIPR-DGAFLIRKR-EGSDSYAITFRARGKVKHCRI-NRDGrHFVLGTSAYFESLVELV 717
Cdd:cd10407    2 YSCQPWYAGAMERLQAETEL--INRvNSTYLVRHRtKESGEYAISIKYNNEVKHIKIlTRDG-FFHIAENRKFKSLMELV 78

                         90
                 ....*....|...
gi 190036    718 SYYEKHSLYRKMR 730
Cdd:cd10407   79 EYYKHHSLKEGFR 91

SH2_SHC

cd09925

Src homology 2 (SH2) domain found in SH2 adaptor protein C (SHC); SHC is involved in a wide ...

529-638

2.41e-09

Src homology 2 (SH2) domain found in SH2 adaptor protein C (SHC); SHC is involved in a wide variety of pathways including regulating proliferation, angiogenesis, invasion and metastasis, and bone metabolism. An adapter protein, SHC has been implicated in Ras activation following the stimulation of a number of different receptors, including growth factors [insulin, epidermal growth factor (EGF), nerve growth factor, and platelet derived growth factor (PDGF)], cytokines [interleukins 2, 3, and 5], erythropoietin, and granulocyte/macrophage colony-stimulating factor, and antigens [T-cell and B-cell receptors]. SHC has been shown to bind to tyrosine-phosphorylated receptors, and receptor stimulation leads to tyrosine phosphorylation of SHC. Upon phosphorylation, SHC interacts with another adapter protein, Grb2, which binds to the Ras GTP/GDP exchange factor mSOS which leads to Ras activation. SHC is composed of an N-terminal domain that interacts with proteins containing phosphorylated tyrosines, a (glycine/proline)-rich collagen-homology domain that contains the phosphorylated binding site, and a C-terminal SH2 domain. SH2 has been shown to interact with the tyrosine-phosphorylated receptors of EGF and PDGF and with the tyrosine-phosphorylated C chain of the T-cell receptor, providing one of the mechanisms of T-cell-mediated Ras activation. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198179 Cd Length: 104 Bit Score: 55.82 E-value: 2.41e-09

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    529 GEKWFHKKVEKRTsAEKLLQEycmetggkDGTFLVRESETFPNDYTLsfwrsgrvqhcrirSTMEGGTLKYYL------- 601
Cdd:cd09925    6 GEPWYHGKMSRRD-AESLLQT--------DGDFLVRESTTTPGQYVL--------------TGMQNGQPKHLLlvdpegv 62

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|.
gi 190036    602 --TDNLRFRRMYALIQHYRETHLP--CAEFELRLTDPVPNP 638
Cdd:cd09925   63 vrTKDRVFESISHLINYHVTNGLPiiSEGSELHLRRPVRRP 103

SH2_SLAP

cd10344

Src homology 2 domain found in Src-like adaptor proteins; SLAP belongs to the subfamily of ...

540-619

2.65e-09

Src homology 2 domain found in Src-like adaptor proteins; SLAP belongs to the subfamily of adapter proteins that negatively regulate cellular signaling initiated by tyrosine kinases. It has a myristylated N-terminus, SH3 and SH2 domains with high homology to Src family tyrosine kinases, and a unique C-terminal tail, which is important for c-Cbl binding. SLAP negatively regulates platelet-derived growth factor (PDGF)-induced mitogenesis in fibroblasts and regulates F-actin assembly for dorsal ruffles formation. c-Cbl mediated SLAP inhibition towards actin remodeling. Moreover, SLAP enhanced PDGF-induced c-Cbl phosphorylation by SFK. In contrast, SLAP mitogenic inhibition was not mediated by c-Cbl, but it rather involved a competitive mechanism with SFK for PDGF-receptor (PDGFR) association and mitogenic signaling. Accordingly, phosphorylation of the Src mitogenic substrates Stat3 and Shc were reduced by SLAP. Thus, we concluded that SLAP regulates PDGFR signaling by two independent mechanisms: a competitive mechanism for PDGF-induced Src mitogenic signaling and a non-competitive mechanism for dorsal ruffles formation mediated by c-Cbl. SLAP is a hematopoietic adaptor containing Src homology (SH)3 and SH2 motifs and a unique carboxy terminus. Unlike c-Src, SLAP lacks a tyrosine kinase domain. Unlike c-Src, SLAP does not impact resorptive function of mature osteoclasts but induces their early apoptosis. SLAP negatively regulates differentiation of osteoclasts and proliferation of their precursors. Conversely, SLAP decreases osteoclast death by inhibiting activation of caspase 3. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198207 Cd Length: 104 Bit Score: 55.96 E-value: 2.65e-09

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    540 RTSAEKLLqeycMETGGKDGTFLVRESETFPNDYTLSFWRSG-----RVQHCRIRSTMEGGtlkYYLTDNLRFRRMYALI 614
Cdd:cd10344   19 REKAEELL----MLPGNQVGSFLIRESETRRGCYSLSVRHRGsqsrdSVKHYRIFRLDNGW---FYISPRLTFQCLEDMV 91


                 ....*
gi 190036    615 QHYRE 619
Cdd:cd10344   92 NHYSE 96

SH2_Src_Src

cd10365

Src homology 2 (SH2) domain found in tyrosine kinase sarcoma (Src); Src is a member of the Src ...

530-619

3.31e-09

Src homology 2 (SH2) domain found in tyrosine kinase sarcoma (Src); Src is a member of the Src non-receptor type tyrosine kinase family of proteins. Src is thought to play a role in the regulation of embryonic development and cell growth. Members here include v-Src and c-Src. v-Src lacks the C-terminal inhibitory phosphorylation site and is therefore constitutively active as opposed to normal cellular src (c-Src) which is only activated under certain circumstances where it is required (e.g. growth factor signaling). v-Src is an oncogene whereas c-Src is a proto-oncogene. c-Src consists of three domains, an N-terminal SH3 domain, a central SH2 domain and a tyrosine kinase domain. The SH2 and SH3 domains work together in the auto-inhibition of the kinase domain. The phosphorylation of an inhibitory tyrosine near the c-terminus of the protein produces a binding site for the SH2 domain which then facilitates binding of the SH3 domain to a polyproline site within the linker between the SH2 domain and the kinase domain. Binding of the SH3 domain inactivates the enzyme. This allows for multiple mechanisms for c-Src activation: dephosphorylation of the C-terminal tyrosine by a protein tyrosine phosphatase, binding of the SH2 domain by a competitive phospho-tyrosine residue, or competitive binding of a polyproline binding site to the SH3 domain. Unlike most other Src members Src lacks cysteine residues in the SH4 domain that undergo palmitylation. Serine and threonine phosphorylation sites have also been identified in the unique domains of Src and are believed to modulate protein-protein interactions or regulate catalytic activity. Alternatively spliced forms of Src, which contain 6- or 11-amino acid insertions in the SH3 domain, are expressed in CNS neurons. c-Src has a unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail, as do the other members of the family. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198228 Cd Length: 101 Bit Score: 55.44 E-value: 3.31e-09

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    530 EKWFHKKVEKRTSaEKLLqeycMETGGKDGTFLVRESETFPNDYTLSFW-----RSGRVQHCRIRSTMEGGtlkYYLTDN 604
Cdd:cd10365    3 EEWYFGKITRRES-ERLL----LNAENPRGTFLVRESETTKGAYCLSVSdfdnaKGLNVKHYKIRKLDSGG---FYITSR 74

                         90
                 ....*....|....*
gi 190036    605 LRFRRMYALIQHYRE 619
Cdd:cd10365   75 TQFNSLQQLVAYYSK 89

SH3_Sdc25

cd11883

Src Homology 3 domain of Sdc25/Cdc25 guanine nucleotide exchange factors; This subfamily is ...

773-823

3.96e-09

Src Homology 3 domain of Sdc25/Cdc25 guanine nucleotide exchange factors; This subfamily is composed of the Saccharomyces cerevisiae guanine nucleotide exchange factors (GEFs) Sdc25 and Cdc25, and similar proteins. These GEFs regulate Ras by stimulating the GDP/GTP exchange on Ras. Cdc25 is involved in the Ras/PKA pathway that plays an important role in the regulation of metabolism, stress responses, and proliferation, depending on available nutrients and conditions. Proteins in this subfamily contain an N-terminal SH3 domain as well as REM (Ras exchanger motif) and RasGEF domains at the C-terminus. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212816 Cd Length: 55 Bit Score: 53.82 E-value: 3.96e-09

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 190036    773 TVKALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKG---DYGTRIQQ-YFPSNY 823
Cdd:cd11883    1 VVVALYDFTPKSKNQLSFKAGDIIYVLNKDPSGWWDGviiSSSGKVKRgWFPSNY 55

SH2_SH2B_family

cd10346

Src homology 2 (SH2) domain found in SH2B adapter protein family; The SH2B adapter protein ...

532-623

4.85e-09

Src homology 2 (SH2) domain found in SH2B adapter protein family; The SH2B adapter protein family has 3 members: SH2B1 (SH2-B, PSM), SH2B2 (APS), and SH2B3 (Lnk). SH2B family members contain a pleckstrin homology domain, at least one dimerization domain, and a C-terminal SH2 domain which binds to phosphorylated tyrosines in a variety of tyrosine kinases. SH2B1 and SH2B2 function in signaling pathways found downstream of growth hormone receptor and receptor tyrosine kinases, including the insulin, insulin-like growth factor-I (IGF-I), platelet-derived growth factor (PDGF), nerve growth factor, hepatocyte growth factor, and fibroblast growth factor receptors. SH2B2beta, a new isoform of SH2B2, is an endogenous inhibitor of SH2B1 and/or SH2B2 (SH2B2alpha), negatively regulating insulin signaling and/or JAK2-mediated cellular responses. SH2B3 negatively regulates lymphopoiesis and early hematopoiesis. The lnk-deficiency results in enhanced production of B cells, and expansion as well as enhanced function of hematopoietic stem cells (HSCs), demonstrating negative regulatory functions of Sh2b3/Lnk in cytokine signaling. Sh2b3/Lnk also functions in responses controlled by cell adhesion and in crosstalk between integrin- and cytokine-mediated signaling. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198209 Cd Length: 97 Bit Score: 54.73 E-value: 4.85e-09

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    532 WFHKKVEKRTSAEKLLQeycmetGGKD--GTFLVRESETFPNDYTLSFWRSGRVQHCRIrSTMEGGTLKyylTDNLRFRR 609
Cdd:cd10346   10 WFHGTLSRSDAAQLVLH------SGADghGVFLVRQSETRRGEFVLTFNFQGRAKHLRL-TLNEKGQCR---VQHLWFPS 79

                         90
                 ....*....|....
gi 190036    610 MYALIQHYRETHLP 623
Cdd:cd10346   80 IFDMLEHFRQNPIP 93

SH3_CIN85_1

cd12052

First Src Homology 3 domain (SH3A) of Cbl-interacting protein of 85 kDa; CIN85, also called ...

778-826

4.87e-09

First Src Homology 3 domain (SH3A) of Cbl-interacting protein of 85 kDa; CIN85, also called SH3 domain-containing kinase-binding protein 1 (SH3KBP1) or CD2-binding protein 3 (CD2BP3) or Ruk, is an adaptor protein that is involved in the downregulation of receptor tyrosine kinases by facilitating endocytosis through interaction with endophilin-associated ubiquitin ligase Cbl proteins. It is also important in many other cellular processes including vesicle-mediated transport, cytoskeletal remodelling, apoptosis, cell adhesion and migration, and viral infection, among others. CIN85 exists as multiple variants from alternative splicing; the main variant contains three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. This alignment model represents the first SH3 domain (SH3A) of CIN85; SH3A binds to internal proline-rich motifs within the proline-rich region. This intramolecular interaction serves as a regulatory mechanism to keep CIN85 in a closed conformation, preventing the recruitment of other proteins. SH3A has also been shown to bind ubiquitin and to an atypical PXXXPR motif at the C-terminus of Cbl and the cytoplasmic end of the cell adhesion protein CD2. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212985 [Multi-domain] Cd Length: 53 Bit Score: 53.36 E-value: 4.87e-09

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*....
gi 190036    778 YDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRiQQYFPSNYVED 826
Cdd:cd12052    6 FDYKAQHEDELTITVGDIITKIKKDDGGWWEGEIKGR-RGLFPDNFVRE 53

SH2_Nterm_shark_like

cd10347

N-terminal Src homology 2 (SH2) domain found in SH2 domains, ANK, and kinase domain (shark) ...

646-720

4.92e-09

Pssm-ID: 198210 Cd Length: 81 Bit Score: 54.31 E-value: 4.92e-09

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 190036    646 WYYDSLSRGEAEDMLMRI-PRDGAFLIRK-REGSDSYAITFRARGKVKHCRINR--DGRHFVLGTSAYFESLVELVSYY 720
Cdd:cd10347    3 WYHGKISREVAEALLLREgGRDGLFLVREsTSAPGDYVLSLLAQGEVLHYQIRRhgEDAFFSDDGPLIFHGLDTLIEHY 81

SH3_Intersectin1_5

cd11995

Fifth Src homology 3 domain (or SH3E) of Intersectin-1; Intersectin-1 (ITSN1) is an adaptor ...

774-825

5.83e-09

Fifth Src homology 3 domain (or SH3E) of Intersectin-1; Intersectin-1 (ITSN1) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN1 localizes in membranous organelles, CCPs, the Golgi complex, and may be involved in the cell membrane trafficking system. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The fifth SH3 domain (or SH3E) of ITSN1 has been shown to bind many protein partners including SGIP1, Sos1, dynamin1/2, CIN85, c-Cbl, SHIP2, N-WASP, and synaptojanin-1, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212928 [Multi-domain] Cd Length: 54 Bit Score: 53.03 E-value: 5.83e-09

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 190036    774 VKALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRIqQYFPSNYVE 825
Cdd:cd11995    3 VIGMYDYTAQNDDELAFSKGQIINVLNKEDPDWWKGELNGQV-GLFPSNYVK 53

SH3_Intersectin2_5

cd11996

Fifth Src homology 3 domain (or SH3E) of Intersectin-2; Intersectin-2 (ITSN2) is an adaptor ...

774-825

7.17e-09

Fifth Src homology 3 domain (or SH3E) of Intersectin-2; Intersectin-2 (ITSN2) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN2 also functions as a specific GEF for Cdc42 activation in epithelial morphogenesis, and is required in mitotic spindle orientation. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The fifth SH3 domain (or SH3E) of ITSN2 is expected to bind protein partners, similar to ITSN1 which has been shown to bind many protein partners including SGIP1, Sos1, dynamin1/2, CIN85, c-Cbl, SHIP2, N-WASP, and synaptojanin-1, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212929 [Multi-domain] Cd Length: 54 Bit Score: 53.06 E-value: 7.17e-09

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 190036    774 VKALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTrIQQYFPSNYVE 825
Cdd:cd11996    3 VIAMYDYTANNEDELSFSKGQLINVLNKDDPDWWQGEING-VTGLFPSNYVK 53

SH3_Abp1_eu

cd11960

Src homology 3 domain of eumetazoan Actin-binding protein 1; Abp1, also called drebrin-like ...

773-825

7.79e-09

Src homology 3 domain of eumetazoan Actin-binding protein 1; Abp1, also called drebrin-like protein, is an adaptor protein that functions in receptor-mediated endocytosis and vesicle trafficking. It contains an N-terminal actin-binding module, the actin-depolymerizing factor (ADF) homology domain, a helical domain, and a C-terminal SH3 domain. Mammalian Abp1, unlike yeast Abp1, does not contain an acidic domain that interacts with the Arp2/3 complex. It regulates actin dynamics indirectly by interacting with dynamin and WASP family proteins. Abp1 deficiency causes abnormal organ structure and function of the spleen, heart, and lung of mice. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212893 [Multi-domain] Cd Length: 54 Bit Score: 52.79 E-value: 7.79e-09

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 190036    773 TVKALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRIQQYFPSNYVE 825
Cdd:cd11960    1 RARALYDYQAADDTEISFDPGDIITDIEQIDEGWWRGTGPDGTYGLFPANYVE 53

SH2_SHB_SHD_SHE_SHF_like

cd09945

Src homology 2 domain found in SH2 domain-containing adapter proteins B, D, E, and F (SHB, SHD, ...

532-623

8.23e-09

Pssm-ID: 198198 Cd Length: 98 Bit Score: 54.36 E-value: 8.23e-09

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    532 WFHKKVeKRTSAEKLLQeycmetGGKDGTFLVRESETFPNDYTLSFWRSGRVQHCRIRSTMEGgtlKYYLTDNLR-FRRM 610
Cdd:cd09945    3 WYHGAI-TRIEAESLLR------PCKEGSYLVRNSESTKQDYSLSLKSAKGFMHMRIQRNETG---QYILGQFSRpFETI 72

                         90
                 ....*....|...
gi 190036    611 YALIQHYRETHLP 623
Cdd:cd09945   73 PEMIRHYCLNKLP 85

SH2_Nck_family

cd09943

Src homology 2 (SH2) domain found in the Nck family; Nck proteins are adaptors that modulate ...

532-618

8.42e-09

Pssm-ID: 198196 Cd Length: 93 Bit Score: 54.06 E-value: 8.42e-09

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    532 WFHKKVeKRTSAEKLLQEYcmetgGKDGTFLVRESETFPNDYTLSFWRSGRVQHCRIRSTMeggtlKYYLTDNLRFRRMY 611
Cdd:cd09943    3 WYYGRI-TRHQAETLLNEH-----GHEGDFLIRDSESNPGDYSVSLKAPGRNKHFKVQVVD-----NVYCIGQRKFHTMD 71


                 ....*..
gi 190036    612 ALIQHYR 618
Cdd:cd09943   72 ELVEHYK 78

SH3_MLK

cd11876

Src Homology 3 domain of Mixed Lineage Kinases; MLKs are Serine/Threonine Kinases (STKs), ...

776-826

9.80e-09

Src Homology 3 domain of Mixed Lineage Kinases; MLKs are Serine/Threonine Kinases (STKs), catalyzing the transfer of the gamma-phosphoryl group from ATP to S/T residues on protein substrates. MLKs act as mitogen-activated protein kinase kinase kinases (MAP3Ks, MKKKs, MAPKKKs), which phosphorylate and activate MAPK kinases (MAPKKs or MKKs or MAP2Ks), which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals. MLKs play roles in immunity and inflammation, as well as in cell death, proliferation, and cell cycle regulation. Mammals have four MLKs (MLK1-4), mostly conserved in vertebrates, which contain an SH3 domain, a catalytic kinase domain, a leucine zipper, a proline-rich region, and a CRIB domain that mediates binding to GTP-bound Cdc42 and Rac. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212809 [Multi-domain] Cd Length: 58 Bit Score: 52.52 E-value: 9.80e-09

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 190036    776 ALYDYKAKRSDELSFCRGALIHNVSKEPG-----GWWKGDYGTRIqQYFPSNYVED 826
Cdd:cd11876    4 ALFDYDARGEDELTLRRGQPVEVLSKDAAvsgdeGWWTGKIGDKV-GIFPSNYVAP 58

SH2_Src_Lck

cd10362

Src homology 2 (SH2) domain in lymphocyte cell kinase (Lck); Lck is a member of the Src ...

530-617

1.05e-08

Src homology 2 (SH2) domain in lymphocyte cell kinase (Lck); Lck is a member of the Src non-receptor type tyrosine kinase family of proteins. It is expressed in the brain, T-cells, and NK cells. The unique domain of Lck mediates its interaction with two T-cell surface molecules, CD4 and CD8. It associates with their cytoplasmic tails on CD4 T helper cells and CD8 cytotoxic T cells to assist signaling from the T cell receptor (TCR) complex. When the T cell receptor is engaged by the specific antigen presented by MHC, Lck phosphorylase the intracellular chains of the CD3 and zeta-chains of the TCR complex, allowing ZAP-70 to bind them. Lck then phosphorylates and activates ZAP-70, which in turn phosphorylates Linker of Activated T cells (LAT), a transmembrane protein that serves as a docking site for proteins including: Shc-Grb2-SOS, PI3K, and phospholipase C (PLC). The tyrosine phosphorylation cascade culminates in the intracellular mobilization of a calcium ions and activation of important signaling cascades within the lymphocyte, including the Ras-MEK-ERK pathway, which goes on to activate certain transcription factors such as NFAT, NF-kappaB, and AP-1. These transcription factors regulate the production cytokines such as Interleukin-2 that promote long-term proliferation and differentiation of the activated lymphocytes. The N-terminal tail of Lck is myristoylated and palmitoylated and it tethers the protein to the plasma membrane of the cell. Lck also contains a SH3 domain, a SH2 domain, and a C-terminal tyrosine kinase domain. Lck has 2 phosphorylation sites, the first an autophosphorylation site that is linked to activation of the protein and the second which is phosphorylated by Csk, which inhibits it. Lck is also inhibited by SHP-1 dephosphorylation and by Cbl ubiquitin ligase, which is part of the ubiquitin-mediated pathway. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198225 Cd Length: 101 Bit Score: 54.11 E-value: 1.05e-08

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    530 EKWFHKKVEKRTSAEKLLQEycmetGGKDGTFLVRESETFPNDYTLSFW-----RSGRVQHCRIRSTMEGGtlkYYLTDN 604
Cdd:cd10362    3 EPWFFKNLSRNDAERQLLAP-----GNTHGSFLIRESETTAGSFSLSVRdfdqnQGEVVKHYKIRNLDNGG---FYISPR 74

                         90
                 ....*....|...
gi 190036    605 LRFRRMYALIQHY 617
Cdd:cd10362   75 ITFPGLHELVRHY 87

SH2_csk_like

cd09937

Src homology 2 (SH2) domain found in Carboxyl-Terminal Src Kinase (Csk); Both the C-terminal ...

645-722

1.06e-08

Pssm-ID: 198190 Cd Length: 98 Bit Score: 53.83 E-value: 1.06e-08

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    645 PWYYDSLSRGEAEDMLmRIPRDGAFLIRK--REGSDsYAITFRARGKVKHCRINRDGRHFVLGTSAYFESLVELVSYYEK 722
Cdd:cd09937    4 PWFHGKISREEAERLL-QPPEDGLFLVREstNYPGD-YTLCVSFEGKVEHYRVIYRNGKLTIDEEEYFENLIQLVEHYTK 81

SH3_CD2AP-like_3

cd11875

Third Src Homology 3 domain (SH3C) of CD2-associated protein and similar proteins; This ...

773-825

1.08e-08

Third Src Homology 3 domain (SH3C) of CD2-associated protein and similar proteins; This subfamily is composed of the third SH3 domain (SH3C) of CD2AP, CIN85 (Cbl-interacting protein of 85 kDa), and similar domains. CD2AP and CIN85 are adaptor proteins that bind to protein partners and assemble complexes that have been implicated in T cell activation, kidney function, and apoptosis of neuronal cells. They also associate with endocytic proteins, actin cytoskeleton components, and other adaptor proteins involved in receptor tyrosine kinase (RTK) signaling. CD2AP and the main isoform of CIN85 contain three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP and CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. SH3C of both proteins have been shown to bind to ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212808 [Multi-domain] Cd Length: 55 Bit Score: 52.35 E-value: 1.08e-08

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 190036    773 TVKALYDYKAKRSDELSFCRGALIHNVSKEPG--GWWKGDYGTRIqQYFPSNYVE 825
Cdd:cd11875    1 KARVLFDYEAENEDELTLREGDIVTILSKDCEdkGWWKGELNGKR-GVFPDNFVE 54

SH2_SOCS7

cd10388

Src homology 2 (SH2) domain found in suppressor of cytokine signaling (SOCS) proteins; SH2 ...

646-728

1.09e-08

Src homology 2 (SH2) domain found in suppressor of cytokine signaling (SOCS) proteins; SH2 domain found in SOCS proteins. SOCS was first recognized as a group of cytokine-inducible SH2 (CIS) domain proteins comprising eight family members in human (CIS and SOCS1-SOCS7). In addition to the SH2 domain, SOCS proteins have a variable N-terminal domain and a conserved SOCS box in the C-terminal domain. SOCS proteins bind to a substrate via their SH2 domain. The prototypical members, CIS and SOCS1-SOCS3, have been shown to regulate growth hormone signaling in vitro and in a classic negative feedback response compete for binding at phosphotyrosine sites in JAK kinase and receptor pathways to displace effector proteins and target bound receptors for proteasomal degradation. Loss of SOCS activity results in excessive cytokine signaling associated with a variety of hematopoietic, autoimmune, and inflammatory diseases and certain cancers. Members (SOCS4-SOCS7) were identified by their conserved SOCS box, an adapter motif of 3 helices that associates substrate binding domains, such as the SOCS SH2 domain, ankryin, and WD40 with ubiquitin ligase components. These show limited cytokine induction. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198251 Cd Length: 101 Bit Score: 53.90 E-value: 1.09e-08

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    646 WYYDSLSRGEAEDMLMRIPrDGAFLIRKREgSDSY--AITFRARGKVKHCRINRDGRHFVLGTSAYFE----SLVELVSY 719
Cdd:cd10388   12 WYWGPMSWEDAEKVLSNKP-DGSFLVRDSS-DDRYifSLSFRSQGSVHHTRIEQYQGTFSLGSRNKFVdrsqSLVEFIER 89


                 ....*....
gi 190036    720 YEKHSLYRK 728
Cdd:cd10388   90 AVEHSRSGR 98

SH2_Src_Src42

cd10370

Src homology 2 (SH2) domain found in the Src oncogene at 42A (Src42); Src42 is a member of the ...

642-724

1.16e-08

Pssm-ID: 198233 Cd Length: 96 Bit Score: 53.66 E-value: 1.16e-08

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    642 ESKPWYYDSLSRGEAEDMLMrIPRD--GAFLIRKREG-SDSYAITFRARGKVKHCRINR-DGRHFVLGTSAYFESLVELV 717
Cdd:cd10370    1 EAEPWYFGKIKRIEAEKKLL-LPENehGAFLIRDSESrHNDYSLSVRDGDTVKHYRIRQlDEGGFFIARRTTFRTLQELV 79


                 ....*..
gi 190036    718 SYYEKHS 724
Cdd:cd10370   80 EHYSKDS 86

SH3_PACSIN

cd11843

Src homology 3 domain of Protein kinase C and Casein kinase Substrate in Neurons (PACSIN) ...

774-825

1.23e-08

Src homology 3 domain of Protein kinase C and Casein kinase Substrate in Neurons (PACSIN) proteins; PACSINs, also called Synaptic dynamin-associated proteins (Syndapins), act as regulators of cytoskeletal and membrane dynamics. They bind both dynamin and Wiskott-Aldrich syndrome protein (WASP), and may provide direct links between the actin cytoskeletal machinery through WASP and dynamin-dependent endocytosis. Vetebrates harbor three isoforms with distinct expression patterns and specific functions. PACSINs contain an N-terminal F-BAR domain and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212777 [Multi-domain] Cd Length: 53 Bit Score: 52.04 E-value: 1.23e-08

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 190036    774 VKALYDYKAKRSDELSFCRGALIHNVSKEPG-GWWKGDYGTRIQQYfPSNYVE 825
Cdd:cd11843    2 VRALYDYEGQESDELSFKAGDILTKLEEEDEqGWCKGRLDGRVGLY-PANYVE 53

SH2_Nck2

cd10409

Src homology 2 (SH2) domain found in Nck; Nck proteins are adaptors that modulate actin ...

644-726

1.23e-08

Pssm-ID: 198272 Cd Length: 98 Bit Score: 53.89 E-value: 1.23e-08

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    644 KPWYYDSLSRGEAEDMLMRIPRDGAFLIRKREGSDS-YAITFRARGKVKHCRINRDGRHFVLGTSAyFESLVELVSYYEK 722
Cdd:cd10409    1 KEWYYGNVTRHQAECALNERGVEGDFLIRDSESSPSdFSVSLKAVGKNKHFKVQLVDNVYCIGQRR-FNSMDELVEHYKK 79


                 ....
gi 190036    723 HSLY 726
Cdd:cd10409   80 APIF 83

SH2_C-SH2_SHP_like

cd09931

C-terminal Src homology 2 (C-SH2) domain found in SH2 domain Phosphatases (SHP) proteins; The ...

646-725

1.28e-08

Pssm-ID: 198185 Cd Length: 99 Bit Score: 53.82 E-value: 1.28e-08

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    646 WYYDSLSRGEAEDMLMRIPRDGAFLIRKregSDS----YAITFRAR-GKVKHCRINRDGRHFVLGTSAYFESLVELVSYY 720
Cdd:cd09931    2 WFHGHLSGKEAEKLLLEKGKPGSFLVRE---SQSkpgdFVLSVRTDdDKVTHIMIRCQGGKYDVGGGEEFDSLTDLVEHY 78


                 ....*
gi 190036    721 EKHSL 725
Cdd:cd09931   79 KKNPM 83

SH3_Abi1

cd11971

Src homology 3 domain of Abl Interactor 1; Abi1, also called e3B1, is a central regulator of ...

774-827

1.39e-08

Src homology 3 domain of Abl Interactor 1; Abi1, also called e3B1, is a central regulator of actin cytoskeletal reorganization through interactions with many protein complexes. It is part of WAVE, a nucleation-promoting factor complex, that links Rac 1 activation to actin polymerization causing lamellipodia protrusion at the plasma membrane. Abi1 interact with formins to promote protrusions at the leading edge of motile cells. It also is a target of alpha4 integrin, regulating membrane protrusions at sites of integrin engagement. Abi proteins are adaptor proteins serving as binding partners and substrates of Abl tyrosine kinases. They are involved in regulating actin cytoskeletal reorganization and play important roles in membrane-ruffling, endocytosis, cell motility, and cell migration. Abi proteins contain a homeobox homology domain, a proline-rich region, and a SH3 domain. The SH3 domain of Abi binds to a PxxP motif in Abl. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212904 [Multi-domain] Cd Length: 59 Bit Score: 52.33 E-value: 1.39e-08

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....
gi 190036    774 VKALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGdYGTRIQQYFPSNYVEDI 827
Cdd:cd11971    2 VVAIYDYSKDKDDELSFMEGAIIYVIKKNDDGWYEG-VCNGVTGLFPGNYVESI 54

SH2_SHF

cd10392

Src homology 2 domain found in SH2 domain-containing adapter protein F (SHF); SHF is thought ...

646-735

1.45e-08

Src homology 2 domain found in SH2 domain-containing adapter protein F (SHF); SHF is thought to play a role in PDGF-receptor signaling and regulation of apoptosis. SHF is mainly expressed in skeletal muscle, brain, liver, prostate, testis, ovary, small intestine, and colon. SHF contains four putative tyrosine phosphorylation sites and an SH2 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198255 Cd Length: 98 Bit Score: 53.53 E-value: 1.45e-08

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    646 WYYDSLSRGEAEDmLMRIPRDGAFLIRKREGS-DSYAITFRARGKVKHCRINRDGRH-FVLG-TSAYFESLVELVSYYEK 722
Cdd:cd10392    3 WYHGAISRTDAEN-LLRLCKEASYLVRNSETSkNDFSLSLKSSQGFMHMKLSRTKEHkYVLGqNSPPFSSVPEIIHHYAS 81

                         90
                 ....*....|....*..
gi 190036    723 HSLYRK----MRLRYPV 735
Cdd:cd10392   82 RKLPIKgaehMSLLYPV 98

SH3_FCHSD2_2

cd11894

Second Src Homology 3 domain of FCH and double SH3 domains protein 2; FCHSD2 has a domain ...

774-826

1.51e-08

Second Src Homology 3 domain of FCH and double SH3 domains protein 2; FCHSD2 has a domain structure consisting of an N-terminal F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs), two SH3, and C-terminal proline-rich domains. It has only been characterized in silico and its function is unknown. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212827 Cd Length: 56 Bit Score: 52.25 E-value: 1.51e-08

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 190036    774 VKALYDYKAKRSDELSFCRGALIHNVSKE---PGGWWKGDYGTRIqQYFPSNYVED 826
Cdd:cd11894    2 VKALYDYEGQTDDELSFPEGAIIRILNKEnqdDDGFWEGEFNGRI-GVFPSVLVEE 56

SH2_Tec_Txk

cd10398

Src homology 2 (SH2) domain found in Tec protein, Txk; A member of the Tec protein tyrosine ...

642-735

1.69e-08

Src homology 2 (SH2) domain found in Tec protein, Txk; A member of the Tec protein tyrosine kinase Txk is expressed in thymus, spleen, lymph node, T lymphocytes, NK cells, mast cell lines, and myeloid cell line. Txk plays a role in TCR signal transduction, T cell development, and selection which is analogous to the function of Itk. Txk has been shown to interact with IFN-gamma. Unlike most of the Tec family members Txk lacks a PH domain. Instead Txk has a unique region containing a palmitoylated cysteine string which has a similar membrane tethering function as the PH domain. Txk also has a zinc-binding motif, a SH3 domain, a SH2 domain, and a protein kinase catalytic domain. The TH domain consists of a Zn2+-binding Btk motif and a proline-rich region. The Btk motif is found in Tec kinases, Ras GAP, and IGBP and crucial to the function of the PH domain. It is not present in Txk which is not surprising since it lacks a PH domain. The type 1 splice form of the Drosophila homolog also lacks both the PH domain and the Btk motif. The proline-rich regions are highly conserved for the most part with the exception of Bmx whose residues surrounding the PXXP motif are not conserved (TH-like) and Btk29A which is entirely unique with large numbers of glycine residues (TH-extended). Tec family members all lack a C-terminal tyrosine having an autoinhibitory function in its phosphorylated state. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198261 Cd Length: 106 Bit Score: 53.41 E-value: 1.69e-08

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    642 ESKPWYYDSLSRGEAEDMLMRIPRDGAFLIRKREGSDSYAITFRARGK------VKHCRINR-DGRHFVLGTSAYFESLV 714
Cdd:cd10398    4 EIYEWYHKNITRNQAERLLRQESKEGAFIVRDSRHLGSYTISVFTRARrsteasIKHYQIKKnDSGQWYVAERHLFQSIP 83

                         90       100
                 ....*....|....*....|.
gi 190036    715 ELVSYYEKHSLYRKMRLRYPV 735
Cdd:cd10398   84 ELIQYHQHNAAGLMSRLRYPV 104

SH3_GRB2_like_C

cd11805

C-terminal Src homology 3 domain of Growth factor receptor-bound protein 2 (GRB2) and related ...

774-825

1.85e-08

C-terminal Src homology 3 domain of Growth factor receptor-bound protein 2 (GRB2) and related proteins; This family includes the adaptor protein GRB2 and related proteins including Drosophila melanogaster Downstream of receptor kinase (DRK), Caenorhabditis elegans Sex muscle abnormal protein 5 (Sem-5), GRB2-related adaptor protein (GRAP), GRAP2, and similar proteins. Family members contain an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. GRB2/Sem-5/DRK is a critical signaling molecule that regulates the Ras pathway by linking tyrosine kinases to the Ras guanine nucleotide releasing protein Sos (son of sevenless), which converts Ras to the active GTP-bound state. GRAP2 plays an important role in T cell receptor (TCR) signaling by promoting the formation of the SLP-76:LAT complex, which couples the TCR to the Ras pathway. GRAP acts as a negative regulator of T cell receptor (TCR)-induced lymphocyte proliferation by downregulating the signaling to the Ras/ERK pathway. The C-terminal SH3 domains (SH3c) of GRB2 and GRAP2 have been shown to bind to classical PxxP motif ligands, as well as to non-classical motifs. GRB2 SH3c binds Gab2 (Grb2-associated binder 2) through epitopes containing RxxK motifs, while the SH3c of GRAP2 binds to the phosphatase-like protein HD-PTP via a RxxxxK motif. SH3 domains are protein interaction domains that typically bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212739 [Multi-domain] Cd Length: 53 Bit Score: 51.86 E-value: 1.85e-08

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 190036    774 VKALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRIqQYFPSNYVE 825
Cdd:cd11805    2 VQALYDFNPQEPGELEFRRGDIITVLDSSDPDWWKGELRGRV-GIFPANYVQ 52

SH2_SH2B3

cd10412

Src homology 2 (SH2) domain found in SH2B adapter proteins (SH2B1, SH2B2, SH2B3); SH2B3 (Lnk), ...

532-623

1.90e-08

Src homology 2 (SH2) domain found in SH2B adapter proteins (SH2B1, SH2B2, SH2B3); SH2B3 (Lnk), like other members of the SH2B adapter protein family, contains a pleckstrin homology domain, at least one dimerization domain, and a C-terminal SH2 domain which binds to phosphorylated tyrosines in a variety of tyrosine kinases. SH2B3 negatively regulates lymphopoiesis and early hematopoiesis. The lnk-deficiency results in enhanced production of B cells, and expansion as well as enhanced function of hematopoietic stem cells (HSCs), demonstrating negative regulatory functions of Sh2b3/Lnk in cytokine signaling. Sh2b3/Lnk also functions in responses controlled by cell adhesion and in crosstalk between integrin- and cytokine-mediated signaling. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198275 Cd Length: 97 Bit Score: 52.97 E-value: 1.90e-08

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    532 WFHKKVEkRTSAEKLLQEYCMETggkDGTFLVRESETFPNDYTLSFWRSGRVQHCRIRSTmEGGTLKyylTDNLRFRRMY 611
Cdd:cd10412   10 WFHGPIS-RVKAAQLVQLQGPDA---HGVFLVRQSETRRGEYVLTFNFQGRAKHLRLSLT-ERGQCR---VQHLHFPSVV 81

                         90
                 ....*....|..
gi 190036    612 ALIQHYRETHLP 623
Cdd:cd10412   82 DMLHHFQRSPIP 93

SH2_SH2D2A

cd10416

Src homology 2 domain found in the SH2 domain containing protein 2A (SH2D2A); SH2D2A contains ...

641-725

2.09e-08

Src homology 2 domain found in the SH2 domain containing protein 2A (SH2D2A); SH2D2A contains a single SH2 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198279 Cd Length: 102 Bit Score: 53.12 E-value: 2.09e-08

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    641 HESKP-WYYDSLSRGEAEDMLMRIPRdGAFLIRKREGSDSYAITFRARGKVKHCRIN--RDGRHFVLGTSAYFESLVELV 717
Cdd:cd10416    3 HGAAPaWFHGFITRREAERLLEPKPQ-GCYLVRFSESAVTFVLTYRSRTCCRHFLLAqlRDGRHVVLGEDSAHARLQDLL 81


                 ....*...
gi 190036    718 SYYEKHSL 725
Cdd:cd10416   82 LHYTAHPL 89

SH2_Grb2_like

cd09941

Src homology 2 domain found in Growth factor receptor-bound protein 2 (Grb2) and similar ...

532-621

2.10e-08

Pssm-ID: 199828 Cd Length: 95 Bit Score: 53.04 E-value: 2.10e-08

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    532 WFHKKVEkRTSAEKLLQEycmetGGKDGTFLVRESETFPNDYTLSFWRSGRVQHCRIRSTMEGgtlKYYLTDNlRFRRMY 611
Cdd:cd09941    5 WFHGKIS-RAEAEEILMN-----QRPDGAFLIRESESSPGDFSLSVKFGNDVQHFKVLRDGAG---KYFLWVV-KFNSLN 74

                         90
                 ....*....|
gi 190036    612 ALIQHYRETH 621
Cdd:cd09941   75 ELVDYHRTTS 84

SH3_Abp1_fungi_C2

cd11961

Second C-terminal Src homology 3 domain of Fungal Actin-binding protein 1; Abp1 is an adaptor ...

773-825

2.13e-08

Second C-terminal Src homology 3 domain of Fungal Actin-binding protein 1; Abp1 is an adaptor protein that functions in receptor-mediated endocytosis and vesicle trafficking. It contains an N-terminal actin-binding module, the actin-depolymerizing factor (ADF) homology domain, a central proline-rich region, and a C-terminal SH3 domain (many yeast Abp1 proteins contain two C-terminal SH3 domains). Yeast Abp1 also contains two acidic domains that bind directly to the Arp2/3 complex, which is required to initiate actin polymerization. The SH3 domain of yeast Abp1 binds and localizes the kinases, Ark1p and Prk1p, which facilitate actin patch disassembly following vesicle internalization. It also mediates the localization to the actin patch of the synaptojanin-like protein, Sjl2p, which plays a key role in endocytosis. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212894 [Multi-domain] Cd Length: 53 Bit Score: 51.37 E-value: 2.13e-08

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 190036    773 TVKALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRiQQYFPSNYVE 825
Cdd:cd11961    1 WAKALYDYDAAEDNELSFFENDKIINIEFVDDDWWLGECHGS-RGLFPSNYVE 52

SH2_Src_Yes

cd10366

Src homology 2 (SH2) domain found in Yes; Yes is a member of the Src non-receptor type ...

529-619

2.26e-08

Src homology 2 (SH2) domain found in Yes; Yes is a member of the Src non-receptor type tyrosine kinase family of proteins. Yes is the cellular homolog of the Yamaguchi sarcoma virus oncogene. In humans it is encoded by the YES1 gene which maps to chromosome 18 and is in close proximity to thymidylate synthase. A corresponding Yes pseudogene has been found on chromosome 22. YES1 has been shown to interact with Janus kinase 2, CTNND1,RPL10, and Occludin. Yes1 has a unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail, as do the other members of the family. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198229 Cd Length: 101 Bit Score: 53.10 E-value: 2.26e-08

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    529 GEKWFHKKVeKRTSAEKLLqeycMETGGKDGTFLVRESETFPNDYTLSF--W---RSGRVQHCRIRSTMEGGtlkYYLTD 603
Cdd:cd10366    2 AEEWYFGKM-GRKDAERLL----LNPGNQRGIFLVRESETTKGAYSLSIrdWdevRGDNVKHYKIRKLDNGG---YYITT 73

                         90
                 ....*....|....*.
gi 190036    604 NLRFRRMYALIQHYRE 619
Cdd:cd10366   74 RAQFDTLQKLVKHYTE 89

SH2_N-SH2_SHP_like

cd10340

N-terminal Src homology 2 (N-SH2) domain found in SH2 domain Phosphatases (SHP) proteins; The ...

646-735

2.64e-08

Pssm-ID: 198203 Cd Length: 99 Bit Score: 52.79 E-value: 2.64e-08

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    646 WYYDSLSRGEAEDMLMRIPRDGAFLIRKREGS-DSYAITFRARGKVKHCRINRDGRHFVLGTSAYFESLVELVSYY-EKH 723
Cdd:cd10340    2 WFHPVISGIEAENLLKTRGVDGSFLARPSKSNpGDFTLSVRRGDEVTHIKIQNTGDYYDLYGGEKFATLSELVQYYmEQH 81

                         90
                 ....*....|....*..
gi 190036    724 SLYRK-----MRLRYPV 735
Cdd:cd10340   82 GQLREkngdvIELKYPL 98

SH2_Tec_family

cd09934

Src homology 2 (SH2) domain found in Tec-like proteins; The Tec protein tyrosine kinase is the ...

532-618

3.21e-08

Pssm-ID: 198188 Cd Length: 104 Bit Score: 52.79 E-value: 3.21e-08

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    532 WFHKKVeKRTSAEKLLQEycmetGGKDGTFLVRESETfPNDYTLSFW----RSGRVQHCRIRSTMEGgtlKYYLTDNLRF 607
Cdd:cd09934    8 WYVGDM-SRQRAESLLKQ-----EDKEGCFVVRNSST-KGLYTVSLFtkvpGSPHVKHYHIKQNARS---EFYLAEKHCF 77

                         90
                 ....*....|.
gi 190036    608 RRMYALIQHYR 618
Cdd:cd09934   78 ETIPELINYHQ 88

SH2_Fps_family

cd10361

Src homology 2 (SH2) domain found in feline sarcoma, Fujinami poultry sarcoma, and fes-related ...

640-725

3.38e-08

Src homology 2 (SH2) domain found in feline sarcoma, Fujinami poultry sarcoma, and fes-related (Fes/Fps/Fer) proteins; The Fps family consists of members Fps/Fes and Fer/Flk/Tyk3. They are cytoplasmic protein-tyrosine kinases implicated in signaling downstream from cytokines, growth factors and immune receptors. Fes/Fps/Fer contains three coiled-coil regions, an SH2 (Src-homology-2) and a TK (tyrosine kinase catalytic) domain signature. Members here include: Fps/Fes, Fer, Kin-31, and In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198224 Cd Length: 90 Bit Score: 52.14 E-value: 3.38e-08

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    640 PHESKPWYYDSLSRGEAEDMLMRiprDGAFLIRKREGSD----SYAITFRARGKVKHCRINRD--GRHFVLGTSayFESL 713
Cdd:cd10361    2 DLENEPYYHGLLPREDAEELLKN---DGDFLVRKTEPKGggkrKLVLSVRWDGKIRHFVINRDdgGKYYIEGKS--FKSI 76

                         90
                 ....*....|..
gi 190036    714 VELVSYYEKHSL 725
Cdd:cd10361   77 SELINYYQKTKE 88

SH2_Tec_Btk

cd10397

Src homology 2 (SH2) domain found in Tec protein, Bruton's tyrosine kinase (Btk); A member of ...

639-736

3.41e-08

Src homology 2 (SH2) domain found in Tec protein, Bruton's tyrosine kinase (Btk); A member of the Tec protein tyrosine kinase Btk is expressed in bone marrow, spleen, all hematopoietic cells except T lymphocytes and plasma cells where it plays a crucial role in B cell maturation and mast cell activation. Btk has been shown to interact with GNAQ, PLCG2, protein kinase D1, B-cell linker, SH3BP5, caveolin 1, ARID3A, and GTF2I. Most of the Tec family members have a PH domain (Txk and the short (type 1) splice variant of Drosophila Btk29A are exceptions), a Tec homology (TH) domain, a SH3 domain, a SH2 domain, and a protein kinase catalytic domain. Btk is implicated in the primary immunodeficiency disease X-linked agammaglobulinemia (Bruton's agammaglobulinemia). The TH domain consists of a Zn2+-binding Btk motif and a proline-rich region. The Btk motif is found in Tec kinases, Ras GAP, and IGBP. It is crucial for the function of Tec PH domains and it's lack of presence in Txk is not surprising since it lacks a PH domain. The type 1 splice form of the Drosophila homolog also lacks both the PH domain and the Btk motif. The proline-rich regions are highly conserved for the most part with the exception of Bmx whose residues surrounding the PXXP motif are not conserved (TH-like) and Btk29A which is entirely unique with large numbers of glycine residues (TH-extended). Tec family members all lack a C-terminal tyrosine having an autoinhibitory function in its phosphorylated state. Two tyrosine phosphorylation (pY) sites have been identified in Btk: one located in the activation loop of the catalytic domain which regulates the transition between open (active) and closed (inactive) states and the other in its SH3 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198260 [Multi-domain] Cd Length: 106 Bit Score: 52.53 E-value: 3.41e-08

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    639 NPHESKPWYYDSLSRGEAEDMLMRIPRDGAFLIRKREGSDSYAITFRAR------GKVKHCRI-NRDGRHFVLGTSAYFE 711
Cdd:cd10397    1 DSLEMYEWYSKNMTRSQAEQLLKQEGKEGGFIVRDSSKAGKYTVSVFAKsagdpqGVIRHYVVcSTPQSQYYLAEKHLFS 80

                         90       100
                 ....*....|....*....|....*
gi 190036    712 SLVELVSYYEKHSLYRKMRLRYPVT 736
Cdd:cd10397   81 TIPELINYHQHNAAGLISRLKYPVS 105

SH2_Src_HCK

cd10363

Src homology 2 (SH2) domain found in HCK; HCK is a member of the Src non-receptor type ...

530-619

3.53e-08

Src homology 2 (SH2) domain found in HCK; HCK is a member of the Src non-receptor type tyrosine kinase family of proteins and is expressed in hemopoietic cells. HCK is proposed to couple the Fc receptor to the activation of the respiratory burst. It may also play a role in neutrophil migration and in the degranulation of neutrophils. It has two different translational starts that have different subcellular localization. HCK has been shown to interact with BCR gene, ELMO1 Cbl gene, RAS p21 protein activator 1, RASA3, Granulocyte colony-stimulating factor receptor, ADAM15 and RAPGEF1. Like the other members of the Src family the SH2 domain in addition to binding the target, also plays an autoinhibitory role by binding to its C-terminal tail. In general SH2 domains are involved in signal transduction. HCK has a unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail, as do the other members of the family. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198226 Cd Length: 104 Bit Score: 52.66 E-value: 3.53e-08

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    530 EKWFHKKVEKRTSAEKLLQeycmeTGGKDGTFLVRESETFPNDYTLSF-----WRSGRVQHCRIRSTMEGGtlkYYLTDN 604
Cdd:cd10363    3 EEWFFKGISRKDAERQLLA-----PGNMLGSFMIRDSETTKGSYSLSVrdydpQHGDTVKHYKIRTLDNGG---FYISPR 74

                         90
                 ....*....|....*
gi 190036    605 LRFRRMYALIQHYRE 619
Cdd:cd10363   75 STFSTLQELVDHYKK 89

SH2_Src_Frk

cd10369

Src homology 2 (SH2) domain found in the Fyn-related kinase (Frk); Frk is a member of the Src ...

530-620

4.05e-08

Pssm-ID: 199831 Cd Length: 96 Bit Score: 52.19 E-value: 4.05e-08

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    530 EKWFHKKVeKRTSAEKLLqeycMETGGKDGTFLVRESETFPNDYTLSFWRSGRVQHCRIRSTMEGGtlkYYLTDNLRFRR 609
Cdd:cd10369    3 EPWFFGAI-KRADAEKQL----LYSENQTGAFLIRESESQKGEFSLSVLDGGVVKHYRIRRLDEGG---FFLTRRKTFST 74

                         90
                 ....*....|.
gi 190036    610 MYALIQHYRET 620
Cdd:cd10369   75 LNEFVNYYTTT 85

SH2_Vav_family

cd09940

Src homology 2 (SH2) domain found in the Vav family; Vav proteins are involved in several ...

532-622

4.80e-08

Pssm-ID: 198193 Cd Length: 102 Bit Score: 51.91 E-value: 4.80e-08

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    532 WFHKKVEkRTSAEKLLqeycmeTGGKDGTFLVRESETFPNDYTLSFWRSGRVQHCRIRSTMEGgtlKYYLTDNLRFRRMY 611
Cdd:cd09940    7 WFVGEME-RDTAENRL------ENRPDGTYLVRVRPQGETQYALSIKYNGDVKHMKIEQRSDG---LYYLSESRHFKSLV 76

                         90
                 ....*....|.
gi 190036    612 ALIQHYRETHL 622
Cdd:cd09940   77 ELVNYYERNSL 87

SH2_C-SH2_Zap70

cd10402

C-terminal Src homology 2 (SH2) domain found in Zeta-chain-associated protein kinase 70 ...

641-719

5.19e-08

C-terminal Src homology 2 (SH2) domain found in Zeta-chain-associated protein kinase 70 (ZAP-70); ZAP-70 and Syk comprise a family of hematopoietic cell specific protein tyrosine kinases (PTKs) that are required for antigen and antibody receptor function. ZAP-70 is expressed in T and natural killer (NK) cells and Syk is expressed in B cells, mast cells, polymorphonuclear leukocytes, platelets, macrophages, and immature T cells. They are required for the proper development of T and B cells, immune receptors, and activating NK cells. They consist of two N-terminal Src homology 2 (SH2) domains and a C-terminal kinase domain separated from the SH2 domains by a linker or hinge region. Phosphorylation of both tyrosine residues within the Immunoreceptor Tyrosine-based Activation Motifs (ITAM; consensus sequence Yxx[LI]x(7,8)Yxx[LI]) by the Src-family PTKs is required for efficient interaction of ZAP-70 and Syk with the receptor subunits and for receptor function. ZAP-70 forms two phosphotyrosine binding pockets, one of which is shared by both SH2 domains. In Syk the two SH2 domains do not form such a phosphotyrosine-binding site. The SH2 domains here are believed to function independently. In addition, the two SH2 domains of Syk display flexibility in their relative orientation, allowing Syk to accommodate a greater variety of spacing sequences between the ITAM phosphotyrosines and singly phosphorylated non-classical ITAM ligands. This model contains the C-terminus SH2 domains of Zap70. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198265 Cd Length: 105 Bit Score: 52.23 E-value: 5.19e-08

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    641 HESKPWYYDSLSRGEAEDMLMRIPR-DGAFLIRKREGSDSYAITFRARGKVKHCRINRDGR-HFVLGTSAYFESLVELVS 718
Cdd:cd10402    7 HERMPWYHGSIARDEAERRLYSGAQpDGKFLLRERKESGTYALSLVYGKTVYHYRIDQDKSgKYSIPEGTKFDTLWQLVE 86


                 .
gi 190036    719 Y 719
Cdd:cd10402   87 Y 87

SH3_Intersectin_4

cd11839

Fourth Src homology 3 domain (or SH3D) of Intersectin; Intersectins (ITSNs) are adaptor ...

775-825

5.79e-08

Fourth Src homology 3 domain (or SH3D) of Intersectin; Intersectins (ITSNs) are adaptor proteins that function in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. They are essential for initiating clathrin-coated pit formation. They bind to many proteins through their multidomain structure and facilitate the assembly of multimeric complexes. Vertebrates contain two ITSN proteins, ITSN1 and ITSN2, which exist in alternatively spliced short and long isoforms. The short isoforms contain two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoforms, in addition, contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. ITSN1 and ITSN2 are both widely expressed, with variations depending on tissue type and stage of development. The fourth SH3 domain (or SH3D) of ITSN1 has been shown to bind SHIP2, Numb, CdGAP, and N-WASP. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212773 [Multi-domain] Cd Length: 58 Bit Score: 50.41 E-value: 5.79e-08

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 190036    775 KALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRIQQ----YFPSNYVE 825
Cdd:cd11839    3 QVIAPFTATAENQLSLAVGQLVLVRKKSPSGWWEGELQARGKKrqigWFPANYVK 57

SH2_cSH2_p85_like

cd09930

C-terminal Src homology 2 (cSH2) domain found in p85; Phosphoinositide 3-kinases (PI3Ks) are ...

527-622

5.81e-08

Pssm-ID: 198184 Cd Length: 104 Bit Score: 52.03 E-value: 5.81e-08

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    527 HFGEK-WFHKKVeKRTSAEKLLQeycmetGGKDGTFLVRESETfPNDYTLSFWRSGRVQHCRIRSTMEGGTLK--YYLTD 603
Cdd:cd09930    2 HHDERtWLVGDI-NRTQAEELLR------GKPDGTFLIRESST-QGCYACSVVCNGEVKHCVIYKTETGYGFAepYNLYE 73

                         90
                 ....*....|....*....
gi 190036    604 NLRfrrmyALIQHYRETHL 622
Cdd:cd09930   74 SLK-----ELVLHYAHNSL 87

SH3_Cortactin

cd11959

Src homology 3 domain of Cortactin; Cortactin was originally identified as a substrate of Src ...

773-825

6.40e-08

Src homology 3 domain of Cortactin; Cortactin was originally identified as a substrate of Src kinase. It is an actin regulatory protein that binds to the Arp2/3 complex and stabilizes branched actin filaments. It is involved in cellular processes that affect cell motility, adhesion, migration, endocytosis, and invasion. It is expressed ubiquitously except in hematopoietic cells, where the homolog hematopoietic lineage cell-specific 1 (HS1) is expressed instead. Cortactin contains an N-terminal acidic domain, several copies of a repeat domain found in cortactin and HS1, a proline-rich region, and a C-terminal SH3 domain. The N-terminal region interacts with the Arp2/3 complex and F-actin, and is crucial in regulating branched actin assembly. Cortactin also serves as a scaffold and provides a bridge to the actin cytoskeleton for membrane trafficking and signaling proteins that bind to its SH3 domain. Binding partners for the SH3 domain of cortactin include dynamin2, N-WASp, MIM, FGD1, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212892 [Multi-domain] Cd Length: 53 Bit Score: 50.11 E-value: 6.40e-08

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 190036    773 TVKALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRIqQYFPSNYVE 825
Cdd:cd11959    1 TAVALYDYQAADDDEISFDPDDIITNIEMIDEGWWRGVCRGKY-GLFPANYVE 52

SH3_Nck1_2

cd11901

Second Src Homology 3 domain of Nck1 adaptor protein; Nck1 (also called Nckalpha) plays a ...

778-826

6.94e-08

Second Src Homology 3 domain of Nck1 adaptor protein; Nck1 (also called Nckalpha) plays a crucial role in connecting signaling pathways of tyrosine kinase receptors and important effectors in actin dynamics and cytoskeletal remodeling. It binds and activates RasGAP, resulting in the downregulation of Ras. It is also involved in the signaling of endothilin-mediated inhibition of cell migration. Nck adaptor proteins regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates. They contain three SH3 domains and a C-terminal SH2 domain. They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics. Vertebrates contain two Nck adaptor proteins: Nck1 (also called Nckalpha) and Nck2, which show partly overlapping functions but also bind distinct targets. The second SH3 domain of Nck appears to prefer ligands containing the APxxPxR motif. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity, preferentially a PxxP motif. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212834 [Multi-domain] Cd Length: 55 Bit Score: 50.03 E-value: 6.94e-08

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*....
gi 190036    778 YDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRIqQYFPSNYVED 826
Cdd:cd11901    8 FNYTAEREDELSLVKGTKVIVMEKCSDGWWRGSYNGQV-GWFPSNYVTE 55

SH2_SOCS6

cd10387

Src homology 2 (SH2) domain found in suppressor of cytokine signaling (SOCS) proteins; SH2 ...

646-717

7.08e-08

Pssm-ID: 198250 Cd Length: 100 Bit Score: 51.76 E-value: 7.08e-08

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 190036    646 WYYDSLSRGEAEDMLMRIPrDGAFLIRKrEGSDSY--AITFRARGKVKHCRINRDGRHFVL---GTSAYFESLVELV 717
Cdd:cd10387   12 WYWGPITRWEAEGKLANVP-DGSFLVRD-SSDDRYllSLSFRSHGKTLHTRIEHSNGRFSFyeqPDVEGHTSIVDLI 86

SH3_MLK4

cd12058

Src Homology 3 domain of Mixed Lineage Kinase 4; MLK4 is a Serine/Threonine Kinase (STK), ...

776-824

8.17e-08

Src Homology 3 domain of Mixed Lineage Kinase 4; MLK4 is a Serine/Threonine Kinase (STK), catalyzing the transfer of the gamma-phosphoryl group from ATP to S/T residues on protein substrates. MLKs act as mitogen-activated protein kinase kinase kinases (MAP3Ks, MKKKs, MAPKKKs), which phosphorylate and activate MAPK kinases (MAPKKs or MKKs or MAP2Ks), which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals. MLKs play roles in immunity and inflammation, as well as in cell death, proliferation, and cell cycle regulation. The specific function of MLK4 is yet to be determined. Mutations in the kinase domain of MLK4 have been detected in colorectal cancers. MLK4 contains an SH3 domain, a catalytic kinase domain, a leucine zipper, a proline-rich region, and a CRIB domain that mediates binding to GTP-bound Cdc42 and Rac. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212991 [Multi-domain] Cd Length: 58 Bit Score: 49.94 E-value: 8.17e-08

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....
gi 190036    776 ALYDYKAKRSDELSFCRGALIHNVSKEPG-----GWWKGDYGTRIqQYFPSNYV 824
Cdd:cd12058    4 ALYDYEASGEDELSLRRGDVVEVLSQDAAvsgddGWWAGKIRHRL-GIFPANYV 56

SH2_SHF

cd10392

Src homology 2 domain found in SH2 domain-containing adapter protein F (SHF); SHF is thought ...

532-635

8.38e-08

Pssm-ID: 198255 Cd Length: 98 Bit Score: 51.22 E-value: 8.38e-08

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    532 WFHKKVEkRTSAEKLLQeYCmetggKDGTFLVRESETFPNDYTLSFWRSGRVQHCRIRSTMEGgtlKYYLTDN-LRFRRM 610
Cdd:cd10392    3 WYHGAIS-RTDAENLLR-LC-----KEASYLVRNSETSKNDFSLSLKSSQGFMHMKLSRTKEH---KYVLGQNsPPFSSV 72

                         90       100
                 ....*....|....*....|....*.
gi 190036    611 YALIQHYRETHLPCAEFE-LRLTDPV 635
Cdd:cd10392   73 PEIIHHYASRKLPIKGAEhMSLLYPV 98

SH3_Abi2

cd11972

Src homology 3 domain of Abl Interactor 2; Abi2 is highly expressed in the brain and eye. It ...

774-828

8.93e-08

Src homology 3 domain of Abl Interactor 2; Abi2 is highly expressed in the brain and eye. It regulates actin cytoskeletal reorganization at adherens junctions and dendritic spines, which is important in cell morphogenesis, migration, and cognitive function. Mice deficient with Abi2 show defects in orientation and migration of lens fibers, neuronal migration, dendritic spine morphology, as well as deficits in learning and memory. Abi proteins are adaptor proteins serving as binding partners and substrates of Abl tyrosine kinases. They are involved in regulating actin cytoskeletal reorganization and play important roles in membrane-ruffling, endocytosis, cell motility, and cell migration. Abi proteins contain a homeobox homology domain, a proline-rich region, and a SH3 domain. The SH3 domain of Abi binds to a PxxP motif in Abl. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212905 [Multi-domain] Cd Length: 61 Bit Score: 50.01 E-value: 8.93e-08

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 190036    774 VKALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTrIQQYFPSNYVEDIS 828
Cdd:cd11972    5 VVAIYDYTKDKEDELSFQEGAIIYVIKKNDDGWYEGVMNG-VTGLFPGNYVESIM 58

SH3_Nebulin_family_C

cd11789

C-terminal Src Homology 3 domain of the Nebulin family of proteins; Nebulin family proteins ...

773-825

1.01e-07

C-terminal Src Homology 3 domain of the Nebulin family of proteins; Nebulin family proteins contain multiple nebulin repeats, and may contain an N-terminal LIM domain and/or a C-terminal SH3 domain. They have molecular weights ranging from 34 to 900 kD, depending on the number of nebulin repeats, and they all bind actin. They are involved in the regulation of actin filament architecture and function as stabilizers and scaffolds for cytoskeletal structures with which they associate, such as long actin filaments or focal adhesions. Nebulin family proteins that contain a C-terminal SH3 domain include the giant filamentous protein nebulin, nebulette, Lasp1, and Lasp2. Lasp2, also called LIM-nebulette, is an alternatively spliced variant of nebulette. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212723 [Multi-domain] Cd Length: 55 Bit Score: 49.62 E-value: 1.01e-07

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 190036    773 TVKALYDYKAKRSDELSFCRGALIHNVSKEPGGWWkgdYGT--RIQQY--FPSNYVE 825
Cdd:cd11789    1 RYRAMYDYAAADDDEVSFQEGDVIINVEIIDDGWM---EGTvqRTGQSgmLPANYVE 54

SH2_C-SH2_Syk_like

cd10401

C-terminal Src homology 2 (SH2) domain found in Spleen tyrosine kinase (Syk) proteins; ZAP-70 ...

642-720

1.06e-07

C-terminal Src homology 2 (SH2) domain found in Spleen tyrosine kinase (Syk) proteins; ZAP-70 and Syk comprise a family of hematopoietic cell specific protein tyrosine kinases (PTKs) that are required for antigen and antibody receptor function. ZAP-70 is expressed in T and natural killer (NK) cells and Syk is expressed in B cells, mast cells, polymorphonuclear leukocytes, platelets, macrophages, and immature T cells. They are required for the proper development of T and B cells, immune receptors, and activating NK cells. They consist of two N-terminal Src homology 2 (SH2) domains and a C-terminal kinase domain separated from the SH2 domains by a linker or hinge region. Phosphorylation of both tyrosine residues within the Immunoreceptor Tyrosine-based Activation Motifs (ITAM; consensus sequence Yxx[LI]x(7,8)Yxx[LI]) by the Src-family PTKs is required for efficient interaction of ZAP-70 and Syk with the receptor subunits and for receptor function. ZAP-70 forms two phosphotyrosine binding pockets, one of which is shared by both SH2 domains. In Syk the two SH2 domains do not form such a phosphotyrosine-binding site. The SH2 domains here are believed to function independently. In addition, the two SH2 domains of Syk display flexibility in their relative orientation, allowing Syk to accommodate a greater variety of spacing sequences between the ITAM phosphotyrosines and singly phosphorylated non-classical ITAM ligands. This model contains the C-terminus SH2 domains of Syk. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198264 Cd Length: 99 Bit Score: 51.05 E-value: 1.06e-07

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    642 ESKPWYYDSLSRGEAEDMLMRIPR-DGAFLIRKREGSDSYAITFRARGKVKHCRINRD--GRhFVLGTSAYFESLVELVS 718
Cdd:cd10401    1 EKMPWFHGKISREESEQILLIGSKtNGKFLIRERDNNGSYALCLLHDGKVLHYRIDKDktGK-LSIPDGKKFDTLWQLVE 79


                 ..
gi 190036    719 YY 720
Cdd:cd10401   80 HY 81

SH2_Src_Src

cd10365

Src homology 2 (SH2) domain found in tyrosine kinase sarcoma (Src); Src is a member of the Src ...

642-724

1.34e-07

Pssm-ID: 198228 Cd Length: 101 Bit Score: 50.82 E-value: 1.34e-07

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    642 ESKPWYYDSLSRGEAEDMLMRIP-RDGAFLIRKREGSD-SYAITF----RARG-KVKHCRINR-DGRHFVLGTSAYFESL 713
Cdd:cd10365    1 QAEEWYFGKITRRESERLLLNAEnPRGTFLVRESETTKgAYCLSVsdfdNAKGlNVKHYKIRKlDSGGFYITSRTQFNSL 80

                         90
                 ....*....|.
gi 190036    714 VELVSYYEKHS 724
Cdd:cd10365   81 QQLVAYYSKHA 91

SH2_PTK6_Brk

cd10358

Src homology 2 domain found in protein-tyrosine kinase-6 (PTK6) which is also known as breast ...

643-734

1.41e-07

Src homology 2 domain found in protein-tyrosine kinase-6 (PTK6) which is also known as breast tumor kinase (Brk); Human protein-tyrosine kinase-6 (PTK6, also known as breast tumor kinase (Brk)) is a member of the non-receptor protein-tyrosine kinase family and is expressed in two-thirds of all breast tumors. PTK6 (9). PTK6 contains a SH3 domain, a SH2 domain, and catalytic domains. For the case of the non-receptor protein-tyrosine kinases, the SH2 domain is typically involved in negative regulation of kinase activity by binding to a phosphorylated tyrosine residue near to the C terminus. The C-terminal sequence of PTK6 (PTSpYENPT where pY is phosphotyrosine) is thought to be a self-ligand for the SH2 domain. The structure of the SH2 domain resembles other SH2 domains except for a centrally located four-stranded antiparallel beta-sheet (strands betaA, betaB, betaC, and betaD). There are also differences in the loop length which might be responsible for PTK6 ligand specificity. There are two possible means of regulation of PTK6: autoinhibitory with the phosphorylation of Tyr playing a role in its negative regulation and autophosphorylation at this site, though it has been shown that PTK6 might phosphorylate signal transduction-associated proteins Sam68 and signal transducing adaptor family member 2 (STAP/BKS) in vivo. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198221 Cd Length: 100 Bit Score: 50.90 E-value: 1.41e-07

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    643 SKPWYYDSLSRGEAEDMLM-RIPRDGAFLIR--KREGSDsYAITFRARGKVKHCRI--NRDGRhFVLGTSAYFESLVELV 717
Cdd:cd10358    1 SEPWFFGCISRSEAVRRLQaEGNATGAFLIRvsEKPSAD-YVLSVRDTQAVRHYKIwrRAGGR-LHLNEAVSFLSLPELV 78

                         90
                 ....*....|....*..
gi 190036    718 SYYEKHSLYRKMRLRYP 734
Cdd:cd10358   79 NYHRAQSLSHGLRLAAP 95

SH3_STAM

cd11820

Src homology 3 domain of Signal Transducing Adaptor Molecules; STAMs were discovered as ...

772-824

1.49e-07

Src homology 3 domain of Signal Transducing Adaptor Molecules; STAMs were discovered as proteins that are highly phosphorylated following cytokine and growth factor stimulation. They function in cytokine signaling and surface receptor degradation, as well as regulate Golgi morphology. They associate with many proteins including Jak2 and Jak3 tyrosine kinases, Hrs, AMSH, and UBPY. STAM adaptor proteins contain VHS (Vps27, Hrs, STAM homology), ubiquitin interacting (UIM), and SH3 domains. There are two vertebrate STAMs, STAM1 and STAM2, which may be functionally redundant; vertebrate STAMs contain ITAM motifs. They are part of the endosomal sorting complex required for transport (ESCRT-0). STAM2 deficiency in mice did not cause any obvious abnormality, while STAM1 deficiency resulted in growth retardation. Loss of both STAM1 and STAM2 in mice proved lethal, indicating that STAMs are important for embryonic development. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212754 [Multi-domain] Cd Length: 54 Bit Score: 49.00 E-value: 1.49e-07

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 190036    772 RTVKALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGdYGTRIQQYFPSNYV 824
Cdd:cd11820    1 RKVRALYDFEAAEDNELTFKAGEIITVLDDSDPNWWKG-SNHRGEGLFPANFV 52

SH2_Nterm_RasGAP

cd10353

N-terminal Src homology 2 (SH2) domain found in Ras GTPase-activating protein 1 (GAP); RasGAP ...

514-624

1.62e-07

N-terminal Src homology 2 (SH2) domain found in Ras GTPase-activating protein 1 (GAP); RasGAP is part of the GAP1 family of GTPase-activating proteins. The protein is located in the cytoplasm and stimulates the GTPase activity of normal RAS p21, but not its oncogenic counterpart. Acting as a suppressor of RAS function, the protein enhances the weak intrinsic GTPase activity of RAS proteins resulting in RAS inactivation, thereby allowing control of cellular proliferation and differentiation. Mutations leading to changes in the binding sites of either protein are associated with basal cell carcinomas. Alternative splicing results in two isoforms. The shorter isoform which lacks the N-terminal hydrophobic region, has the same activity, and is expressed in placental tissues. In general the longer isoform contains 2 SH2 domains, a SH3 domain, a pleckstrin homology (PH) domain, and a calcium-dependent phospholipid-binding C2 domain. The C-terminus contains the catalytic domain of RasGap which catalyzes the activation of Ras by hydrolyzing GTP-bound active Ras into an inactive GDP-bound form of Ras. This model contains the N-terminal SH2 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198216 Cd Length: 103 Bit Score: 50.60 E-value: 1.62e-07

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    514 EEEVPQDIPPTElhfgeKWFHKKVEkRTSAEKLLQEycmetGGKDGTFLVRESETFPNDYTLSFWRSGRVQHCRIrSTME 593
Cdd:cd10353    8 EVAIPLTAPPTN-----QWYHGRLD-RTIAEERLRQ-----AGKLGSYLIRESDRRPGSFVLSFLSRTGVNHFRI-IAMC 75

                         90       100       110
                 ....*....|....*....|....*....|.
gi 190036    594 GgtlKYYLTDNlRFRRMYALIQHYreTHLPC 624
Cdd:cd10353   76 G---DYYIGGR-RFSSLSDLIGYY--SHVSC 100

SH2_Tec_Bmx

cd10399

Src homology 2 (SH2) domain found in Tec protein, Bmx; A member of the Tec protein tyrosine ...

646-736

1.70e-07

Src homology 2 (SH2) domain found in Tec protein, Bmx; A member of the Tec protein tyrosine kinase Bmx is expressed in the endothelium of large arteries, fetal endocardium, adult endocardium of the left ventricle, bone marrow, lung, testis, granulocytes, myeloid cell lines, and prostate cell lines. Bmx is involved in the regulation of Rho and serum response factor (SRF). Bmx has been shown to interact with PAK1, PTK2, PTPN21, and RUFY1. Most of the Tec family members have a PH domain (Txk and the short (type 1) splice variant of Drosophila Btk29A are exceptions), a Tec homology (TH) domain, a SH3 domain, a SH2 domain, and a protein kinase catalytic domain. The TH domain consists of a Zn2+-binding Btk motif and a proline-rich region. The Btk motif is found in Tec kinases, Ras GAP, and IGBP. It is crucial for the function of Tec PH domains. It is not present in Txk and the type 1 splice form of the Drosophila homolog. The proline-rich regions are highly conserved for the most part with the exception of Bmx whose residues surrounding the PXXP motif are not conserved (TH-like) and Btk29A which is entirely unique with large numbers of glycine residues (TH-extended). Tec family members all lack a C-terminal tyrosine having an autoinhibitory function in its phosphorylated state. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198262 Cd Length: 106 Bit Score: 50.72 E-value: 1.70e-07

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    646 WYYDSLSRGEAEDMLMRIPRDGAFLIRKREGSDSYAITFRA------RGKVKHCRINRDGRH-FVLGTSAYFESLVELVS 718
Cdd:cd10399    8 WFAGNISRSQSEQLLRQKGKEGAFMVRNSSQVGMYTVSLFSkavndkKGTVKHYHVHTNAENkLYLAENYCFDSIPKLIH 87

                         90
                 ....*....|....*...
gi 190036    719 YYEKHSLYRKMRLRYPVT 736
Cdd:cd10399   88 YHQHNSAGMITRLRHPVS 105

SH3_STAM2

cd11963

Src homology 3 domain of Signal Transducing Adaptor Molecule 2; STAM2, also called EAST ...

772-824

1.93e-07

Src homology 3 domain of Signal Transducing Adaptor Molecule 2; STAM2, also called EAST (Epidermal growth factor receptor-associated protein with SH3 and TAM domain) or Hbp (Hrs binding protein), is part of the endosomal sorting complex required for transport (ESCRT-0). It plays a role in sorting mono-ubiquinated endosomal cargo for trafficking to the lysosome for degradation. It is also involved in the regulation of exocytosis. STAMs were discovered as proteins that are highly phosphorylated following cytokine and growth factor stimulation. They function in cytokine signaling and surface receptor degradation, as well as regulate Golgi morphology. They associate with many proteins including Jak2 and Jak3 tyrosine kinases, Hrs, AMSH, and UBPY. STAM adaptor proteins contain VHS (Vps27, Hrs, STAM homology), ubiquitin interacting (UIM), and SH3 domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212896 [Multi-domain] Cd Length: 57 Bit Score: 48.86 E-value: 1.93e-07

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 190036    772 RTVKALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDyGTRIQQYFPSNYV 824
Cdd:cd11963    2 RKVRALYDFEAVEDNELTFKHGEIIIVLDDSDANWWKGE-NHRGVGLFPSNFV 53

SH2_SHE

cd10391

Src homology 2 domain found in SH2 domain-containing adapter protein E (SHE); SHE is expressed ...

644-735

1.98e-07

Src homology 2 domain found in SH2 domain-containing adapter protein E (SHE); SHE is expressed in heart, lung, brain, and skeletal muscle. SHE contains two pTry protein binding domains, protein interaction domain (PID) and a SH2 domain, followed by a glycine-proline rich region, all of which are N-terminal to the phosphotyrosine binding (PTB) domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198254 Cd Length: 98 Bit Score: 50.34 E-value: 1.98e-07

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    644 KPWYYDSLSRGEAEDMLMRIpRDGAFLIRKRE-GSDSYAITFRARGKVKHCRI--NRDGRHFVLGTSAYFESLVELVSYY 720
Cdd:cd10391    1 QPWYHGSISRAEAESRLQPC-KEASYLVRNSEsGNSKYSIALKTSQGCVHIIVaqTKDNKYTLNQTSAVFDSIPEVVHYY 79

                         90
                 ....*....|....*....
gi 190036    721 EKHSLYRK----MRLRYPV 735
Cdd:cd10391   80 SNEKLPFKgaehMTLLHPV 98

SH2_Src_HCK

cd10363

Src homology 2 (SH2) domain found in HCK; HCK is a member of the Src non-receptor type ...

642-734

1.99e-07

Pssm-ID: 198226 Cd Length: 104 Bit Score: 50.35 E-value: 1.99e-07

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    642 ESKPWYYDSLSRGEAEDMLMRiPRD--GAFLIRKREGSD-SYAITFR-----ARGKVKHCRINR-DGRHFVLGTSAYFES 712
Cdd:cd10363    1 ETEEWFFKGISRKDAERQLLA-PGNmlGSFMIRDSETTKgSYSLSVRdydpqHGDTVKHYKIRTlDNGGFYISPRSTFST 79

                         90       100
                 ....*....|....*....|..
gi 190036    713 LVELVSYYEKHSLYRKMRLRYP 734
Cdd:cd10363   80 LQELVDHYKKGNDGLCQKLSVP 101

SH3_FCHSD1_2

cd11895

Second Src Homology 3 domain of FCH and double SH3 domains protein 1; FCHSD1 has a domain ...

774-827

2.00e-07

Second Src Homology 3 domain of FCH and double SH3 domains protein 1; FCHSD1 has a domain structure consisting of an N-terminal F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs), two SH3, and C-terminal proline-rich domains. It has only been characterized in silico and its function is unknown. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212828 Cd Length: 58 Bit Score: 48.81 E-value: 2.00e-07

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 190036    774 VKALYDYKAKRSDELSFCRGALIHNVSK-EPG---GWWKGDYGTRIqQYFPSNYVEDI 827
Cdd:cd11895    2 ARALYSYTGQSPEELSFPEGALIRLLPRaQDGvddGFWRGEFGGRV-GVFPSLLVEEL 58

SH3_VAV1_2

cd11976

C-terminal (or second) Src homology 3 domain of VAV1 protein; VAV1 is expressed predominantly ...

773-826

3.08e-07

C-terminal (or second) Src homology 3 domain of VAV1 protein; VAV1 is expressed predominantly in the hematopoietic system and it plays an important role in the development and activation of B and T cells. It is activated by tyrosine phosphorylation to function as a guanine nucleotide exchange factor (GEF) for Rho GTPases following cell surface receptor activation, triggering various effects such as cytoskeletal reorganization, transcription regulation, cell cycle progression, and calcium mobilization. It also serves as a scaffold protein and has been shown to interact with Ku70, Socs1, Janus kinase 2, SIAH2, S100B, Abl gene, ZAP-70, SLP76, and Syk, among others. VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. The C-terminal SH3 domain of Vav1 interacts with a wide variety of proteins including cytoskeletal regulators (zyxin), RNA-binding proteins (Sam68), transcriptional regulators, viral proteins, and dynamin 2. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212909 [Multi-domain] Cd Length: 54 Bit Score: 48.40 E-value: 3.08e-07

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 190036    773 TVKALYDYKAKRSDELSFCRGALIHNVSKE-PGGWWKGDYGTRIqQYFPSNYVED 826
Cdd:cd11976    1 TAKARYDFCARDRSELSLKEGDIIKILNKKgQQGWWRGEIYGRV-GWFPANYVEE 54

SH2_Vav1

cd10405

Src homology 2 (SH2) domain found in the Vav1 proteins; Proto-oncogene vav is a member of the ...

646-725

3.09e-07

Src homology 2 (SH2) domain found in the Vav1 proteins; Proto-oncogene vav is a member of the Dbl family of guanine nucleotide exchange factors (GEF) for the Rho family of GTP binding proteins. All vavs are activated by tyrosine phosphorylation leading to their activation. There are three Vav mammalian family members: Vav1 which is expressed in the hematopoietic system, and Vav2 and Vav3 are more ubiquitously expressed. Vav1 plays a role in T-cell and B-cell development and activation. It has been identified as the specific binding partner of Nef proteins from HIV-1, resulting in morphological changes, cytoskeletal rearrangements, and the JNK/SAPK signaling cascade, leading to increased levels of viral transcription and replication. Vav1 has been shown to interact with Ku70, PLCG1, Lymphocyte cytosolic protein 2, Janus kinase 2, SIAH2, S100B, Abl gene, ARHGDIB, SHB, PIK3R1, PRKCQ, Grb2, MAPK1, Syk, Linker of activated T cells, Cbl gene and EZH2. Vav proteins are involved in several processes that require cytoskeletal reorganization, such as the formation of the immunological synapse (IS), phagocytosis, platelet aggregation, spreading, and transformation. Vavs function as guanine nucleotide exchange factors (GEFs) for the Rho/Rac family of GTPases. Vav family members have several conserved motifs/domains including: a leucine-rich region, a leucine-zipper, a calponin homology (CH) domain, an acidic domain, a Dbl-homology (DH) domain, a pleckstrin homology (PH) domain, a cysteine-rich domain, 2 SH3 domains, a proline-rich region, and a SH2 domain. Vavs are the only known Rho GEFs that have both the DH/PH motifs and SH2/SH3 domains in the same protein. The leucine-rich helix-loop-helix (HLH) domain is thought to be involved in protein heterodimerization with other HLH proteins and it may function as a negative regulator by forming inactive heterodimers. The CH domain is usually involved in the association with filamentous actin, but in Vav it controls NFAT stimulation, Ca2+ mobilization, and its transforming activity. Acidic domains are involved in protein-protein interactions and contain regulatory tyrosines. The DH domain is a GDP-GTP exchange factor on Rho/Rac GTPases. The PH domain in involved in interactions with GTP-binding proteins, lipids and/or phosphorylated serine/threonine residues. The SH3 domain is involved in localization of proteins to specific sites within the cell interacting with protein with proline-rich sequences. The SH2 domain mediates a high affinity interaction with tyrosine phosphorylated proteins. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198268 Cd Length: 103 Bit Score: 50.01 E-value: 3.09e-07

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    646 WYYDSLSRGEAEDMLMRiPRDGAFLIRKR-EGSDSYAITFRARGKVKHCRINRDGRHFVLGTSAYFESLVELVSYYEKHS 724
Cdd:cd10405    7 WYAGPMERAGAESILAN-RSDGTYLVRQRvKDAAEFAISIKYNVEVKHIKIMTAEGLYRITEKKAFRGLTELVEFYQQNS 85


                 .
gi 190036    725 L 725
Cdd:cd10405   86 L 86

SH3_STAM1

cd11964

Src homology 3 domain of Signal Transducing Adaptor Molecule 1; STAM1 is part of the endosomal ...

772-831

3.34e-07

Src homology 3 domain of Signal Transducing Adaptor Molecule 1; STAM1 is part of the endosomal sorting complex required for transport (ESCRT-0) and is involved in sorting ubiquitinated cargo proteins from the endosome. It may also be involved in the regulation of IL2 and GM-CSF mediated signaling, and has been implicated in neural cell survival. STAMs were discovered as proteins that are highly phosphorylated following cytokine and growth factor stimulation. They function in cytokine signaling and surface receptor degradation, as well as regulate Golgi morphology. They associate with many proteins including Jak2 and Jak3 tyrosine kinases, Hrs, AMSH, and UBPY. STAM adaptor proteins contain VHS (Vps27, Hrs, STAM homology), ubiquitin interacting (UIM), and SH3 domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212897 [Multi-domain] Cd Length: 55 Bit Score: 48.41 E-value: 3.34e-07

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 190036    772 RTVKALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGD--YGTRIqqyFPSNYVedisTAD 831
Cdd:cd11964    1 RKVRAIYDFEAAEDNELTFKAGDIITILDDSDPNWWKGEtpQGTGL---FPSNFV----TAD 55

SH2_Src_Lck

cd10362

Src homology 2 (SH2) domain in lymphocyte cell kinase (Lck); Lck is a member of the Src ...

642-724

3.34e-07

Pssm-ID: 198225 Cd Length: 101 Bit Score: 49.87 E-value: 3.34e-07

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    642 ESKPWYYDSLSRGEAEDMLMrIPRD--GAFLIRKREGSD-SYAITFR----ARGK-VKHCRI-NRDGRHFVLGTSAYFES 712
Cdd:cd10362    1 EPEPWFFKNLSRNDAERQLL-APGNthGSFLIRESETTAgSFSLSVRdfdqNQGEvVKHYKIrNLDNGGFYISPRITFPG 79

                         90
                 ....*....|..
gi 190036    713 LVELVSYYEKHS 724
Cdd:cd10362   80 LHELVRHYTNAS 91

SH3_Nebulin_C

cd11933

C-terminal Src Homology 3 domain of Nebulin; Nebulin is a giant filamentous protein (600-900 ...

772-827

4.01e-07

C-terminal Src Homology 3 domain of Nebulin; Nebulin is a giant filamentous protein (600-900 kD) that is expressed abundantly in skeletal muscle. It binds to actin thin filaments and regulates its assembly and function. Nebulin was thought to be part of a molecular ruler complex that is critical in determining the lengths of actin thin filaments in skeletal muscle since its length, which varies due to alternative splicing, correlates with the length of thin filaments in various muscle types. Recent studies indicate that nebulin regulates thin filament length by stabilizing the filaments and preventing depolymerization. Mutations in nebulin can cause nemaline myopathy, characterized by muscle weakness which can be severe and can lead to neonatal lethality. Nebulin contains an N-terminal LIM domain, many nebulin repeats/super repeats, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212866 [Multi-domain] Cd Length: 58 Bit Score: 48.08 E-value: 4.01e-07

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 190036    772 RTVKALYDYKAKRSDELSFCRGALIHNVSKEPGGWWkgdYGTrIQQ-----YFPSNYVEDI 827
Cdd:cd11933    2 KSFRAMYDYRAADDDEVSFKDGDTIVNVQTIDEGWM---YGT-VQRtgktgMLPANYVEAI 58

SH2_SH2D7

cd10417

Src homology 2 domain found in the SH2 domain containing protein 7 (SH2D7); SH2D7 contains a ...

645-722

4.26e-07

Src homology 2 domain found in the SH2 domain containing protein 7 (SH2D7); SH2D7 contains a single SH2 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 199832 Cd Length: 102 Bit Score: 49.51 E-value: 4.26e-07

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    645 PWYYDSLSRGEAEDMLmRIPRDGAFLIRKREGSDSYAITFRARGKVKHCRIN--RDGRHFVLGTSAYFESLVELVSYYEK 722
Cdd:cd10417    8 PWFHGFITRKQTEQLL-RDKALGSFLIRLSDRATGYILSYRGSDRCRHFVINqlRNRRYLISGDTSSHSTLAELVRHYQE 86

SH2_nSH2_p85_like

cd09942

N-terminal Src homology 2 (nSH2) domain found in p85; Phosphoinositide 3-kinases (PI3Ks) are ...

558-639

4.73e-07

Pssm-ID: 198195 Cd Length: 110 Bit Score: 49.63 E-value: 4.73e-07

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    558 DGTFLVRESETFPNDYTLSFWRSGRVQHCRIrSTMEGgtlKYYLTDNLRFRRMYALIQHYRETHLpcAEF----ELRLTD 633
Cdd:cd09942   28 DGTFLVRDASTMKGDYTLTLRKGGNNKLIKI-FHRDG---KYGFSDPLTFNSVVELINYYRNNSL--AEYnrklDVKLLY 101


                 ....*.
gi 190036    634 PVPNPN 639
Cdd:cd09942  102 PVSRFQ 107

SH2_Nck1

cd10408

Src homology 2 (SH2) domain found in Nck; Nck proteins are adaptors that modulate actin ...

531-626

5.10e-07

Pssm-ID: 198271 Cd Length: 97 Bit Score: 49.26 E-value: 5.10e-07

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    531 KWFHKKVeKRTSAEKLLQEYcmetgGKDGTFLVRESETFPNDYTLSFWRSGRVQHCRIRstmeggtLK--YYLTDNLRFR 608
Cdd:cd10408    2 PWYYGKV-TRHQAEMALNER-----GNEGDFLIRDSESSPNDFSVSLKAQGKNKHFKVQ-------LKecVYCIGQRKFS 68

                         90
                 ....*....|....*...
gi 190036    609 RMYALIQHYRETHLPCAE 626
Cdd:cd10408   69 SMEELVEHYKKAPIFTSE 86

SH3_CD2AP_3

cd12056

Third Src Homology 3 domain (SH3C) of CD2-associated protein; CD2AP, also called CMS (Cas ...

775-824

5.61e-07

Third Src Homology 3 domain (SH3C) of CD2-associated protein; CD2AP, also called CMS (Cas ligand with Multiple SH3 domains) or METS1 (Mesenchyme-to-Epithelium Transition protein with SH3 domains), is a cytosolic adaptor protein that plays a role in regulating the cytoskeleton. It is critical in cell-to-cell union necessary for kidney function. It also stabilizes the contact between a T cell and antigen-presenting cells. It is primarily expressed in podocytes at the cytoplasmic face of the slit diaphragm and serves as a linker anchoring podocin and nephrin to the actin cytoskeleton. CD2AP contains three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP to bind various protein partners and assemble complexes that have been implicated in many different functions. This alignment model represents the third SH3 domain (SH3C) of CD2AP. SH3C has been shown to bind ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212989 [Multi-domain] Cd Length: 57 Bit Score: 47.51 E-value: 5.61e-07

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 190036    775 KALYDYKAKRSDELSFCRGALIHNVSKEPG--GWWKGDYGTRiQQYFPSNYV 824
Cdd:cd12056    5 KALFHYEGTNEDELDFKEGEIILIISKDTGepGWWKGELNGK-EGVFPDNFV 55

SH3_GRAP2_C

cd11950

C-terminal Src homology 3 domain of GRB2-related adaptor protein 2; GRAP2 is also called GADS ...

774-825

5.98e-07

C-terminal Src homology 3 domain of GRB2-related adaptor protein 2; GRAP2 is also called GADS (GRB2-related adapter downstream of Shc), GrpL, GRB2L, Mona, or GRID (Grb2-related protein with insert domain). It is expressed specifically in the hematopoietic system. It plays an important role in T cell receptor (TCR) signaling by promoting the formation of the SLP-76:LAT complex, which couples the TCR to the Ras pathway. It also has roles in antigen-receptor and tyrosine kinase mediated signaling. GRAP2 is unique from other GRB2-like adaptor proteins in that it can be regulated by caspase cleavage. It contains an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. The C-terminal SH3 domain of GRAP2 binds to different motifs found in substrate peptides including the typical PxxP motif in hematopoietic progenitor kinase 1 (HPK1), the RxxK motif in SLP-76 and HPK1, and the RxxxxK motif in phosphatase-like protein HD-PTP. SH3 domains are protein interaction domains that typically bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212883 [Multi-domain] Cd Length: 53 Bit Score: 47.51 E-value: 5.98e-07

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 190036    774 VKALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRIqQYFPSNYVE 825
Cdd:cd11950    2 VRALYDFEALEDDELGFNSGDVIEVLDSSNPSWWKGRLHGKL-GLFPANYVA 52

SH3_Yes

cd12007

Src homology 3 domain of Yes Protein Tyrosine Kinase; Yes (or c-Yes) is a member of the Src ...

776-824

6.42e-07

Src homology 3 domain of Yes Protein Tyrosine Kinase; Yes (or c-Yes) is a member of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. c-Yes kinase is the cellular homolog of the oncogenic protein (v-Yes) encoded by the Yamaguchi 73 and Esh sarcoma viruses. It displays functional overlap with other Src subfamily members, particularly Src. It also shows some unique functions such as binding to occludins, transmembrane proteins that regulate extracellular interactions in tight junctions. Yes also associates with a number of proteins in different cell types that Src does not interact with, like JAK2 and gp130 in pre-adipocytes, and Pyk2 in treated pulmonary vein endothelial cells. Although the biological function of Yes remains unclear, it appears to have a role in regulating cell-cell interactions and vesicle trafficking in polarized cells. Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212940 [Multi-domain] Cd Length: 58 Bit Score: 47.72 E-value: 6.42e-07

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|
gi 190036    776 ALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKG-DYGTRIQQYFPSNYV 824
Cdd:cd12007    5 ALYDYEARTTEDLSFKKGERFQIINNTEGDWWEArSIATGKNGYIPSNYV 54

SH3_VAV_2

cd11830

C-terminal (or second) Src homology 3 domain of VAV proteins; VAV proteins function both as ...

773-826

6.90e-07

C-terminal (or second) Src homology 3 domain of VAV proteins; VAV proteins function both as cytoplasmic guanine nucleotide exchange factors (GEFs) for Rho GTPases and scaffold proteins and they play important roles in cell signaling by coupling cell surface receptors to various effector functions. They play key roles in processes that require cytoskeletal reorganization including immune synapse formation, phagocytosis, cell spreading, and platelet aggregation, among others. Vertebrates have three VAV proteins (VAV1, VAV2, and VAV3). VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. The SH3 domain of VAV is involved in the localization of proteins to specific sites within the cell, by interacting with proline-rich sequences within target proteins. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212764 [Multi-domain] Cd Length: 54 Bit Score: 47.24 E-value: 6.90e-07

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 190036    773 TVKALYDYKAKRSDELSFCRGALIHNVSKE-PGGWWKGDYGTRIqQYFPSNYVED 826
Cdd:cd11830    1 TAKARYDFCARDMRELSLKEGDVVKIYNKKgQQGWWRGEINGRI-GWFPSTYVEE 54

SH2_Src_Fyn

cd10368

Src homology 2 (SH2) domain found in Fyn; Fyn is a member of the Src non-receptor type ...

642-720

7.19e-07

Pssm-ID: 198231 [Multi-domain] Cd Length: 101 Bit Score: 48.87 E-value: 7.19e-07

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    642 ESKPWYYDSLSRGEAEDMLMRI--PRdGAFLIRKREGSD-SYAITFR----ARG-KVKHCRINR-DGRHFVLGTSAYFES 712
Cdd:cd10368    1 QAEEWYFGKLGRKDAERQLLSFgnPR-GTFLIRESETTKgAYSLSIRdwddMKGdHVKHYKIRKlDNGGYYITTRAQFET 79


                 ....*...
gi 190036    713 LVELVSYY 720
Cdd:cd10368   80 LQQLVQHY 87

SH3_Myosin-I_fungi

cd11858

Src homology 3 domain of Type I fungal Myosins; Type I myosins (myosin-I) are actin-dependent ...

773-825

7.68e-07

Src homology 3 domain of Type I fungal Myosins; Type I myosins (myosin-I) are actin-dependent motors in endocytic actin structures and actin patches. They play roles in membrane traffic in endocytic and secretory pathways, cell motility, and mechanosensing. Saccharomyces cerevisiae has two myosins-I, Myo3 and Myo5, which are involved in endocytosis and the polarization of the actin cytoskeleton. Myosin-I contains an N-terminal actin-activated ATPase, a phospholipid-binding TH1 (tail homology 1) domain, and a C-terminal extension which includes an F-actin-binding TH2 domain, an SH3 domain, and an acidic peptide that participates in activating the Arp2/3complex. The SH3 domain of myosin-I is required for myosin-I-induced actin polymerization. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212792 [Multi-domain] Cd Length: 55 Bit Score: 46.99 E-value: 7.68e-07

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....
gi 190036    773 TVKALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKG-DYGTRIQQYFPSNYVE 825
Cdd:cd11858    1 TYKALYDFAGSVANELSLKKDDIVYIVQKEDNGWWLAkKLDESKEGWVPAAYLE 54

SH2_SLAP

cd10344

Src homology 2 domain found in Src-like adaptor proteins; SLAP belongs to the subfamily of ...

646-720

8.40e-07

Pssm-ID: 198207 Cd Length: 104 Bit Score: 48.64 E-value: 8.40e-07

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    646 WYYDSLSRGEAEDMLMrIP--RDGAFLIRKREG-SDSYAITFRARG-----KVKHCRINR-DGRHFVLGTSAYFESLVEL 716
Cdd:cd10344   12 WLFEGLSREKAEELLM-LPgnQVGSFLIRESETrRGCYSLSVRHRGsqsrdSVKHYRIFRlDNGWFYISPRLTFQCLEDM 90


                 ....
gi 190036    717 VSYY 720
Cdd:cd10344   91 VNHY 94

PH_PLC_plant-like

cd13365

Plant-like Phospholipase C (PLC) pleckstrin homology (PH) domain; PLC-gamma (PLCgamma) was the ...

34-131

9.35e-07

Plant-like Phospholipase C (PLC) pleckstrin homology (PH) domain; PLC-gamma (PLCgamma) was the second class of PLC discovered. PLC-gamma consists of an N-terminal PH domain, a EF hand domain, a catalytic domain split into X and Y halves internal to which is a PH domain split by two SH2 domains and a single SH3 domain, and a C-terminal C2 domain. PLCs (EC 3.1.4.3) play a role in the initiation of cellular activation, proliferation, differentiation and apoptosis. They are central to inositol lipid signalling pathways, facilitating intracellular Ca2+ release and protein kinase C (PKC) activation. Specificaly, PLCs catalyze the cleavage of phosphatidylinositol-4,5-bisphosphate (PIP2) and result in the release of 1,2-diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3). These products trigger the activation of protein kinase C (PKC) and the release of Ca2+ from intracellular stores. There are fourteen kinds of mammalian phospholipase C proteins which are are classified into six isotypes (beta, gamma, delta, epsilon, zeta, eta). This cd contains PLC members from fungi and plants. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

Pssm-ID: 270171 Cd Length: 115 Bit Score: 48.82 E-value: 9.35e-07

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036     34 RKSTPERRTVQVIMETRQVAWSKTADKIEGFLDIMEIKEIRPGKNSKDFERaKAVRQKEDCCFTILYGTQfvLSTLSLAA 113
Cdd:cd13365   21 RRGKPHFRYFWLSPDELTLYWSSPKKGSEKRVRLSSVSRIIPGQRTVVFKR-PPPPGLEEHSFSIIYADG--ERSLDLTC 97

                         90
                 ....*....|....*...
gi 190036    114 DSKEDAVNWLSGLKILHQ 131
Cdd:cd13365   98 KDRQEFDTWFTGLRYLLS 115

SH3_Nck2_2

cd11902

Second Src Homology 3 domain of Nck2 adaptor protein; Nck2 (also called Nckbeta or Growth ...

778-824

9.72e-07

Second Src Homology 3 domain of Nck2 adaptor protein; Nck2 (also called Nckbeta or Growth factor receptor-bound protein 4, Grb4) plays a crucial role in connecting signaling pathways of tyrosine kinase receptors and important effectors in actin dynamics and cytoskeletal remodeling. It binds neuronal signaling proteins such as ephrinB and Disabled-1 (Dab-1) exclusively. Nck adaptor proteins regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates. They contain three SH3 domains and a C-terminal SH2 domain. They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics. Vertebrates contain two Nck adaptor proteins: Nck1 (also called Nckalpha) and Nck2, which show partly overlapping functions but also bind distinct targets. The second SH3 domain of Nck appears to prefer ligands containing the APxxPxR motif. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity, preferentially a PxxP motif. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212835 [Multi-domain] Cd Length: 55 Bit Score: 46.92 E-value: 9.72e-07

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*..
gi 190036    778 YDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRIqQYFPSNYV 824
Cdd:cd11902    7 FAYVAEREDELSLVKGSRVTVMEKCSDGWWRGSYNGQI-GWFPSNYV 52

SH2_Nck2

cd10409

Src homology 2 (SH2) domain found in Nck; Nck proteins are adaptors that modulate actin ...

532-626

1.16e-06

Pssm-ID: 198272 Cd Length: 98 Bit Score: 48.11 E-value: 1.16e-06

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    532 WFHKKVeKRTSAEKLLQEYcmetgGKDGTFLVRESETFPNDYTLSFWRSGRVQHCRIRSTMEggtlkYYLTDNLRFRRMY 611
Cdd:cd10409    3 WYYGNV-TRHQAECALNER-----GVEGDFLIRDSESSPSDFSVSLKAVGKNKHFKVQLVDN-----VYCIGQRRFNSMD 71

                         90
                 ....*....|....*
gi 190036    612 ALIQHYRETHLPCAE 626
Cdd:cd10409   72 ELVEHYKKAPIFTSE 86

SH2_Src_Fyn_isoform_a_like

cd10418

Src homology 2 (SH2) domain found in Fyn isoform a like proteins; Fyn is a member of the Src ...

642-734

1.30e-06

Pssm-ID: 198281 Cd Length: 101 Bit Score: 48.07 E-value: 1.30e-06

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    642 ESKPWYYDSLSRGEAEDMLMRI--PRdGAFLIRKREGSD-SYAITFR----ARGK-VKHCRINR-DGRHFVLGTSAYFES 712
Cdd:cd10418    1 QAEEWYFGKLGRKDAERQLLSFgnPR-GTFLIRESETTKgAYSLSIRdwddMKGDhVKHYKIRKlDNGGYYITTRAQFET 79

                         90       100
                 ....*....|....*....|..
gi 190036    713 LVELVSYYEKHSLYRKMRLRYP 734
Cdd:cd10418   80 LQQLVQHYSERAAGLCCRLVVP 101

SH2_Grb7

cd10413

Src homology 2 (SH2) domain found in the growth factor receptor bound, subclass 7 (Grb7) ...

526-624

1.60e-06

Src homology 2 (SH2) domain found in the growth factor receptor bound, subclass 7 (Grb7) proteins; The Grb family binds to the epidermal growth factor receptor (EGFR, erbB1) via their SH2 domains. Grb7 is part of the Grb7 family of proteins which also includes Grb10, and Grb14. They are composed of an N-terminal Proline-rich domain, a Ras Associating-like (RA) domain, a Pleckstrin Homology (PH) domain, a phosphotyrosine interaction region (PIR, BPS) and a C-terminal SH2 domain. The SH2 domains of Grb7, Grb10 and Grb14 preferentially bind to a different RTK. Grb7 binds strongly to the erbB2 receptor, unlike Grb10 and Grb14 which bind weakly to it. Grb7 family proteins are phosphorylated on serine/threonine as well as tyrosine residues. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198276 Cd Length: 108 Bit Score: 47.98 E-value: 1.60e-06

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    526 LHFGEKWFHKKVEKRTSaekllQEYCMETGGKDGTFLVRESETFPNDYTLSFWRSGRVQHCRIRSTMEGGTLKYYLTD-N 604
Cdd:cd10413    1 IHRTQPWFHGRISREES-----QRLIGQQGLVDGVFLVRESQRNPQGFVLSLCHLQKVKHYLILPSEEEGRLYFSMDDgQ 75

                         90       100
                 ....*....|....*....|..
gi 190036    605 LRFRRMYALIQHYRETH--LPC 624
Cdd:cd10413   76 TRFTDLLQLVEFHQLNRgiLPC 97

SH3_GRAF3

cd12066

Src Homology 3 domain of GTPase Regulator Associated with Focal adhesion kinase 3; GRAF3 is ...

775-825

1.75e-06

Src Homology 3 domain of GTPase Regulator Associated with Focal adhesion kinase 3; GRAF3 is also called Rho GTPase activating protein 42 (ARHGAP42) or ARHGAP10-like. Though its function has not been characterized, it may be a GAP with activity towards RhoA and Cdc42, based on its similarity to GRAF and GRAF2. It contains an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, a Rho GAP domain, and a C-terminal SH3 domain. The SH3 domain of GRAF and GRAF2 binds PKNbeta, a target of the small GTPase Rho. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212999 Cd Length: 55 Bit Score: 46.21 E-value: 1.75e-06

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 190036    775 KALYDYKAKRSDELSFCRGALIHNV--SKEPgGWWKGDYGTRiQQYFPSNYVE 825
Cdd:cd12066    3 KAMYSCKAEHSHELSFPQGAIFSNVypSVEP-GWLKATYEGK-TGLVPENYVV 53

SH3_Nebulette_C

cd11935

C-terminal Src Homology 3 domain of Nebulette and LIM-nebulette (or Lasp2); Nebulette is a ...

772-827

1.80e-06

C-terminal Src Homology 3 domain of Nebulette and LIM-nebulette (or Lasp2); Nebulette is a cardiac-specific protein that localizes to the Z-disc. It interacts with tropomyosin and is important in stabilizing actin thin filaments in cardiac muscles. Polymorphisms in the nebulette gene are associated with dilated cardiomyopathy, with some mutations resulting in severe heart failure. Nebulette is a 107kD protein that contains an N-terminal acidic region, multiple nebulin repeats, and a C-terminal SH3 domain. LIM-nebulette, also called Lasp2 (LIM and SH3 domain protein 2), is an alternatively spliced variant of nebulette. Although it shares a gene with nebulette, Lasp2 is not transcribed from a muscle-specific promoter, giving rise to its multiple tissue expression pattern with highest amounts in the brain. It can crosslink actin filaments and it affects cell spreading. Lasp2 is a 34kD protein containing an N-terminal LIM domain, three nebulin repeats, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212868 [Multi-domain] Cd Length: 58 Bit Score: 46.15 E-value: 1.80e-06

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 190036    772 RTVKALYDYKAKRSDELSFCRGALIHNVSKEPGGWWkgdYGTrIQQ-----YFPSNYVEDI 827
Cdd:cd11935    1 RTYRAMYDYSAQDEDEVSFRDGDYIVNVQPIDEGWM---YGT-VQRtgrtgMLPANYIEFV 57

SH3_GRB2_C

cd11949

C-terminal Src homology 3 domain of Growth factor receptor-bound protein 2; GRB2 is a critical ...

773-825

1.94e-06

C-terminal Src homology 3 domain of Growth factor receptor-bound protein 2; GRB2 is a critical signaling molecule that regulates the Ras pathway by linking tyrosine kinases to the Ras guanine nucleotide releasing protein Sos (son of sevenless), which converts Ras to the active GTP-bound state. It is ubiquitously expressed in all tissues throughout development and is important in cell cycle progression, motility, morphogenesis, and angiogenesis. In lymphocytes, GRB2 is associated with antigen receptor signaling components. GRB2 contains an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. The C-terminal SH3 domain of GRB2 binds to Gab2 (Grb2-associated binder 2) through epitopes containing RxxK motifs, as well as to the proline-rich C-terminus of FGRF2. SH3 domains are protein interaction domains that typically bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212882 [Multi-domain] Cd Length: 53 Bit Score: 45.99 E-value: 1.94e-06

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 190036    773 TVKALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRIQQyFPSNYVE 825
Cdd:cd11949    1 YVQALFDFDPQEDGELGFRRGDFIEVMDNSDPNWWKGACHGQTGM-FPRNYVT 52

SH3_HS1

cd12073

Src homology 3 domain of Hematopoietic lineage cell-specific protein 1; HS1, also called HCLS1 ...

776-825

1.97e-06

Src homology 3 domain of Hematopoietic lineage cell-specific protein 1; HS1, also called HCLS1 (hematopoietic cell-specific Lyn substrate 1), is a cortactin homolog expressed specifically in hematopoietic cells. It is an actin regulatory protein that binds the Arp2/3 complex and stabilizes branched actin filaments. It is required for cell spreading and signaling in lymphocytes. It regulates cytoskeletal remodeling that controls lymphocyte trafficking, and it also affects tissue invasion and infiltration of leukemic B cells. Like cortactin, HS1 contains an N-terminal acidic domain, several copies of a repeat domain found in cortactin and HS1, a proline-rich region, and a C-terminal SH3 domain. The N-terminal region binds the Arp2/3 complex and F-actin, while the C-terminal region acts as an adaptor or scaffold that can connect varied proteins that bind the SH3 domain within the actin network. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 213006 [Multi-domain] Cd Length: 55 Bit Score: 45.98 E-value: 1.97e-06

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|
gi 190036    776 ALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRIqQYFPSNYVE 825
Cdd:cd12073    5 ALYDYQGEGDDEISFDPQETITDIEMVDEGWWKGTCHGHR-GLFPANYVE 53

SH3_2

pfam07653

Variant SH3 domain; SH3 (Src homology 3) domains are often indicative of a protein involved in ...

774-825

2.21e-06

Variant SH3 domain; SH3 (Src homology 3) domains are often indicative of a protein involved in signal transduction related to cytoskeletal organization. First described in the Src cytoplasmic tyrosine kinase. The structure is a partly opened beta barrel.

Pssm-ID: 429575 [Multi-domain] Cd Length: 54 Bit Score: 45.66 E-value: 2.21e-06

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 190036      774 VKALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRiQQYFPSNYVE 825
Cdd:pfam07653    2 GRVIFDYVGTDKNGLTLKKGDVVKVLGKDNDGWWEGETGGR-VGLVPSTAVE 52

SH3_PACSIN_like

cd11999

Src homology 3 domain of an unknown subfamily of proteins with similarity to Protein kinase C ...

774-825

2.78e-06

Src homology 3 domain of an unknown subfamily of proteins with similarity to Protein kinase C and Casein kinase Substrate in Neurons (PACSIN) proteins; PACSINs, also called Synaptic dynamin-associated proteins (Syndapins), act as regulators of cytoskeletal and membrane dynamics. They bind both dynamin and Wiskott-Aldrich syndrome protein (WASP), and may provide direct links between the actin cytoskeletal machinery through WASP and dynamin-dependent endocytosis. Vetebrates harbor three isoforms with distinct expression patterns and specific functions. PACSINs contain an N-terminal F-BAR domain and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212932 [Multi-domain] Cd Length: 56 Bit Score: 45.70 E-value: 2.78e-06

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 190036    774 VKALYDYKAKRSDELSFCRGALIHNVSKE-PGGWWKGDYGTRIQQYFPSNYVE 825
Cdd:cd11999    4 VRAVYDYTGQEPDELSFKAGEELLKVEDEdEQGWCKGVTDGGAVGLYPANYVE 56

SH3_PACSIN3

cd11997

Src homology 3 domain of Protein kinase C and Casein kinase Substrate in Neurons 3 (PACSIN3); ...

774-825

2.83e-06

Src homology 3 domain of Protein kinase C and Casein kinase Substrate in Neurons 3 (PACSIN3); PACSIN 3 or Syndapin III (Synaptic dynamin-associated protein III) is expressed ubiquitously and regulates glucose uptake in adipocytes through its role in GLUT1 trafficking. It also modulates the subcellular localization and stimulus-specific function of the cation channel TRPV4. PACSINs act as regulators of cytoskeletal and membrane dynamics. Vetebrates harbor three isoforms with distinct expression patterns and specific functions. PACSINs contain an N-terminal F-BAR domain and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212930 [Multi-domain] Cd Length: 56 Bit Score: 45.72 E-value: 2.83e-06

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....
gi 190036    774 VKALYDYKAKRSDELSFCRGALIHNVSKE-PGGWWKGDYGT-RIQQYfPSNYVE 825
Cdd:cd11997    4 VRALYDYTGQEADELSFKAGEELLKIGEEdEQGWCKGRLLSgRIGLY-PANYVE 56

SH3_Sho1p

cd11855

Src homology 3 domain of High osmolarity signaling protein Sho1p; Sho1p (or Sho1), also called ...

773-825

2.85e-06

Src homology 3 domain of High osmolarity signaling protein Sho1p; Sho1p (or Sho1), also called SSU81 (Suppressor of SUA8-1 mutation), is a yeast membrane protein that regulates adaptation to high salt conditions by activating the HOG (high-osmolarity glycerol) pathway. High salt concentrations lead to the localization to the membrane of the MAPKK Pbs2, which is then activated by the MAPKK Ste11 and in turn, activates the MAPK Hog1. Pbs2 is localized to the membrane though the interaction of its PxxP motif with the SH3 domain of Sho1p. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212789 [Multi-domain] Cd Length: 55 Bit Score: 45.49 E-value: 2.85e-06

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 190036    773 TVKALYDYKAKRSD--ELSFCRGAlIHNVSKEPGGWWKGDYGTRIQQYFPSNYVE 825
Cdd:cd11855    1 RARALYPYDASPDDpnELSFEKGE-ILEVSDTSGKWWQARKSNGETGICPSNYLQ 54

SH2_HSH2_like

cd09946

Src homology 2 domain found in hematopoietic SH2 (HSH2) protein; HSH2 is thought to function ...

646-722

3.14e-06

Src homology 2 domain found in hematopoietic SH2 (HSH2) protein; HSH2 is thought to function as an adapter protein involved in tyrosine kinase signaling. It may also be involved in regulating cytokine signaling and cytoskeletal reorganization in hematopoietic cells. HSH2 contains several putative protein-binding motifs, SH3-binding proline-rich regions, and phosphotyrosine sites, but lacks enzymatic motifs. HSH2 was found to interact with cytokine-regulated tyrosine kinase c-FES and an activated Cdc42-associated tyrosine kinase ACK1. HSH2 binds c-FES through both its C-terminal region and its N-terminal region including the SH2 domain and binds ACK1 via its N-terminal proline-rich region. Both kinases bound and tyrosine-phosphorylated HSH2 in mammalian cells. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198199 Cd Length: 102 Bit Score: 46.81 E-value: 3.14e-06

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 190036    646 WYYDSLSRGEAEDMLMRIPRdGAFLIRKREGSDSYAITFRARGKVKHCRIN--RDGRHFVLGTSAYFESLVELVSYYEK 722
Cdd:cd09946    9 WFHGAISREAAENMLESQPL-GSFLIRVSHSHVGYTLSYKAQSSCRHFMVKllDDGTFMIPGEKVAHTSLHALVTFHQQ 86

SH2_Grb10

cd10415

Src homology 2 (SH2) domain found in the growth factor receptor bound, subclass 10 (Grb10) ...

526-624

3.31e-06

Src homology 2 (SH2) domain found in the growth factor receptor bound, subclass 10 (Grb10) proteins; The Grb family binds to the epidermal growth factor receptor (EGFR, erbB1) via their SH2 domains. Grb10 is part of the Grb7 family of proteins which also includes Grb7, and Grb14. They are composed of an N-terminal Proline-rich domain, a Ras Associating-like (RA) domain, a Pleckstrin Homology (PH) domain, a phosphotyrosine interaction region (PIR, BPS) and a C-terminal SH2 domain. The SH2 domains of Grb7, Grb10 and Grb14 preferentially bind to a different RTK. Grb10 has been shown to interact with many different proteins, including the insulin and IGF1 receptors, platelet-derived growth factor (PDGF) receptor-beta, Ret, Kit, Raf1 and MEK1, and Nedd4. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198278 Cd Length: 108 Bit Score: 46.94 E-value: 3.31e-06

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    526 LHFGEKWFHKKVEKRTSAEKLLQEycmetGGKDGTFLVRESETFPNDYTLSFWRSGRVQHCRIRSTMEGGTLKYYLTD-N 604
Cdd:cd10415    1 IHRTQHWFHGRISREESHRIIKQQ-----GLVDGLFLLRDSQSNPKAFVLTLCHHQKIKNFQILPCEDDGQTFFSLDDgN 75

                         90       100
                 ....*....|....*....|..
gi 190036    605 LRFRRMYALIQHYRETH--LPC 624
Cdd:cd10415   76 TKFSDLIQLVDFYQLNKgvLPC 97

SH3_ephexin1_like

cd11793

Src homology 3 domain of ephexin-1-like SH3 domain containing Rho guanine nucleotide exchange ...

774-825

3.86e-06

Src homology 3 domain of ephexin-1-like SH3 domain containing Rho guanine nucleotide exchange factors; Members of this family contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), and C-terminal SH3 domains. They include the Rho guanine nucleotide exchange factors ARHGEF5, ARHGEF16, ARHGEF19, ARHGEF26, ARHGEF27 (also called ephexin-1), and similar proteins, and are also called ephexins because they interact directly with ephrin A receptors. GEFs interact with Rho GTPases via their DH domains to catalyze nucleotide exchange by stabilizing the nucleotide-free GTPase intermediate. They play important roles in neuronal development. The SH3 domains of ARHGEFs play an autoinhibitory role through intramolecular interactions with a proline-rich region N-terminal to the DH domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212727 [Multi-domain] Cd Length: 55 Bit Score: 45.02 E-value: 3.86e-06

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 190036    774 VKALYDYKAKRSDELSFCRGALIHNVSKEPGGWWkgdYGTRI----QQYFPSNYVE 825
Cdd:cd11793    2 VQCVHAYTAQQPDELTLEEGDVVNVLRKMPDGWY---EGERLrdgeRGWFPSSYTE 54

SH2_SH2B_family

cd10346

Src homology 2 (SH2) domain found in SH2B adapter protein family; The SH2B adapter protein ...

645-723

4.16e-06

Pssm-ID: 198209 Cd Length: 97 Bit Score: 46.26 E-value: 4.16e-06

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    645 PWYYDSLSRGEAEDMLMRIPRD--GAFLIRKREG-SDSYAITFRARGKVKHCRI--NRDGRHFVlgTSAYFESLVELVSY 719
Cdd:cd10346    9 PWFHGTLSRSDAAQLVLHSGADghGVFLVRQSETrRGEFVLTFNFQGRAKHLRLtlNEKGQCRV--QHLWFPSIFDMLEH 86


                 ....
gi 190036    720 YEKH 723
Cdd:cd10346   87 FRQN 90

SH2_SOCS_family

cd09923

Src homology 2 (SH2) domain found in suppressor of cytokine signaling (SOCS) family; SH2 ...

645-720

4.25e-06

Src homology 2 (SH2) domain found in suppressor of cytokine signaling (SOCS) family; SH2 domain found in SOCS proteins. SOCS was first recognized as a group of cytokine-inducible SH2 (CIS) domain proteins comprising eight family members in human (CIS and SOCS1-SOCS7). In addition to the SH2 domain, SOCS proteins have a variable N-terminal domain and a conserved SOCS box in the C-terminal domain. SOCS proteins bind to a substrate via their SH2 domain. The prototypical members, CIS and SOCS1-SOCS3, have been shown to regulate growth hormone signaling in vitro and in a classic negative feedback response compete for binding at phosphotyrosine sites in JAK kinase and receptor pathways to displace effector proteins and target bound receptors for proteasomal degradation. Loss of SOCS activity results in excessive cytokine signaling associated with a variety of hematopoietic, autoimmune, and inflammatory diseases and certain cancers. Members (SOCS4-SOCS7) were identified by their conserved SOCS box, an adapter motif of 3 helices that associates substrate binding domains, such as the SOCS SH2 domain, ankryin, and WD40 with ubiquitin ligase components. These show limited cytokine induction. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198178 Cd Length: 81 Bit Score: 46.04 E-value: 4.25e-06

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    645 PWYYDSLSRGEAEDmLMRIPRDGAFLIRKREGSDSY-AITFRARGKVKHCRIN-RDGRhFVLGTSA----YFESLVELVS 718
Cdd:cd09923    1 GWYWGGITRYEAEE-LLAGKPEGTFLVRDSSDSRYLfSVSFRTYGRTLHARIEySNGR-FSFDSSDpsvpRFPCVVELIE 78


                 ..
gi 190036    719 YY 720
Cdd:cd09923   79 HY 80

SH3_Sorbs2_1

cd11920

First Src Homology 3 domain of Sorbin and SH3 domain containing 2 (Sorbs2), also called ...

775-827

4.65e-06

First Src Homology 3 domain of Sorbin and SH3 domain containing 2 (Sorbs2), also called Arg-binding protein 2 (ArgBP2); Sorbs2 or ArgBP2 is an adaptor protein containing one sorbin homology (SoHo) and three SH3 domains. It regulates actin-dependent processes including cell adhesion, morphology, and migration. It is expressed in many tissues and is abundant in the heart. Like vinexin, it is found in focal adhesion where it interacts with vinculin and afadin. It also localizes in epithelial cell stress fibers and in cardiac muscle cell Z-discs. Sorbs2 has been implicated to play roles in the signaling of c-Arg, Akt, and Pyk2. Other interaction partners of Sorbs2 include c-Abl, flotillin, spectrin, dynamin 1/2, synaptojanin, PTP-PEST, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212853 [Multi-domain] Cd Length: 55 Bit Score: 45.00 E-value: 4.65e-06

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 190036    775 KALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRIqQYFPSNYVEDI 827
Cdd:cd11920    4 RAVYDFKAQTSKELSFKKGDTVYILRKIDQNWYEGEHHGRV-GIFPISYVEKL 55

SH3_Ysc84p_like

cd11842

Src homology 3 domain of Ysc84p and similar fungal proteins; This family is composed of the ...

776-825

4.87e-06

Src homology 3 domain of Ysc84p and similar fungal proteins; This family is composed of the Saccharomyces cerevisiae proteins, Ysc84p (also called LAS17-binding protein 4, Lsb4p) and Lsb3p, and similar fungal proteins. They contain an N-terminal SYLF domain (also called DUF500) and a C-terminal SH3 domain. Ysc84p localizes to actin patches and plays an important in actin polymerization during endocytosis. The N-terminal domain of both Ysc84p and Lsb3p can bind and bundle actin filaments. A study of the yeast SH3 domain interactome predicts that the SH3 domains of Lsb3p and Lsb4p may function as molecular hubs for the assembly of endocytic complexes. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212776 [Multi-domain] Cd Length: 55 Bit Score: 45.11 E-value: 4.87e-06

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 190036    776 ALYDYKAKRSDELSFCRGALIHNVSK--EPGGWWKGDYGTRiQQYFPSNYVE 825
Cdd:cd11842    4 ALYDFAGEQPGDLAFQKGDIITILKKsdSQNDWWTGRIGGR-EGIFPANYVE 54

SH3_Fyn_Yrk

cd12006

Src homology 3 domain of Fyn and Yrk Protein Tyrosine Kinases; Fyn and Yrk (Yes-related kinase) ...

776-824

5.44e-06

Src homology 3 domain of Fyn and Yrk Protein Tyrosine Kinases; Fyn and Yrk (Yes-related kinase) are members of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. Fyn, together with Lck, plays a critical role in T-cell signal transduction by phosphorylating ITAM (immunoreceptor tyr activation motif) sequences on T-cell receptors, ultimately leading to the proliferation and differentiation of T-cells. In addition, Fyn is involved in the myelination of neurons, and is implicated in Alzheimer's and Parkinson's diseases. Yrk has been detected only in chickens. It is primarily found in neuronal and epithelial cells and in macrophages. It may play a role in inflammation and in response to injury. Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212939 [Multi-domain] Cd Length: 56 Bit Score: 45.04 E-value: 5.44e-06

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|
gi 190036    776 ALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKG-DYGTRIQQYFPSNYV 824
Cdd:cd12006    5 ALYDYEARTEDDLSFHKGEKFQILNSSEGDWWEArSLTTGETGYIPSNYV 54

SH3_CD2AP-like_2

cd11874

Second Src Homology 3 domain (SH3B) of CD2-associated protein and similar proteins; This ...

775-825

5.60e-06

Second Src Homology 3 domain (SH3B) of CD2-associated protein and similar proteins; This subfamily is composed of the second SH3 domain (SH3B) of CD2AP, CIN85 (Cbl-interacting protein of 85 kDa), and similar domains. CD2AP and CIN85 are adaptor proteins that bind to protein partners and assemble complexes that have been implicated in T cell activation, kidney function, and apoptosis of neuronal cells. They also associate with endocytic proteins, actin cytoskeleton components, and other adaptor proteins involved in receptor tyrosine kinase (RTK) signaling. CD2AP and the main isoform of CIN85 contain three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP and CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. SH3B of both proteins have been shown to bind to Cbl. In the case of CD2AP, its SH3B binds to Cbl at a site distinct from the c-Cbl/SH3A binding site. The CIN85 SH3B also binds ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212807 [Multi-domain] Cd Length: 53 Bit Score: 44.63 E-value: 5.60e-06

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 190036    775 KALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRIqQYFPSNYVE 825
Cdd:cd11874    3 KVLFSYTPQNEDELELKVGDTIEVLGEVEEGWWEGKLNGKV-GVFPSNFVK 52

SH3_PACSIN1-2

cd11998

Src homology 3 domain of Protein kinase C and Casein kinase Substrate in Neurons 1 (PACSIN1) ...

774-825

5.77e-06

Src homology 3 domain of Protein kinase C and Casein kinase Substrate in Neurons 1 (PACSIN1) and PACSIN 2; PACSIN 1 or Syndapin I (Synaptic dynamin-associated protein I) is expressed specifically in the brain and is localized in neurites and synaptic boutons. It binds the brain-specific proteins dynamin I, synaptojanin, synapsin I, and neural Wiskott-Aldrich syndrome protein (nWASP), and functions as a link between the cytoskeletal machinery and synaptic vesicle endocytosis. PACSIN 1 interacts with huntingtin and may be implicated in the neuropathology of Huntington's disease. PACSIN 2 or Syndapin II is expressed ubiquitously and is involved in the regulation of tubulin polymerization. It associates with Golgi membranes and forms a complex with dynamin II which is crucial in promoting vesicle formation from the trans-Golgi network. PACSINs act as regulators of cytoskeletal and membrane dynamics. Vetebrates harbor three isoforms with distinct expression patterns and specific functions. PACSINs contain an N-terminal F-BAR domain and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212931 [Multi-domain] Cd Length: 56 Bit Score: 44.94 E-value: 5.77e-06

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 190036    774 VKALYDYKAKRSDELSFCRG-ALIHNVSKEPGGWWKGDYGTRIQQYFPSNYVE 825
Cdd:cd11998    3 VRALYDYDGQEQDELSFKAGdELTKLEDEDEQGWCKGRLDSGQVGLYPANYVE 55

SH3_MLK1-3

cd12059

Src Homology 3 domain of Mixed Lineage Kinases 1, 2, and 3; MLKs 1, 2, and 3 are Serine ...

776-824

5.95e-06

Src Homology 3 domain of Mixed Lineage Kinases 1, 2, and 3; MLKs 1, 2, and 3 are Serine/Threonine Kinases (STKs), catalyzing the transfer of the gamma-phosphoryl group from ATP to S/T residues on protein substrates. MLKs act as mitogen-activated protein kinase kinase kinases (MAP3Ks, MKKKs, MAPKKKs), which phosphorylate and activate MAPK kinases (MAPKKs or MKKs or MAP2Ks), which in turn phosphorylate and activate MAPKs during signaling cascades that are important in mediating cellular responses to extracellular signals. MLKs play roles in immunity and inflammation, as well as in cell death, proliferation, and cell cycle regulation. Little is known about the specific function of MLK1, also called MAP3K9. It is capable of activating the c-Jun N-terminal kinase pathway. Mice lacking both MLK1 and MLK2 are viable, fertile, and have normal life spans. MLK2, also called MAP3K10, is abundant in brain, skeletal muscle, and testis. It functions upstream of the MAPK, c-Jun N-terminal kinase. It binds hippocalcin, a calcium-sensor protein that protects neurons against calcium-induced cell death. Both MLK2 and hippocalcin may be associated with the pathogenesis of Parkinson's disease. MLK3, also called MAP3K11, is highly expressed in breast cancer cells and its signaling through c-Jun N-terminal kinase has been implicated in the migration, invasion, and malignancy of cancer cells. It also functions as a negative regulator of Inhibitor of Nuclear Factor-KappaB Kinase (IKK) and thus, impacts inflammation and immunity. MLKs contain an SH3 domain, a catalytic kinase domain, a leucine zipper, a proline-rich region, and a CRIB domain that mediates binding to GTP-bound Cdc42 and Rac. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212992 [Multi-domain] Cd Length: 58 Bit Score: 44.76 E-value: 5.95e-06

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....
gi 190036    776 ALYDYKAKRSDELSFCRGALIHNVSKEPG-----GWWKGDYGTRIqQYFPSNYV 824
Cdd:cd12059    4 AVFDYEASAEDELTLRRGDRVEVLSKDSAvsgdeGWWTGKINDRV-GIFPSNYV 56

PH_PLC_fungal

cd13360

Fungal Phospholipase C (PLC) pleckstrin homology (PH) domain; Fungal PLC have mostly been ...

22-131

6.04e-06

Fungal Phospholipase C (PLC) pleckstrin homology (PH) domain; Fungal PLC have mostly been characterized in the yeast Saccharomyces cerevisiae via deletion studies which resulted in a pleiotropic phenotype, with defects in growth, carbon source utilization, and sensitivity to osmotic stress and high temperature. Unlike Saccharomyces several other fungi including Neurospora crassa, Cryphonectria parasitica , and Magnaporthe oryzae (Mo) have several PLC proteins, some of which lack a PH domain, with varied functions. MoPLC1-mediated regulation of Ca2+ level is important for conidiogenesis and appressorium formation while both MoPLC2 and MoPLC3 are required for asexual reproduction, cell wall integrity, appressorium development, and pathogenicity. The fungal PLCs in this hierarchy contain an N-terminal PH domain, a EF hand domain, a catalytic domain split into X and Y halves, and a C-terminal C2 domain. PLCs (EC 3.1.4.3) play a role in the initiation of cellular activation, proliferation, differentiation and apoptosis. They are central to inositol lipid signalling pathways, facilitating intracellular Ca2+ release and protein kinase C (PKC) activation. Specificaly, PLCs catalyze the cleavage of phosphatidylinositol-4,5-bisphosphate (PIP2) and result in the release of 1,2-diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3). These products trigger the activation of protein kinase C (PKC) and the release of Ca2+ from intracellular stores. There are fourteen kinds of mammalian phospholipase C proteins which are are classified into six isotypes (beta, gamma, delta, epsilon, zeta, eta). PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

Pssm-ID: 241514 Cd Length: 118 Bit Score: 46.41 E-value: 6.04e-06

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036     22 LELGTVMTVFSFRKSTpeRRTVQVIMETRQVAWSKTadKIEGFLDIMEIKEIRPGKNSKDF-ERAKAVRQKEDCCFTILY 100
Cdd:cd13360    1 LRQGTPLLKVTKKKKK--RILFKLDPESGKITWDSK--KPSKSLYIDDIKEIRTGEDARNYrEEFGISEEFEDRWITIIY 76

                         90       100       110
                 ....*....|....*....|....*....|...
gi 190036    101 GTQF--VLSTLSLAADSKEDAVNWLSGLKILHQ 131
Cdd:cd13360   77 FVPKknKLKTLHLIADTEEDFKLWTTTLEGLVK 109

SH3_Intersectin1_4

cd11993

Fourth Src homology 3 domain (or SH3D) of Intersectin-1; Intersectin-1 (ITSN1) is an adaptor ...

780-828

7.02e-06

Fourth Src homology 3 domain (or SH3D) of Intersectin-1; Intersectin-1 (ITSN1) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN1 localizes in membranous organelles, CCPs, the Golgi complex, and may be involved in the cell membrane trafficking system. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The fourth SH3 domain (or SH3D) of ITSN1 has been shown to bind SHIP2, Numb, CdGAP, and N-WASP. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212926 Cd Length: 65 Bit Score: 44.72 E-value: 7.02e-06

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 190036    780 YKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRIQQ----YFPSNYVEDIS 828
Cdd:cd11993   12 YTATGPEQLTLAPGQLILIRKKNPGGWWEGELQARGKKrqigWFPANYVKLLS 64

SH2_Src_Fgr

cd10367

Src homology 2 (SH2) domain found in Gardner-Rasheed feline sarcoma viral (v-fgr) oncogene ...

642-720

7.80e-06

Pssm-ID: 198230 Cd Length: 101 Bit Score: 45.67 E-value: 7.80e-06

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    642 ESKPWYYDSLSRGEAEDMLMRI--PRdGAFLIRKREGSD-SYAITFR----ARGK-VKHCRINR-DGRHFVLGTSAYFES 712
Cdd:cd10367    1 QAEEWYFGKIGRKDAERQLLSPgnPR-GAFLIRESETTKgAYSLSIRdwdqNRGDhVKHYKIRKlDTGGYYITTRAQFDT 79


                 ....*...
gi 190036    713 LVELVSYY 720
Cdd:cd10367   80 VQELVQHY 87

SH2_SHB

cd10389

Src homology 2 domain found in SH2 domain-containing adapter protein B (SHB); SHB functions in ...

646-735

8.41e-06

Src homology 2 domain found in SH2 domain-containing adapter protein B (SHB); SHB functions in generating signaling compounds in response to tyrosine kinase activation. SHB contains proline-rich motifs, a phosphotyrosine binding (PTB) domain, tyrosine phosphorylation sites, and a SH2 domain. SHB mediates certain aspects of platelet-derived growth factor (PDGF) receptor-, fibroblast growth factor (FGF) receptor-, neural growth factor (NGF) receptor TRKA-, T cell receptor-, interleukin-2 (IL-2) receptor- and focal adhesion kinase- (FAK) signaling. SRC-like FYN-Related Kinase FRK/RAK (also named BSK/IYK or GTK) and SHB regulate apoptosis, proliferation and differentiation. SHB promotes apoptosis and is also required for proper mitogenicity, spreading and tubular morphogenesis in endothelial cells. SHB also plays a role in preventing early cavitation of embryoid bodies and reduces differentiation to cells expressing albumin, amylase, insulin and glucagon. SHB is a multifunctional protein that has difference responses in different cells under various conditions. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198252 Cd Length: 97 Bit Score: 45.47 E-value: 8.41e-06

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    646 WYYDSLSRGEAEDmLMRIPRDGAFLIRKREGSD-SYAITFRARGKVKHCRINRDGRHFVLG-TSAYFESLVELVSYYEKH 723
Cdd:cd10389    3 WYHGAISRGDAEN-LLRLCKECSYLVRNSQTSKhDYSLSLKSNQGFMHMKLAKTKEKYVLGqNSPPFDSVPEVIHYYTTR 81

                         90
                 ....*....|....*.
gi 190036    724 SLYRK----MRLRYPV 735
Cdd:cd10389   82 KLPIKgaehLSLLYPV 97

SH3_Intersectin2_3

cd11992

Third Src homology 3 domain (or SH3C) of Intersectin-2; Intersectin-2 (ITSN2) is an adaptor ...

776-824

9.18e-06

Third Src homology 3 domain (or SH3C) of Intersectin-2; Intersectin-2 (ITSN2) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN2 also functions as a specific GEF for Cdc42 activation in epithelial morphogenesis, and is required in mitotic spindle orientation. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The third SH3 domain (SH3C) of ITSN2 has been shown to bind the K15 protein of Kaposi's sarcoma-associated herpesvirus. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212925 Cd Length: 52 Bit Score: 44.23 E-value: 9.18e-06

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*....
gi 190036    776 ALYDYKAKRSDELSFCRGALIHnVSKEPGGWWKGDYGTRiQQYFPSNYV 824
Cdd:cd11992    4 ALYPYSSSEPGDLTFNEGEEIL-VTQKDGEWWTGSIEDR-TGIFPSNYV 50

SH2_CRK_like

cd09926

Src homology 2 domain found in cancer-related signaling adaptor protein CRK; SH2 domain in the ...

540-620

1.01e-05

Src homology 2 domain found in cancer-related signaling adaptor protein CRK; SH2 domain in the CRK proteins. CRKI (SH2-SH3) and CRKII (SH2-SH3-SH3) are splicing isoforms of the oncoprotein CRK. CRKs regulate transcription and cytoskeletal reorganization for cell growth and motility by linking tyrosine kinases to small G proteins. The SH2 domain of CRK associates with tyrosine-phosphorylated receptors or components of focal adhesions, such as p130Cas and paxillin. CRK transmits signals to small G proteins through effectors that bind its SH3 domain, such as C3G, the guanine-nucleotide exchange factor (GEF) for Rap1 and R-Ras, and DOCK180, the GEF for Rac6. The binding of p130Cas to the CRK-C3G complex activates Rap1, leading to regulation of cell adhesion, and activates R-Ras, leading to JNK-mediated activation of cell proliferation, whereas the binding of CRK DOCK180 induces Rac1-mediated activation of cellular migration. The activity of the different splicing isoforms varies greatly with CRKI displaying substantial transforming activity, CRKII less so, and phosphorylated CRKII with no biological activity whatsoever. CRKII has a linker region with a phosphorylated Tyr and an additional C-terminal SH3 domain. The phosphorylated Tyr creates a binding site for its SH2 domain which disrupts the association between CRK and its SH2 target proteins. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198180 [Multi-domain] Cd Length: 106 Bit Score: 45.54 E-value: 1.01e-05

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    540 RTSAEKLLQeycmetGGKDGTFLVRESETFPNDYTLSFWRSGRVQHCRIRS-TMEGGTLKYYLTDNLRFRRMYALIQ--- 615
Cdd:cd09926   16 RQEAQELLQ------GQRHGVFLVRDSSTIPGDYVLSVSENSRVSHYIINSlGQPAPNQSRYRIGDQEFDDLPALLEfyk 89


                 ....*.
gi 190036    616 -HYRET 620
Cdd:cd09926   90 lHYLDT 95

SH2_a2chimerin_b2chimerin

cd10352

Src homology 2 (SH2) domain found in alpha2-chimerin and beta2-chimerin proteins; Chimerins ...

647-717

1.06e-05

Src homology 2 (SH2) domain found in alpha2-chimerin and beta2-chimerin proteins; Chimerins are a family of phorbol ester- and diacylglycerol-responsive GTPase-activating proteins. Alpha1-chimerin (formerly known as n-chimerin) and alpha2-chimerin are alternatively spliced products of a single gene, as are beta1- and beta2-chimerin. alpha1- and beta1-chimerin have a relatively short N-terminal region that does not encode any recognizable domains, whereas alpha2- and beta2-chimerin both include a functional SH2 domain that can bind to phosphotyrosine motifs within receptors. All of the isoforms contain a GAP domain with specificity in vitro for Rac1 and a diacylglycerol (DAG)-binding C1 domain which allows them to translocate to membranes in response to DAG signaling and anchors them in close proximity to activated Rac. Other C1 domain-containing diacylglycerol receptors including: PKC, Munc-13 proteins, phorbol ester binding scaffolding proteins involved in Ca2+-stimulated exocytosis, and RasGRPs, diacylglycerol-activated guanine-nucleotide exchange factors (GEFs) for Ras and Rap1. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198215 Cd Length: 91 Bit Score: 45.05 E-value: 1.06e-05

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 190036    647 YYDSLSRGEAEdMLMRIPRDGAFLIRKREGSDSYAI-TFRARGKVKHCRINRDG-RHFVLGTSAYFESLVELV 717
Cdd:cd10352    9 YHGLISREEAE-QLLSGASDGSYLIRESSRDDGYYTlSLRFNGKVKNYKLYYDGkNHYHYVGEKRFDTIHDLV 80

PH_12

pfam16457

Pleckstrin homology domain;

65-129

1.08e-05

Pleckstrin homology domain;

Pssm-ID: 465123 [Multi-domain] Cd Length: 128 Bit Score: 46.10 E-value: 1.08e-05

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 190036       65 LDIMEIKEIRPGKNSKDF--ERAKAVRQKEDCCFTILYGTQFVlSTLSLAADSKEDAVNWLSGLKIL 129
Cdd:pfam16457   61 IDLSDIKEVVTGKECPHVreSGKKSKKTSSTLAFSLIYGADEY-ELLDFVAPSESVAAIWLDGLNML 126

SH2_SH2D4B

cd10351

Src homology 2 domain found in the SH2 domain containing protein 4B (SH2D4B); SH2D4B contains ...

645-702

1.11e-05

Src homology 2 domain found in the SH2 domain containing protein 4B (SH2D4B); SH2D4B contains a single SH2 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198214 Cd Length: 103 Bit Score: 45.27 E-value: 1.11e-05

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 190036    645 PWYYDSLSRGEAEDMLMRIPrDGAFLIRKREGSDSYAITFRARGKVKHCRINRDGRHF 702
Cdd:cd10351    8 PWFHGIISREEAEALLMNAT-EGSFLVRVSEKIWGYTLSYRLQSGFKHFLVDASGDFY 64

SH3_Lasp1_C

cd11934

C-terminal Src Homology 3 domain of LIM and SH3 domain protein 1; Lasp1 is a cytoplasmic ...

775-827

1.12e-05

C-terminal Src Homology 3 domain of LIM and SH3 domain protein 1; Lasp1 is a cytoplasmic protein that binds focal adhesion proteins and is involved in cell signaling, migration, and proliferation. It is overexpressed in several cancer cells including breast, ovarian, bladder, and liver. In cancer cells, it can be found in the nucleus; its degree of nuclear localization correlates with tumor size and poor prognosis. Lasp1 is a 36kD protein containing an N-terminal LIM domain, two nebulin repeats, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212867 [Multi-domain] Cd Length: 59 Bit Score: 44.22 E-value: 1.12e-05

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....
gi 190036    775 KALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYG-TRIQQYFPSNYVEDI 827
Cdd:cd11934    6 RAVYDYNAADEDEVSFQDGDTIVNVQQIDDGWMYGTVErTGDTGMLPANYVEAI 59

SH3_Src_like

cd11845

Src homology 3 domain of Src kinase-like Protein Tyrosine Kinases; Src subfamily members ...

773-823

1.16e-05

Src homology 3 domain of Src kinase-like Protein Tyrosine Kinases; Src subfamily members include Src, Lck, Hck, Blk, Lyn, Fgr, Fyn, Yrk, Yes, and Brk. Src (or c-Src) proteins are cytoplasmic (or non-receptor) PTKs which are anchored to the plasma membrane. They contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). However, Brk lacks the N-terminal myristoylation sites. Src proteins are involved in signaling pathways that regulate cytokine and growth factor responses, cytoskeleton dynamics, cell proliferation, survival, and differentiation. They were identified as the first proto-oncogene products, and they regulate cell adhesion, invasion, and motility in cancer cells, and tumor vasculature, contributing to cancer progression and metastasis. Src kinases are overexpressed in a variety of human cancers, making them attractive targets for therapy. They are also implicated in acute inflammatory responses and osteoclast function. Src, Fyn, Yes, and Yrk are widely expressed, while Blk, Lck, Hck, Fgr, Lyn, and Brk show a limited expression pattern. This subfamily also includes Drosophila Src42A, Src oncogene at 42A (also known as Dsrc41) which accumulates at sites of cell-cell or cell-matrix adhesion, and participates in Drosphila development and wound healing. It has been shown to promote tube elongation in the tracheal system, is essential for proper cell-cell matching during dorsal closure, and regulates cell-cell contacts in developing Drosophila eyes. The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212779 [Multi-domain] Cd Length: 52 Bit Score: 43.73 E-value: 1.16e-05

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 190036    773 TVKALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDY-GTRIQQYFPSNY 823
Cdd:cd11845    1 IYVALYDYEARTDDDLSFKKGDRLQILDDSDGDWWLARHlSTGKEGYIPSNY 52

SH3_Pex13p_fungal

cd11771

Src Homology 3 domain of fungal peroxisomal membrane protein Pex13p; Pex13p, located in the ...

774-825

1.22e-05

Src Homology 3 domain of fungal peroxisomal membrane protein Pex13p; Pex13p, located in the peroxisomal membrane, contains two transmembrane regions and a C-terminal SH3 domain. It binds to the peroxisomal targeting type I (PTS1) receptor Pex5p and the docking factor Pex14p through its SH3 domain. It is essential for both PTS1 and PTS2 protein import pathways into the peroxisomal matrix. Pex13p binds Pex14p, which contains a PxxP motif, in a classical fashion to the proline-rich ligand binding site of its SH3 domain. It binds the WxxxF/Y motif of Pex5p in a novel site that does not compete with Pex14p binding. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212705 [Multi-domain] Cd Length: 60 Bit Score: 43.80 E-value: 1.22e-05

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    774 VKALYDYK-AKRSDELSFCRGALIHNVSK-----EPGGWWKGDygTRIQQ--YFPSNYVE 825
Cdd:cd11771    2 CRALYDFTpENPEMELSLKKGDIVAVLSKtdplgRDSEWWKGR--TRDGRigWFPSNYVE 59

SH3_GRAP_C

cd11951

C-terminal Src homology 3 domain of GRB2-related adaptor protein; GRAP is a GRB-2 like adaptor ...

774-824

1.29e-05

C-terminal Src homology 3 domain of GRB2-related adaptor protein; GRAP is a GRB-2 like adaptor protein that is highly expressed in lymphoid tissues. It acts as a negative regulator of T cell receptor (TCR)-induced lymphocyte proliferation by downregulating the signaling to the Ras/ERK pathway. It has been identified as a regulator of TGFbeta signaling in diabetic kidney tubules and may have a role in the pathogenesis of the disease. GRAP contains an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. The C-terminal SH3 domains (SH3c) of the related proteins, GRB2 and GRAP2, have been shown to bind to classical PxxP motif ligands, as well as to non-classical motifs. GRB2 SH3c binds Gab2 (Grb2-associated binder 2) through epitopes containing RxxK motifs, while the SH3c of GRAP2 binds to the phosphatase-like protein HD-PTP via a RxxxxK motif. SH3 domains are protein interaction domains that typically bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212884 Cd Length: 53 Bit Score: 43.64 E-value: 1.29e-05

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 190036    774 VKALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRIqQYFPSNYV 824
Cdd:cd11951    2 VQAQYDFSAEDPSQLSFRRGDIIEVLDCPDPNWWRGRISGRV-GFFPRNYV 51

SH2_SH2B2

cd10411

Src homology 2 (SH2) domain found in SH2B adapter proteins (SH2B1, SH2B2, SH2B3); SH2B2 (APS), ...

532-623

1.43e-05

Src homology 2 (SH2) domain found in SH2B adapter proteins (SH2B1, SH2B2, SH2B3); SH2B2 (APS), like other members of the SH2B adapter protein family, contains a pleckstrin homology domain, at least one dimerization domain, and a C-terminal SH2 domain which binds to phosphorylated tyrosines in a variety of tyrosine kinases. SH2B1 and SH2B2 function in signaling pathways found downstream of growth hormone receptor and receptor tyrosine kinases, including the insulin, insulin-like growth factor-I (IGF-I), platelet-derived growth factor (PDGF), nerve growth factor, hepatocyte growth factor, and fibroblast growth factor receptors. SH2B2beta, a new isoform of SH2B2, is an endogenous inhibitor of SH2B1 and/or SH2B2 (SH2B2alpha), negatively regulating insulin signaling and/or JAK2-mediated cellular responses. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198274 Cd Length: 97 Bit Score: 44.99 E-value: 1.43e-05

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    532 WFHKKVEKRTSAEKLLqeycmeTGG--KDGTFLVRESETFPNDYTLSFWRSGRVQHCRIrSTMEGGTLKyylTDNLRFRR 609
Cdd:cd10411   10 WFHGTLSRVKAAQLVL------AGGprSHGLFVIRQSETRPGEYVLTFNFQGKAKHLRL-SLNGHGQCH---VQHLWFQS 79

                         90
                 ....*....|....
gi 190036    610 MYALIQHYRETHLP 623
Cdd:cd10411   80 VFDMLRHFHTHPIP 93

SH3_D21-like

cd12142

Src Homology 3 domain of SH3 domain-containing protein 21 (SH3D21) and similar proteins; ...

775-825

1.44e-05

Src Homology 3 domain of SH3 domain-containing protein 21 (SH3D21) and similar proteins; N-terminal SH3 domain of the uncharacterized protein SH3 domain-containing protein 21, and similar uncharacterized domains, it belongs to the CD2AP-like_3 subfamily of proteins. The CD2AP-like_3 subfamily is composed of the third SH3 domain (SH3C) of CD2AP, CIN85 (Cbl-interacting protein of 85 kDa), and similar domains. CD2AP and CIN85 are adaptor proteins that bind to protein partners and assemble complexes that have been implicated in T cell activation, kidney function, and apoptosis of neuronal cells. They also associate with endocytic proteins, actin cytoskeleton components, and other adaptor proteins involved in receptor tyrosine kinase (RTK) signaling. CD2AP and the main isoform of CIN85 contain three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP and CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. SH3C of both proteins have been shown to bind to ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 213018 [Multi-domain] Cd Length: 55 Bit Score: 43.61 E-value: 1.44e-05

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 190036    775 KALYDYKAKRSDELSFCRGALIHNVSKEPG--GWWKGDYGTRiQQYFPSNYVE 825
Cdd:cd12142    3 RVLFDYNPVAPDELALKKGDVIEVISKETEdeGWWEGELNGR-RGFFPDNFVM 54

SH3_Intersectin1_3

cd11991

Third Src homology 3 domain (or SH3C) of Intersectin-1; Intersectin-1 (ITSN1) is an adaptor ...

776-824

1.53e-05

Third Src homology 3 domain (or SH3C) of Intersectin-1; Intersectin-1 (ITSN1) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN1 localizes in membranous organelles, CCPs, the Golgi complex, and may be involved in the cell membrane trafficking system. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The third SH3 domain (or SH3C) of ITSN1 has been shown to bind many proteins including dynamin1/2, CIN85, c-Cbl, SHIP2, Reps1, synaptojanin-1, and WNK, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212924 Cd Length: 52 Bit Score: 43.43 E-value: 1.53e-05

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*....
gi 190036    776 ALYDYKAKRSDELSFCRGALIhNVSKEPGGWWKGDYGTRIqQYFPSNYV 824
Cdd:cd11991    4 AMYTYESNEQGDLTFQQGDVI-LVTKKDGDWWTGTVGDKT-GVFPSNYV 50

SH2_SHD

cd10390

Src homology 2 domain found in SH2 domain-containing adapter proteins D (SHD); The expression ...

644-735

1.54e-05

Src homology 2 domain found in SH2 domain-containing adapter proteins D (SHD); The expression of SHD is restricted to the brain. SHD may be a physiological substrate of c-Abl and may function as an adapter protein in the central nervous system. It is also thought to be involved in apoptotic regulation. SHD contains five YXXP motifs, a substrate sequence preferred by Abl tyrosine kinases, in addition to a poly-proline rich region and a C-terminal SH2 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198253 Cd Length: 98 Bit Score: 45.07 E-value: 1.54e-05

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    644 KPWYYDSLSRGEAEDmLMRIPRDGAFLIRKREGS-DSYAITFRARGKVKHCRINRDGRH-FVLGT-SAYFESLVELVSYY 720
Cdd:cd10390    1 QPWFHGPLSRADAEN-LLSLCKEGSYLVRLSETRpQDCSLSLRSSQGFLHLKFARTRENqVVLGQhSGPFPSVPELVLHY 79

                         90
                 ....*....|....*....
gi 190036    721 EKHSL----YRKMRLRYPV 735
Cdd:cd10390   80 SSRPLpvqgAEHLALLYPV 98

SH3_CIN85_3

cd12057

Third Src Homology 3 domain (SH3C) of Cbl-interacting protein of 85 kDa; CIN85, also called ...

775-825

1.56e-05

Third Src Homology 3 domain (SH3C) of Cbl-interacting protein of 85 kDa; CIN85, also called SH3 domain-containing kinase-binding protein 1 (SH3KBP1) or CD2-binding protein 3 (CD2BP3) or Ruk, is an adaptor protein that is involved in the downregulation of receptor tyrosine kinases by facilitating endocytosis through interaction with endophilin-associated ubiquitin ligase Cbl proteins. It is also important in many other cellular processes including vesicle-mediated transport, cytoskeletal remodelling, apoptosis, cell adhesion and migration, and viral infection, among others. CIN85 exists as multiple variants from alternative splicing; the main variant contains three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. This alignment model represents the third SH3 domain (SH3C) of CIN85. SH3C has been shown to bind ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212990 [Multi-domain] Cd Length: 56 Bit Score: 43.73 E-value: 1.56e-05

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 190036    775 KALYDYKAKRSDELSFCRGALIHNVSKE--PGGWWKGDYGTRiQQYFPSNYVE 825
Cdd:cd12057    3 KVLFPYEAQNEDELTIKEGDIVTLISKDciDAGWWEGELNGR-RGVFPDNFVK 54

SH2_SHC

cd09925

Src homology 2 (SH2) domain found in SH2 adaptor protein C (SHC); SHC is involved in a wide ...

644-725

1.72e-05

Pssm-ID: 198179 Cd Length: 104 Bit Score: 45.03 E-value: 1.72e-05

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    644 KPWYYDSLSRGEAEDMLMripRDGAFLIRKREGS-DSYAITFRARGKVKH-CRINRDGRhfVLGTSAYFESLVELVSYYE 721
Cdd:cd09925    7 EPWYHGKMSRRDAESLLQ---TDGDFLVRESTTTpGQYVLTGMQNGQPKHlLLVDPEGV--VRTKDRVFESISHLINYHV 81


                 ....
gi 190036    722 KHSL 725
Cdd:cd09925   82 TNGL 85

SH2_SH2B1

cd10410

Src homology 2 (SH2) domain found in SH2B adapter proteins (SH2B1, SH2B2, SH2B3); SH2B1 (SH2-B, ...

529-623

1.84e-05

Src homology 2 (SH2) domain found in SH2B adapter proteins (SH2B1, SH2B2, SH2B3); SH2B1 (SH2-B, PSM), like other members of the SH2B adapter protein family, contains a pleckstrin homology domain, at least one dimerization domain, and a C-terminal SH2 domain which binds to phosphorylated tyrosines in a variety of tyrosine kinases. SH2B1 and SH2B2 function in signaling pathways found downstream of growth hormone receptor and receptor tyrosine kinases, including the insulin, insulin-like growth factor-I (IGF-I), platelet-derived growth factor (PDGF), nerve growth factor, hepatocyte growth factor, and fibroblast growth factor receptors. SH2B2beta, a new isoform of SH2B2, is an endogenous inhibitor of SH2B1 and/or SH2B2 (SH2B2alpha), negatively regulating insulin signaling and/or JAK2-mediated cellular responses. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198273 Cd Length: 97 Bit Score: 44.62 E-value: 1.84e-05

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    529 GEKWFHKKVEKRTSAEKLLQeycmetGG--KDGTFLVRESETFPNDYTLSFWRSGRVQHCRIrSTMEGGTLKyylTDNLR 606
Cdd:cd10410    7 GYPWFHGMLSRLKAAQLVLE------GGtgSHGVFLVRQSETRRGEYVLTFNFQGKAKHLRL-SLNEEGQCR---VQHLW 76

                         90
                 ....*....|....*..
gi 190036    607 FRRMYALIQHYRETHLP 623
Cdd:cd10410   77 FQSIFDMLEHFRVHPIP 93

PI-PLCc

cd00137

Catalytic domain of prokaryotic and eukaryotic phosphoinositide-specific phospholipase C; This ...

952-1031

1.91e-05

Pssm-ID: 176497 [Multi-domain] Cd Length: 274 Bit Score: 48.03 E-value: 1.91e-05

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    952 FREIRSFVETKADSIIRQK----PVDLLKYNQKGLTRVYPKGQRV---------DSSNYDPFRLW---LCGSQMVALNFQ 1015
Cdd:cd00137  179 SYNISSQDEYKAYDDEKVKlikaTVQFVDYNKNQLSRNYPSGTSGgtawyyyamDSNNYMPQMFWnanPAGCGIVILDFQ 258

                         90
                 ....*....|....*.
gi 190036   1016 TADKYMQMNHALFSLN 1031
Cdd:cd00137  259 TMDLPMQQYMAVIEFN 274

SH3_Lyn

cd12004

Src homology 3 domain of Lyn Protein Tyrosine Kinase; Lyn is a member of the Src subfamily of ...

774-828

1.93e-05

Src homology 3 domain of Lyn Protein Tyrosine Kinase; Lyn is a member of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. Lyn is expressed in B lymphocytes and myeloid cells. It exhibits both positive and negative regulatory roles in B cell receptor (BCR) signaling. Lyn, as well as Fyn and Blk, promotes B cell activation by phosphorylating ITAMs (immunoreceptor tyr activation motifs) in CD19 and in Ig components of BCR. It negatively regulates signaling by its unique ability to phosphorylate ITIMs (immunoreceptor tyr inhibition motifs) in cell surface receptors like CD22 and CD5. Lyn also plays an important role in G-CSF receptor signaling by phosphorylating a variety of adaptor molecules. Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212937 [Multi-domain] Cd Length: 56 Bit Score: 43.44 E-value: 1.93e-05

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 190036    774 VKALYDYKAKRSDELSFCRGALIhNVSKEPGGWWKG-DYGTRIQQYFPSNYVEDIS 828
Cdd:cd12004    2 VVALYPYDGIHEDDLSFKKGEKL-KVIEEHGEWWKArSLTTKKEGFIPSNYVAKVN 56

SH2_Src_Lyn

cd10364

Src homology 2 (SH2) domain found in Lyn; Lyn is a member of the Src non-receptor type ...

642-729

2.45e-05

Pssm-ID: 198227 Cd Length: 101 Bit Score: 44.59 E-value: 2.45e-05

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    642 ESKPWYYDSLSRGEAEDMLMrIPRD--GAFLIRKREGSD-SYAITFR---ARGK--VKHCRINR-DGRHFVLGTSAYFES 712
Cdd:cd10364    1 ETEEWFFKDITRKDAERQLL-APGNsaGAFLIRESETLKgSYSLSVRdydPQHGdvIKHYKIRSlDNGGYYISPRITFPC 79

                         90
                 ....*....|....*....
gi 190036    713 LVELVSYYEKHS--LYRKM 729
Cdd:cd10364   80 ISDMIKHYQKQSdgLCRRL 98

SH3_p47phox_like

cd11856

Src homology 3 domains of the p47phox subunit of NADPH oxidase and similar domains; This ...

776-825

2.49e-05

Src homology 3 domains of the p47phox subunit of NADPH oxidase and similar domains; This family is composed of the tandem SH3 domains of p47phox subunit of NADPH oxidase and Nox Organizing protein 1 (NoxO1), the four SH3 domains of Tks4 (Tyr kinase substrate with four SH3 domains), the five SH3 domains of Tks5, the SH3 domain of obscurin, Myosin-I, and similar domains. Most members of this group also contain Phox homology (PX) domains, except for obscurin and Myosin-I. p47phox and NoxO1 are regulators of the phagocytic NADPH oxidase complex (also called Nox2 or gp91phox) and nonphagocytic NADPH oxidase Nox1, respectively. They play roles in the activation of their respective NADPH oxidase, which catalyzes the transfer of electrons from NADPH to molecular oxygen to form superoxide. Tks proteins are Src substrates and scaffolding proteins that play important roles in the formation of podosomes and invadopodia, the dynamic actin-rich structures that are related to cell migration and cancer cell invasion. Obscurin is a giant muscle protein that plays important roles in the organization and assembly of the myofibril and the sarcoplasmic reticulum. Type I myosins (Myosin-I) are actin-dependent motors in endocytic actin structures and actin patches. They play roles in membrane traffic in endocytic and secretory pathways, cell motility, and mechanosensing. Myosin-I contains an N-terminal actin-activated ATPase, a phospholipid-binding TH1 (tail homology 1) domain, and a C-terminal extension which includes an F-actin-binding TH2 domain, an SH3 domain, and an acidic peptide that participates in activating the Arp2/3complex. The SH3 domain of myosin-I is required for myosin-I-induced actin polymerization. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212790 [Multi-domain] Cd Length: 53 Bit Score: 43.01 E-value: 2.49e-05

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|
gi 190036    776 ALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRiQQYFPSNYVE 825
Cdd:cd11856    4 AIADYEAQGDDEISLQEGEVVEVLEKNDSGWWYVRKGDK-EGWVPASYLE 52

SH3_PSTPIP1

cd11824

Src homology 3 domain of Proline-Serine-Threonine Phosphatase-Interacting Protein 1; PSTPIP1, ...

776-825

2.68e-05

Src homology 3 domain of Proline-Serine-Threonine Phosphatase-Interacting Protein 1; PSTPIP1, also called CD2 Binding Protein 1 (CD2BP1), is mainly expressed in hematopoietic cells. It is a binding partner of the cell surface receptor CD2 and PTP-PEST, a tyrosine phosphatase which functions in cell motility and Rac1 regulation. It also plays a role in the activation of the Wiskott-Aldrich syndrome protein (WASP), which couples actin rearrangement and T cell activation. Mutations in the gene encoding PSTPIP1 cause the autoinflammatory disorder known as PAPA (pyogenic sterile arthritis, pyoderma gangrenosum, and acne) syndrome. PSTPIP1 contains an N-terminal F-BAR domain, PEST motifs, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212758 [Multi-domain] Cd Length: 53 Bit Score: 42.75 E-value: 2.68e-05

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....
gi 190036    776 ALYDYKAKRSDELSFCRGALIHNVSKEPGGWWK----GDYGtriqqYFPSNYVE 825
Cdd:cd11824    4 VLYDYTAQEDDELSISKGDVVAVIEKGEDGWWTvernGQKG-----LVPGTYLE 52

SH3_VAV3_2

cd11978

C-terminal (or second) Src homology 3 domain of VAV3 protein; VAV3 is ubiquitously expressed ...

776-826

2.72e-05

C-terminal (or second) Src homology 3 domain of VAV3 protein; VAV3 is ubiquitously expressed and functions as a phosphorylation-dependent guanine nucleotide exchange factor (GEF) for RhoA, RhoG, and Rac1. It has been implicated to function in the hematopoietic, bone, cerebellar, and cardiovascular systems. VAV3 is essential in axon guidance in neurons that control blood pressure and respiration. It is overexpressed in prostate cancer cells and it plays a role in regulating androgen receptor transcriptional activity. VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. The SH3 domain of VAV is involved in the localization of proteins to specific sites within the cell, by interacting with proline-rich sequences within target proteins. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212911 [Multi-domain] Cd Length: 56 Bit Score: 42.70 E-value: 2.72e-05

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 190036    776 ALYDYKAKRSDELSFCRGALIHNVSKE-PGGWWKGDYGTRIqQYFPSNYVED 826
Cdd:cd11978    5 ARYDFCARDMRELSLLKGDVVKIYTKMsTNGWWRGEVNGRV-GWFPSTYVEE 55

SH3_Bzz1_2

cd11778

Second Src Homology 3 domain of Bzz1 and similar domains; Bzz1 (or Bzz1p) is a WASP ...

773-823

3.10e-05

Second Src Homology 3 domain of Bzz1 and similar domains; Bzz1 (or Bzz1p) is a WASP/Las17-interacting protein involved in endocytosis and trafficking to the vacuole. It physically interacts with type I myosins and functions in the early steps of endocytosis. Together with other proteins, it induces membrane scission in yeast. Bzz1 contains an N-terminal F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs), a central coiled-coil, and two C-terminal SH3 domains. This model represents the second C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212712 [Multi-domain] Cd Length: 51 Bit Score: 42.49 E-value: 3.10e-05

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 190036    773 TVKALYDYKAKRSDELSFCRGALIHNVSKEPG-GWWKGDYGTrIQQYFPSNY 823
Cdd:cd11778    1 YVEALYDYEAQGDDEISIRVGDRIAVIRGDDGsGWTYGEING-VKGLFPTSY 51

SH3_SNX9_like

cd11763

Src Homology 3 domain of Sorting Nexin 9 and similar proteins; Sorting nexins (SNXs) are Phox ...

774-825

3.18e-05

Src Homology 3 domain of Sorting Nexin 9 and similar proteins; Sorting nexins (SNXs) are Phox homology (PX) domain containing proteins that are involved in regulating membrane traffic and protein sorting in the endosomal system. SNXs differ from each other in their lipid-binding specificity, subcellular localization and specific function in the endocytic pathway. This subfamily consists of SH3 domain containing SNXs including SNX9, SNX18, SNX33, and similar proteins. SNX9 is localized to plasma membrane endocytic sites and acts primarily in clathrin-mediated endocytosis, while SNX18 is localized to peripheral endosomal structures, and acts in a trafficking pathway that is clathrin-independent but relies on AP-1 and PACS1. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212697 [Multi-domain] Cd Length: 55 Bit Score: 42.70 E-value: 3.18e-05

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 190036    774 VKALYDYKAKRSDELSFCRGALIHNVSKEPG-GWWKGDYGTRIQQYFPSNYVE 825
Cdd:cd11763    2 VRALYDFDSQPSGELSLRAGEVLTITRQDVGdGWLEGRNSRGEVGLFPSSYVE 54

SH2_Cterm_shark_like

cd10348

C-terminal Src homology 2 (SH2) domain found in SH2 domains, ANK, and kinase domain (shark) ...

646-720

3.23e-05

C-terminal Src homology 2 (SH2) domain found in SH2 domains, ANK, and kinase domain (shark) proteins; These non-receptor protein-tyrosine kinases contain two SH2 domains, five ankyrin (ANK)-like repeats, and a potential tyrosine phosphorylation site in its carboxyl-terminal tail which resembles the phosphorylation site in members of the src family. Like, mammalian non-receptor protein-tyrosine kinases, ZAP-70 and syk proteins, they do not have SH3 domains. However, the presence of ANK makes these unique among protein-tyrosine kinases. Both tyrosine kinases and ANK repeats have been shown to transduce developmental signals, and SH2 domains are known to participate intimately in tyrosine kinase signaling. These tyrosine kinases are believed to be involved in epithelial cell polarity. The members of this family include the shark (SH2 domains, ANK, and kinase domain) gene in Drosophila and yellow fever mosquitos, as well as the hydra protein HTK16. Drosophila Shark is proposed to transduce intracellularly the Crumbs, a protein necessary for proper organization of ectodermal epithelia, intercellular signal. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198211 Cd Length: 86 Bit Score: 43.56 E-value: 3.23e-05

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 190036    646 WYYDSLSRGEA-EDMLMRIPRDGAFLIR-KREGSDSYAITFRARGKVKHCRI-NRDGRHFVLGTSAYFESLVELVSYY 720
Cdd:cd10348    2 WLHGALDRNEAvEILKQKADADGSFLVRySRRRPGGYVLTLVYENHVYHFEIqNRDDKWFYIDDGPYFESLEHLIEHY 79

SH2_Grb7_family

cd09944

Src homology 2 (SH2) domain found in the growth factor receptor bound, subclass 7 (Grb7) ...

641-736

3.48e-05

Pssm-ID: 198197 [Multi-domain] Cd Length: 108 Bit Score: 44.33 E-value: 3.48e-05

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    641 HESKPWYYDSLSRGEAEDMLMRI-PRDGAFLIRKREGS-DSYAITFRARGKVKHCRI---NRDGR-HFVLGTSAY-FESL 713
Cdd:cd09944    2 HRSQPWFHGGISRDEAARLIRQQgLVDGVFLVRESQSNpGAFVLSLKHGQKIKHYQIipiEDEGQwYFTLDDGVTkFYDL 81

                         90       100
                 ....*....|....*....|...
gi 190036    714 VELVSYYEKHSLYRKMRLRYPVT 736
Cdd:cd09944   82 LQLVEFYQLNAGSLPTRLKHYCT 104

SH2_C-SH2_Zap70_Syk_like

cd10345

C-terminal Src homology 2 (SH2) domain found in Zeta-chain-associated protein kinase 70 ...

645-719

3.62e-05

C-terminal Src homology 2 (SH2) domain found in Zeta-chain-associated protein kinase 70 (ZAP-70) and Spleen tyrosine kinase (Syk) proteins; ZAP-70 and Syk comprise a family of hematopoietic cell specific protein tyrosine kinases (PTKs) that are required for antigen and antibody receptor function. ZAP-70 is expressed in T and natural killer (NK) cells and Syk is expressed in B cells, mast cells, polymorphonuclear leukocytes, platelets, macrophages, and immature T cells. They are required for the proper development of T and B cells, immune receptors, and activating NK cells. They consist of two N-terminal Src homology 2 (SH2) domains and a C-terminal kinase domain separated from the SH2 domains by a linker or hinge region. Phosphorylation of both tyrosine residues within the Immunoreceptor Tyrosine-based Activation Motifs (ITAM; consensus sequence Yxx[LI]x(7,8)Yxx[LI]) by the Src-family PTKs is required for efficient interaction of ZAP-70 and Syk with the receptor subunits and for receptor function. ZAP-70 forms two phosphotyrosine binding pockets, one of which is shared by both SH2 domains. In Syk the two SH2 domains do not form such a phosphotyrosine-binding site. The SH2 domains here are believed to function independently. In addition, the two SH2 domains of Syk display flexibility in their relative orientation, allowing Syk to accommodate a greater variety of spacing sequences between the ITAM phosphotyrosines and singly phosphorylated non-classical ITAM ligands. This model contains the C-terminus SH2 domains of both Syk and Zap70. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198208 Cd Length: 95 Bit Score: 43.91 E-value: 3.62e-05

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 190036    645 PWYYDSLSRGEAEDMLMRIPR-DGAFLIRKREGSDSYAITFRARGKVKHCRINRD-GRHFVLGTSAYFESLVELVSY 719
Cdd:cd10345    1 PWFHGKISREESEQIVLIGSKtNGKFLIRARDNNGSYALCLLHEGKVLHYRIDKDkTGKLSIPEGKKFDTLWQLVEH 77

SH2_Tec_Itk

cd10396

Src homology 2 (SH2) domain found in Tec protein, IL2-inducible T-cell kinase (Itk); A member ...

646-737

3.74e-05

Src homology 2 (SH2) domain found in Tec protein, IL2-inducible T-cell kinase (Itk); A member of the Tec protein tyrosine kinase Itk is expressed thymus, spleen, lymph node, T lymphocytes, NK and mast cells. It plays a role in T-cell proliferation and differentiation, analogous to Tec family kinases Txk. Itk has been shown to interact with Fyn, Wiskott-Aldrich syndrome protein, KHDRBS1, PLCG1, Lymphocyte cytosolic protein 2, Linker of activated T cells, Karyopherin alpha 2, Grb2, and Peptidylprolyl isomerase A. Most of the Tec family members have a PH domain (Txk and the short (type 1) splice variant of Drosophila Btk29A are exceptions), a Tec homology (TH) domain, a SH3 domain, a SH2 domain, and a protein kinase catalytic domain. The TH domain consists of a Zn2+-binding Btk motif and a proline-rich region. The Btk motif is found in Tec kinases, Ras GAP, and IGBP. It is crucial for the function of Tec PH domains and it's lack of presence in Txk is not surprising since it lacks a PH domain. The type 1 splice form of the Drosophila homolog also lacks both the PH domain and the Btk motif. The proline-rich regions are highly conserved for the most part with the exception of Bmx whose residues surrounding the PXXP motif are not conserved (TH-like) and Btk29A which is entirely unique with large numbers of glycine residues (TH-extended). Tec family members all lack a C-terminal tyrosine having an autoinhibitory function in its phosphorylated state. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198259 Cd Length: 108 Bit Score: 44.01 E-value: 3.74e-05

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    646 WYYDSLSRGEAEDMLMRIPRDGAFLIRKREGSDSYAITF--RARGK----VKHCRI---NRDGRHFVLGTSAYFESLVEL 716
Cdd:cd10396    8 WYNKNINRSKAEKLLRDEGKEGGFMVRDSSQPGLYTVSLytKAGGEgnpcIRHYHIketNDSPKKYYLAEKHVFNSIPEL 87

                         90       100
                 ....*....|....*....|.
gi 190036    717 VSYYEKHSLYRKMRLRYPVTP 737
Cdd:cd10396   88 IEYHKHNAAGLVTRLRYPVSS 108

C2A_MCTP_PRT_plant

cd04022

C2 domain first repeat found in Multiple C2 domain and Transmembrane region Proteins (MCTP); ...

1063-1147

3.79e-05

C2 domain first repeat found in Multiple C2 domain and Transmembrane region Proteins (MCTP); plant subset; MCTPs are involved in Ca2+ signaling at the membrane. Plant-MCTPs are composed of a variable N-terminal sequence, four C2 domains, two transmembrane regions (TMRs), and a short C-terminal sequence. It is one of four protein classes that are anchored to membranes via a transmembrane region; the others being synaptotagmins, extended synaptotagmins, and ferlins. MCTPs are the only membrane-bound C2 domain proteins that contain two functional TMRs. MCTPs are unique in that they bind Ca2+ but not phospholipids. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the first C2 repeat, C2A, and has a type-II topology.

Pssm-ID: 175989 [Multi-domain] Cd Length: 127 Bit Score: 44.64 E-value: 3.79e-05

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036   1063 LTVKVLGARHL-PKLGRSIACPFVEVeicgaEYGNNKFKTTVVnDNGLSPIWaptQEKVTFEIYDPNLafLRFVVYEEDM 1141
Cdd:cd04022    2 LVVEVVDAQDLmPKDGQGSSSAYVEL-----DFDGQKKRTRTK-PKDLNPVW---NEKLVFNVSDPSR--LSNLVLEVYV 70


                 ....*.
gi 190036   1142 FSDPNF 1147
Cdd:cd04022   71 YNDRRS 76

SH3_Brk

cd11847

Src homology 3 domain of Brk (Breast tumor kinase) Protein Tyrosine Kinase (PTK), also called ...

775-824

3.92e-05

Src homology 3 domain of Brk (Breast tumor kinase) Protein Tyrosine Kinase (PTK), also called PTK6; Brk is a cytoplasmic (or non-receptor) PTK with limited homology to Src kinases. It has been found to be overexpressed in a majority of breast tumors. It plays roles in normal cell differentiation, proliferation, survival, migration, and cell cycle progression. Brk substrates include RNA-binding proteins (SLM-1/2, Sam68), transcription factors (STAT3/5), and signaling molecules (Akt, paxillin, IRS-4). Src kinases in general contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr; they are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). However, Brk lacks the N-terminal myristoylation site. The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212781 [Multi-domain] Cd Length: 58 Bit Score: 42.55 E-value: 3.92e-05

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 190036    775 KALYDYKAKRSDELSFCRGALIHNVSKEpGGWW----KGDYGTRIQQ-YFPSNYV 824
Cdd:cd11847    3 KALWDFKARGDEELSFQAGDQFRIAERS-GDWWtalkLDRAGGVVAQgFVPNNYL 56

SH2_Grb14

cd10414

Src homology 2 (SH2) domain found in the growth factor receptor bound, subclass 14 (Grb14) ...

641-721

4.01e-05

Pssm-ID: 198277 Cd Length: 108 Bit Score: 44.15 E-value: 4.01e-05

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    641 HESKPWYYDSLSRGEAEDMLMRI-PRDGAFLIRKREGS-DSYAITFRARGKVKHCRI---NRDGRHFVLGTSAY--FESL 713
Cdd:cd10414    2 HRSQPWFHHKISRDEAQRLIIQQgLVDGVFLVRDSQSNpRTFVLSMSHGQKIKHFQIipvEDDGELFHTLDDGHtrFTDL 81


                 ....*...
gi 190036    714 VELVSYYE 721
Cdd:cd10414   82 IQLVEFYQ 89

SH3_PRMT2

cd11806

Src homology 3 domain of Protein arginine N-methyltransferase 2; PRMT2, also called HRMT1L1, ...

776-826

4.03e-05

Src homology 3 domain of Protein arginine N-methyltransferase 2; PRMT2, also called HRMT1L1, belongs to the arginine methyltransferase protein family. It functions as a coactivator to both estrogen receptor alpha (ER-alpha) and androgen receptor (AR), presumably through arginine methylation. The ER-alpha transcription factor is involved in cell proliferation, differentiation, morphogenesis, and apoptosis, and is also implicated in the development and progression of breast cancer. PRMT2 and its variants are upregulated in breast cancer cells and may be involved in modulating the ER-alpha signaling pathway during formation of breast cancer. PRMT2 also plays a role in regulating the function of E2F transcription factors, which are critical cell cycle regulators, by binding to the retinoblastoma gene product (RB). It contains an N-terminal SH3 domain and an AdoMet binding domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212740 [Multi-domain] Cd Length: 53 Bit Score: 42.38 E-value: 4.03e-05

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 190036    776 ALYDYKAKRSDELSFCRGALIHNVSKEPGGWW----KGDYGtriqqYFPSNYVED 826
Cdd:cd11806    4 AIADFVATDDSQLSFESGDKLLVLRKPSVDWWwaehNGCCG-----YIPASHLHQ 53

SH2_Cterm_shark_like

cd10348

C-terminal Src homology 2 (SH2) domain found in SH2 domains, ANK, and kinase domain (shark) ...

532-617

4.17e-05

Pssm-ID: 198211 Cd Length: 86 Bit Score: 43.18 E-value: 4.17e-05

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    532 WFHKKVEKRTSAEKLLQEycmetGGKDGTFLVRESETFPNDYTLSFWRSGRVQHCRIRSTMEggtLKYYLTDNLRFRRMY 611
Cdd:cd10348    2 WLHGALDRNEAVEILKQK-----ADADGSFLVRYSRRRPGGYVLTLVYENHVYHFEIQNRDD---KWFYIDDGPYFESLE 73


                 ....*.
gi 190036    612 ALIQHY 617
Cdd:cd10348   74 HLIEHY 79

PH_PLC_beta

cd13361

Phospholipase C-beta (PLC-beta) pleckstrin homology (PH) domain; PLC-beta (PLCbeta) is ...

64-130

4.68e-05

Phospholipase C-beta (PLC-beta) pleckstrin homology (PH) domain; PLC-beta (PLCbeta) is regulated by heterotrimeric G protein-coupled receptors through their C2 domain and long C-terminal extension which forms an autoinhibitory helix. There are four isoforms: PLC-beta1-4. The PH domain of PLC-beta2 and PLC-beta3 plays a dual role, much like PLC-delta1, by binding to the plasma membrane, as well as the interaction site for the catalytic activator. However, PLC-beta binds to the lipid surface independent of PIP2. PLC-beta1 seems to play unspecified roles in cellular proliferation and differentiation. PLC-beta consists of an N-terminal PH domain, a EF hand domain, a catalytic domain split into X and Y halves, a C2 domain and a C-terminal PDZ. Members of the Rho GTPase family (e.g., Rac1, Rac2, Rac3, and cdc42) have been implicated in their activation by binding to an alternate site on the N-terminal PH domain. A basic amino acid region within the enzyme's long C-terminal tail appears to function as a Nuclear Localization Signal for import into the nucleus. PLCs (EC 3.1.4.3) play a role in the initiation of cellular activation, proliferation, differentiation and apoptosis. They are central to inositol lipid signalling pathways, facilitating intracellular Ca2+ release and protein kinase C (PKC) activation. Specificaly, PLCs catalyze the cleavage of phosphatidylinositol-4,5-bisphosphate (PIP2) and result in the release of 1,2-diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3). These products trigger the activation of protein kinase C (PKC) and the release of Ca2+ from intracellular stores. There are fourteen kinds of mammalian phospholipase C proteins which are are classified into six isotypes (beta, gamma, delta, epsilon, zeta, eta). PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.the plasma membrane, but only a few (less than 10%) display strong specificity in binding inositol phosphates. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinases, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, cytoskeletal associated molecules, and in lipid associated enzymes.

Pssm-ID: 270167 Cd Length: 127 Bit Score: 44.10 E-value: 4.68e-05

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 190036     64 FLDIMEIKEIRPGKNSKD----FERAKAVRQK----EDCCFTILYGTQFV-LSTLSLAADSKEDAVNWLSGL-KILH 130
Cdd:cd13361   42 VLDLSLIRDVRTGKYPKDpkdlKEREVNVGGSdedlEDRTLTIVSGTDLVnISFINFVAESEEVAKIWTEGLfKLAH 118

SH2_Src_Fyn_isoform_b_like

cd10419

Src homology 2 (SH2) domain found in Fyn isoform b like proteins; Fyn is a member of the Src ...

644-724

4.82e-05

Pssm-ID: 198282 Cd Length: 101 Bit Score: 43.51 E-value: 4.82e-05

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    644 KPWYYDSLSRGEAEDMLMRI--PRdGAFLIRKREGSD-SYAITFR----ARG-KVKHCRINR-DGRHFVLGTSAYFESLV 714
Cdd:cd10419    3 EEWYFGKLGRKDAERQLLSFgnPR-GTFLIRESETTKgAYSLSIRdwddMKGdHVKHYKIRKlDNGGYYITTRAQFETLQ 81

                         90
                 ....*....|
gi 190036    715 ELVSYYEKHS 724
Cdd:cd10419   82 QLVQHYSEKA 91

SH2_BCAR3

cd10337

Src homology 2 (SH2) domain in the Breast Cancer Anti-estrogen Resistance protein 3; BCAR3 is ...

532-617

4.96e-05

Src homology 2 (SH2) domain in the Breast Cancer Anti-estrogen Resistance protein 3; BCAR3 is part of a growing family of guanine nucleotide exchange factors is responsible for activation of Ras-family GTPases, including Sos1 and 2, GRF1 and 2, CalDAG-GEF/GRP1-4, C3G, cAMP-GEF/Epac 1 and 2, PDZ-GEFs, MR-GEF, RalGDS family members, RalGPS, RasGEF, Smg GDS, and phospholipase C(epsilon). 12102558 21262352 BCAR3 binds to the carboxy-terminus of BCAR1/p130Cas, a focal adhesion adapter protein. Over expression of BCAR1 (p130Cas) and BCAR3 induces estrogen independent growth in normally estrogen-dependent cell lines. They have been linked to resistance to anti-estrogens in breast cancer, Rac activation, and cell motility, though the BCAR3/p130Cas complex is not required for this activity in BCAR3. Many BCAR3-mediated signaling events in epithelial and mesenchymal cells are independent of p130Cas association. Structurally these proteins contain a single SH2 domain upstream of their RasGEF domain, which is responsible for the ability of BCAR3 to enhance p130Cas over-expression-induced migration. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198200 [Multi-domain] Cd Length: 136 Bit Score: 44.25 E-value: 4.96e-05

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    532 WFHKKVEkRTSAEKLLQeycmetggKDGTFLVRESETFPNDYTLS-FWRsGRVQHCRIRSTM----EGGTLKYYLTDNLR 606
Cdd:cd10337    8 WYHGRIP-RQVAESLVQ--------REGDFLVRDSLSSPGDYVLTcRWK-GQPLHFKINRVVlrpsEAYTRVQYQFEDEQ 77

                         90
                 ....*....|.
gi 190036    607 FRRMYALIQHY 617
Cdd:cd10337   78 FDSIPALVHFY 88

SH3_Cyk3p-like

cd11889

Src Homology 3 domain of Cytokinesis protein 3 and similar proteins; Cytokinesis protein 3 ...

774-824

5.38e-05

Src Homology 3 domain of Cytokinesis protein 3 and similar proteins; Cytokinesis protein 3 (Cyk3 or Cyk3p) is a component of the actomyosin ring independent cytokinesis pathway in yeast. It interacts with Inn1 and facilitates its recruitment to the bud neck, thereby promoting cytokinesis. Cyk3p contains an N-terminal SH3 domain and a C-terminal transglutaminase-like domain. The Cyk3p SH3 domain binds to the C-terminal proline-rich region of Inn1. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212822 Cd Length: 53 Bit Score: 42.10 E-value: 5.38e-05

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 190036    774 VKALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDY-GTRIQQYFPSNYV 824
Cdd:cd11889    2 VKAVYSWAGETEGDLGFLEGDLIEVLSIGDGSWWSGKLrRNGAEGIFPSNFV 53

SH2_SH2B2

cd10411

Src homology 2 (SH2) domain found in SH2B adapter proteins (SH2B1, SH2B2, SH2B3); SH2B2 (APS), ...

645-725

5.65e-05

Pssm-ID: 198274 Cd Length: 97 Bit Score: 43.45 E-value: 5.65e-05

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    645 PWYYDSLSRGEAEDMLMRI-PRD-GAFLIRKREGS-DSYAITFRARGKVKHCRINRDGRHFVLGTSAYFESLVELVSYYE 721
Cdd:cd10411    9 PWFHGTLSRVKAAQLVLAGgPRShGLFVIRQSETRpGEYVLTFNFQGKAKHLRLSLNGHGQCHVQHLWFQSVFDMLRHFH 88


                 ....
gi 190036    722 KHSL 725
Cdd:cd10411   89 THPI 92

EFh_PI-PLCdelta

cd16202

EF-hand motif found in phosphoinositide phospholipase C delta (PI-PLC-delta); PI-PLC-delta ...

145-298

5.89e-05

EF-hand motif found in phosphoinositide phospholipase C delta (PI-PLC-delta); PI-PLC-delta isozymes represent a class of metazoan PI-PLCs that are some of the most sensitive to calcium among all PLCs. Their activation is modulated by intracellular calcium ion concentration, phospholipids, polyamines, and other proteins, such as RhoAGAP. Like other PI-PLC isozymes, PI-PLC-delta isozymes contain a core set of domains, including an N-terminal pleckstrin homology (PH) domain, four atypical EF-hand motifs, a PLC catalytic core, and a single C-terminal C2 domain. The PLC catalytic core domain is a TIM barrel with two highly conserved regions (X and Y) split by a highly degenerate linker sequence. There are three PI-PLC-delta isozymes (1, 3 and 4). PI-PLC-delta1 is relatively well characterized. It is activated by high calcium levels generated by other PI-PLC family members, and therefore functions as a calcium amplifier within the cell. Different PI-PLC-delta isozymes have different tissue distribution and different subcellular locations. PI-PLC-delta1 is mostly a cytoplasmic protein, PI-PLC-delta3 is located in the membrane, and PI-PLC-delta4 is predominantly detected in the cell nucleus. PI-PLC-delta isozymes is evolutionarily conserved even in non-mammalian species, such as yeast, slime molds and plants.

Pssm-ID: 320032 [Multi-domain] Cd Length: 140 Bit Score: 44.14 E-value: 5.89e-05

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    145 WLRKQIYSVDQTRRNSISLRELKTILPLINFKVSS--AKFLKdKFVEIGAhKDELSFEQFHLFYKKLMFEQQksiLDE-F 221
Cdd:cd16202    1 WLKDQFRKADKNGDGKLSFKECKKLLKKLNVKVDKdyAKKLF-QEADTSG-EDVLDEEEFVQFYNRLTKRPE---IEElF 75

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    222 KKDSSvfilgntdrpDASAVYLHDFQRFLIHEQQE-----HWAQDL---------NKVRERMTkfiddtmretaepflfV 287
Cdd:cd16202   76 KKYSG----------DDEALTVEELRRFLQEEQKVkdvtlEWAEQLietyepsedLKAQGLMS----------------L 129

                        170
                 ....*....|.
gi 190036    288 DEFLTYLFSRE 298
Cdd:cd16202  130 DGFTLFLLSPD 140

SH2_BCAR3

cd10337

Src homology 2 (SH2) domain in the Breast Cancer Anti-estrogen Resistance protein 3; BCAR3 is ...

643-736

6.07e-05

Pssm-ID: 198200 [Multi-domain] Cd Length: 136 Bit Score: 44.25 E-value: 6.07e-05

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    643 SKPWYYDSLSRGEAEDMLmriPRDGAFLIRKREGS-DSYAITFRARGKVKHCRINRDGRH---------FVLGTSAyFES 712
Cdd:cd10337    5 SHAWYHGRIPRQVAESLV---QREGDFLVRDSLSSpGDYVLTCRWKGQPLHFKINRVVLRpseaytrvqYQFEDEQ-FDS 80

                         90       100
                 ....*....|....*....|....
gi 190036    713 LVELVSYYekhslyrkMRLRYPVT 736
Cdd:cd10337   81 IPALVHFY--------VGNRRPIS 96

C2_ArfGAP

cd04038

C2 domain present in Arf GTPase Activating Proteins (GAP); ArfGAP is a GTPase activating ...

1094-1151

6.33e-05

C2 domain present in Arf GTPase Activating Proteins (GAP); ArfGAP is a GTPase activating protein which regulates the ADP ribosylation factor Arf, a member of the Ras superfamily of GTP-binding proteins. The GTP-bound form of Arf is involved in Golgi morphology and is involved in recruiting coat proteins. ArfGAP is responsible for the GDP-bound form of Arf which is necessary for uncoating the membrane and allowing the Golgi to fuse with an acceptor compartment. These proteins contain an N-terminal ArfGAP domain containing the characteristic zinc finger motif (Cys-x2-Cys-x(16,17)-x2-Cys) and C-terminal C2 domain. C2 domains were first identified in Protein Kinase C (PKC). C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions.

Pssm-ID: 176003 [Multi-domain] Cd Length: 145 Bit Score: 44.24 E-value: 6.33e-05

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 190036   1094 YGNNKFKTTVVNDNgLSPIWaptQEKVTFEIYDPNLAfLRFVVYEEDMFSDPNFLAHA 1151
Cdd:cd04038   30 LGNQKVKTRVIKKN-LNPVW---NEELTLSVPNPMAP-LKLEVFDKDTFSKDDSMGEA 82

SH3_MYO15

cd11884

Src Homology 3 domain of Myosin XV; This subfamily is composed of proteins with similarity to ...

774-825

6.68e-05

Src Homology 3 domain of Myosin XV; This subfamily is composed of proteins with similarity to Myosin XVa. Myosin XVa is an unconventional myosin that is critical for the normal growth of mechanosensory stereocilia of inner ear hair cells. Mutations in the myosin XVa gene are associated with nonsyndromic hearing loss. Myosin XVa contains a unique N-terminal extension followed by a motor domain, light chain-binding IQ motifs, and a tail consisting of a pair of MyTH4-FERM tandems separated by a SH3 domain, and a PDZ domain. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212817 [Multi-domain] Cd Length: 56 Bit Score: 41.54 E-value: 6.68e-05

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 190036    774 VKALYDYKAKRSDELSFCRGALIHNVSKEPG---GWWKGDYGTRIqQYFPSNYVE 825
Cdd:cd11884    2 VVAVRAYITRDQTLLSFHKGDVIKLLPKEGPldpGWLFGTLDGRS-GAFPKEYVQ 55

SH2_SH2B1

cd10410

Src homology 2 (SH2) domain found in SH2B adapter proteins (SH2B1, SH2B2, SH2B3); SH2B1 (SH2-B, ...

639-725

7.36e-05

Pssm-ID: 198273 Cd Length: 97 Bit Score: 43.08 E-value: 7.36e-05

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    639 NPHESKPWYYDSLSRGEAEDMLMR--IPRDGAFLIRKREGS-DSYAITFRARGKVKHCR--INRDGRHFVlgTSAYFESL 713
Cdd:cd10410    3 QPLSGYPWFHGMLSRLKAAQLVLEggTGSHGVFLVRQSETRrGEYVLTFNFQGKAKHLRlsLNEEGQCRV--QHLWFQSI 80

                         90
                 ....*....|..
gi 190036    714 VELVSYYEKHSL 725
Cdd:cd10410   81 FDMLEHFRVHPI 92

SH3_SH3RF_1

cd11786

First Src Homology 3 domain of SH3 domain containing ring finger proteins; This model ...

775-825

7.42e-05

First Src Homology 3 domain of SH3 domain containing ring finger proteins; This model represents the first SH3 domain of SH3RF1 (or POSH), SH3RF2 (or POSHER), SH3RF3 (POSH2), and similar domains. Members of this family are scaffold proteins that function as E3 ubiquitin-protein ligases. They all contain an N-terminal RING finger domain and multiple SH3 domains; SH3RF1 and SH3RF3 have four SH3 domains while SH3RF2 has three. SH3RF1 plays a role in calcium homeostasis through the control of the ubiquitin domain protein Herp. It may also have a role in regulating death receptor mediated and JNK mediated apoptosis. SH3RF3 interacts with p21-activated kinase 2 (PAK2) and GTP-loaded Rac1. It may play a role in regulating JNK mediated apoptosis in certain conditions. SH3RF2 acts as an anti-apoptotic regulator of the JNK pathway by binding to and promoting the degradation of SH3RF1. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212720 [Multi-domain] Cd Length: 53 Bit Score: 41.58 E-value: 7.42e-05

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 190036    775 KALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTrIQQYFPSNYVE 825
Cdd:cd11786    3 KALYNYEGKEPGDLSFKKGDIILLRKRIDENWYHGECNG-KQGFFPASYVQ 52

SH2_Tec_Bmx

cd10399

Src homology 2 (SH2) domain found in Tec protein, Bmx; A member of the Tec protein tyrosine ...

530-618

7.43e-05

Pssm-ID: 198262 Cd Length: 106 Bit Score: 43.02 E-value: 7.43e-05

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    530 EKWFHKKVEkRTSAEKLLQEycmetGGKDGTFLVRESETFpNDYTLSFW------RSGRVQHCRIRSTMEGgtlKYYLTD 603
Cdd:cd10399    6 YDWFAGNIS-RSQSEQLLRQ-----KGKEGAFMVRNSSQV-GMYTVSLFskavndKKGTVKHYHVHTNAEN---KLYLAE 75

                         90
                 ....*....|....*
gi 190036    604 NLRFRRMYALIQHYR 618
Cdd:cd10399   76 NYCFDSIPKLIHYHQ 90

SH3_Intersectin_3

cd11838

Third Src homology 3 domain (or SH3C) of Intersectin; Intersectins (ITSNs) are adaptor ...

776-824

7.47e-05

Third Src homology 3 domain (or SH3C) of Intersectin; Intersectins (ITSNs) are adaptor proteins that function in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. They are essential for initiating clathrin-coated pit formation. They bind to many proteins through their multidomain structure and facilitate the assembly of multimeric complexes. Vertebrates contain two ITSN proteins, ITSN1 and ITSN2, which exist in alternatively spliced short and long isoforms. The short isoforms contain two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoforms, in addition, contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. ITSN1 and ITSN2 are both widely expressed, with variations depending on tissue type and stage of development. The third SH3 domain (or SH3C) of ITSN1 has been shown to bind many proteins including dynamin1/2, CIN85, c-Cbl, SHIP2, Reps1, synaptojanin-1, and WNK, among others. The SH3C of ITSN2 has been shown to bind the K15 protein of Kaposi's sarcoma-associated herpesvirus. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212772 [Multi-domain] Cd Length: 52 Bit Score: 41.63 E-value: 7.47e-05

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*....
gi 190036    776 ALYDYKAKRSDELSFCRGALIhNVSKEPGGWWKGDYGTRiQQYFPSNYV 824
Cdd:cd11838    4 ALYPYESNEPGDLTFNAGDVI-LVTKKDGEWWTGTIGDR-TGIFPSNYV 50

SH3_Intersectin_2

cd11837

Second Src homology 3 domain (or SH3B) of Intersectin; Intersectins (ITSNs) are adaptor ...

773-824

7.47e-05

Second Src homology 3 domain (or SH3B) of Intersectin; Intersectins (ITSNs) are adaptor proteins that function in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. They are essential for initiating clathrin-coated pit formation. They bind to many proteins through their multidomain structure and facilitate the assembly of multimeric complexes. Vertebrates contain two ITSN proteins, ITSN1 and ITSN2, which exist in alternatively spliced short and long isoforms. The short isoforms contain two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoforms, in addition, contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. ITSN1 and ITSN2 are both widely expressed, with variations depending on tissue type and stage of development. The second SH3 domain (or SH3B) of ITSN1 has been shown to bind WNK and CdGAP. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212771 [Multi-domain] Cd Length: 53 Bit Score: 41.58 E-value: 7.47e-05

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 190036    773 TVKALYDYKAKRSDELSFCRGALIhNVSKEPGGWWKGDYGTRIQQYFPSNYV 824
Cdd:cd11837    1 TATALYPWRAKKENHLSFAKGDII-TVLEQQEMWWFGELEGGEEGWFPKSYV 51

SH3_GRAF2

cd12065

Src Homology 3 domain of GTPase Regulator Associated with Focal adhesion kinase 2; GRAF2, also ...

775-825

7.81e-05

Src Homology 3 domain of GTPase Regulator Associated with Focal adhesion kinase 2; GRAF2, also called Rho GTPase activating protein 10 (ARHGAP10) or PS-GAP, is a GAP with activity towards Cdc42 and RhoA. It regulates caspase-activated p21-activated protein kinase-2 (PAK-2p34). GRAF2 interacts with PAK-2p34, leading to its stabilization and decrease of cell death. It is highly expressed in skeletal muscle, and is involved in alpha-catenin recruitment at cell-cell junctions. GRAF2 contains an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, a Rho GAP domain, and a C-terminal SH3 domain. The SH3 domain of GRAF binds PKNbeta, a target of the small GTPase Rho. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212998 [Multi-domain] Cd Length: 54 Bit Score: 41.51 E-value: 7.81e-05

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 190036    775 KALYDYKAKRSDELSFCRGALIHNV--SKEPgGWWKGDYGTRiQQYFPSNYVE 825
Cdd:cd12065    3 KAVYPCEAEHSSELSFEVGAIFEDVtlSREP-GWLEGTLNGK-RGLIPENYVE 53

SH3_CAS

cd11844

Src homology 3 domain of CAS (Crk-Associated Substrate) scaffolding proteins; CAS proteins ...

775-825

1.01e-04

Src homology 3 domain of CAS (Crk-Associated Substrate) scaffolding proteins; CAS proteins function as molecular scaffolds to regulate protein complexes that are involved in many cellular processes including migration, chemotaxis, apoptosis, differentiation, and progenitor cell function. They mediate the signaling of integrins at focal adhesions where they localize, and thus, regulate cell invasion and survival. Over-expression of these proteins is implicated in poor prognosis, increased metastasis, and resistance to chemotherapeutics in many cancers such as breast, lung, melanoma, and glioblastoma. CAS proteins have also been linked to the pathogenesis of inflammatory disorders, Alzheimer's, Parkinson's, and developmental defects. They share a common domain structure that includes an N-terminal SH3 domain, an unstructured substrate domain that contains many YxxP motifs, a serine-rich four-helix bundle, and a FAT-like C-terminal domain. Vertebrates contain four CAS proteins: BCAR1 (or p130Cas), NEDD9 (or HEF1), EFS (or SIN), and CASS4 (or HEPL). The SH3 domain of CAS proteins binds to diverse partners including FAK, FRNK, Pyk2, PTP-PEST, DOCK180, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212778 Cd Length: 56 Bit Score: 41.18 E-value: 1.01e-04

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....
gi 190036    775 KALYDYKAKRSDELSFCRGALIHNVSKEPG---GWWKGDYGTRiQQYFPSNYVE 825
Cdd:cd11844    3 RALYDNVAESPDELAFRRGDILTVLEQNTAgleGWWLCSLRGR-QGIAPGNRLK 55

SH3_Sorbs_1

cd11781

First Src Homology 3 domain of Sorbin and SH3 domain containing (Sorbs) proteins and similar ...

773-825

1.07e-04

First Src Homology 3 domain of Sorbin and SH3 domain containing (Sorbs) proteins and similar domains; This family, also called the vinexin family, is composed predominantly of adaptor proteins containing one sorbin homology (SoHo) and three SH3 domains. Members include the first SH3 domains of Sorbs1 (or ponsin), Sorbs2 (or ArgBP2), Vinexin (or Sorbs3), and similar domains. They are involved in the regulation of cytoskeletal organization, cell adhesion, and growth factor signaling. Members of this family bind multiple partners including signaling molecules like c-Abl, c-Arg, Sos, and c-Cbl, as well as cytoskeletal molecules such as vinculin and afadin. They may have overlapping functions. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212715 [Multi-domain] Cd Length: 53 Bit Score: 41.17 E-value: 1.07e-04

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 190036    773 TVKALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRIqQYFPSNYVE 825
Cdd:cd11781    1 KARALYPFKAQSAKELSLKKGDIIYIRRQIDKNWYEGEHNGRV-GIFPASYVE 52

SH2_Srm

cd10360

Src homology 2 (SH2) domain found in Src-related kinase lacking C-terminal regulatory tyrosine ...

532-617

1.13e-04

Pssm-ID: 198223 Cd Length: 79 Bit Score: 41.87 E-value: 1.13e-04

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    532 WFHKKVEkRTSAEKLLqeycMETGGKDGTFLVRESETFPNDYTLSFWRSGRVQHCRIrSTMEGGTLkyYLTDNLRFRRMY 611
Cdd:cd10360    2 WYFSGIS-RTQAQQLL----LSPPNEPGAFLIRPSESSLGGYSLSVRAQAKVCHYRI-CMAPSGSL--YLQKGRLFPGLE 73


                 ....*.
gi 190036    612 ALIQHY 617
Cdd:cd10360   74 ELLAYY 79

SH2_N-SH2_Zap70_Syk_like

cd09938

N-terminal Src homology 2 (SH2) domain found in Zeta-chain-associated protein kinase 70 ...

645-734

1.34e-04

N-terminal Src homology 2 (SH2) domain found in Zeta-chain-associated protein kinase 70 (ZAP-70) and Spleen tyrosine kinase (Syk) proteins; ZAP-70 and Syk comprise a family of hematopoietic cell specific protein tyrosine kinases (PTKs) that are required for antigen and antibody receptor function. ZAP-70 is expressed in T and natural killer (NK) cells and Syk is expressed in B cells, mast cells, polymorphonuclear leukocytes, platelets, macrophages, and immature T cells. They are required for the proper development of T and B cells, immune receptors, and activating NK cells. They consist of two N-terminal Src homology 2 (SH2) domains and a C-terminal kinase domain separated from the SH2 domains by a linker or hinge region. Phosphorylation of both tyrosine residues within the Immunoreceptor Tyrosine-based Activation Motifs (ITAM; consensus sequence Yxx[LI]x(7,8)Yxx[LI]) by the Src-family PTKs is required for efficient interaction of ZAP-70 and Syk with the receptor subunits and for receptor function. ZAP-70 forms two phosphotyrosine binding pockets, one of which is shared by both SH2 domains. In Syk the two SH2 domains do not form such a phosphotyrosine-binding site. The SH2 domains here are believed to function independently. In addition, the two SH2 domains of Syk display flexibility in their relative orientation, allowing Syk to accommodate a greater variety of spacing sequences between the ITAM phosphotyrosines and singly phosphorylated non-classical ITAM ligands. This model contains the N-terminus SH2 domains of both Syk and Zap70. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198191 Cd Length: 104 Bit Score: 42.38 E-value: 1.34e-04

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    645 PWYYDSLSRGEAEDMLMRI-PRDGAFLIRK-REGSDSYAITFRARGKVKHCRINR--DGRHFVLGTSAyFESLVELVSYY 720
Cdd:cd09938    2 PFFYGSITREEAEEYLKLAgMSDGLFLLRQsLRSLGGYVLSVCHGRKFHHYTIERqlNGTYAIAGGKA-HCGPAELCEYH 80

                         90
                 ....*....|....
gi 190036    721 EKHSLYRKMRLRYP 734
Cdd:cd09938   81 STDLDGLVCLLRKP 94

SH3_Amphiphysin

cd11790

Src Homology 3 domain of Amphiphysin and related domains; Amphiphysins function primarily in ...

773-827

1.37e-04

Src Homology 3 domain of Amphiphysin and related domains; Amphiphysins function primarily in endocytosis and other membrane remodeling events. They exist in several isoforms and mammals possess two amphiphysin proteins from distinct genes. Amphiphysin I proteins, enriched in the brain and nervous system, contain domains that bind clathrin, Adaptor Protein complex 2 (AP2), dynamin, and synaptojanin. They function in synaptic vesicle endocytosis. Human autoantibodies to amphiphysin I hinder GABAergic signaling and contribute to the pathogenesis of paraneoplastic stiff-person syndrome. Some amphiphysin II isoforms, also called Bridging integrator 1 (Bin1), are localized in many different tissues and may function in intracellular vesicle trafficking. In skeletal muscle, Bin1 plays a role in the organization and maintenance of the T-tubule network. Mutations in Bin1 are associated with autosomal recessive centronuclear myopathy. Amphiphysins contain an N-terminal BAR domain with an additional N-terminal amphipathic helix (an N-BAR), a variable central domain, and a C-terminal SH3 domain. The SH3 domain of amphiphysins bind proline-rich motifs present in binding partners such as dynamin, synaptojanin, and nsP3. It also belongs to a subset of SH3 domains that bind ubiquitin in a site that overlaps with the peptide binding site. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212724 [Multi-domain] Cd Length: 64 Bit Score: 41.16 E-value: 1.37e-04

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 190036    773 TVKALYDYKAKRSDELSFCRGALIHNVSKEP-----GGWWKG-DYGTRIQQYFPSNYVEDI 827
Cdd:cd11790    4 KVRATHDYTAEDTDELTFEKGDVILVIPFDDpeeqdEGWLMGvKESTGCRGVFPENFTERI 64

SH3_VAV2_2

cd11977

C-terminal (or second) Src homology 3 domain of VAV2 protein; VAV2 is widely expressed and ...

773-826

1.40e-04

C-terminal (or second) Src homology 3 domain of VAV2 protein; VAV2 is widely expressed and functions as a guanine nucleotide exchange factor (GEF) for RhoA, RhoB and RhoG and also activates Rac1 and Cdc42. It is implicated in many cellular and physiological functions including blood pressure control, eye development, neurite outgrowth and branching, EGFR endocytosis and degradation, and cell cluster morphology, among others. It has been reported to associate with Nek3. VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. The SH3 domain of VAV is involved in the localization of proteins to specific sites within the cell, by interacting with proline-rich sequences within target proteins. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212910 [Multi-domain] Cd Length: 58 Bit Score: 40.77 E-value: 1.40e-04

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 190036    773 TVKALYDYKAKRSDELSFCRGALIHNVSKEPG--GWWKGDYGTRIqQYFPSNYVED 826
Cdd:cd11977    2 TAVARYNFAARDMRELSLREGDVVRIYSRIGGdqGWWKGETNGRI-GWFPSTYVEE 56

SH3_CASS4

cd12000

Src homology 3 domain of CAS (Crk-Associated Substrate) scaffolding protein family member 4; ...

775-808

1.43e-04

Src homology 3 domain of CAS (Crk-Associated Substrate) scaffolding protein family member 4; CASS4, also called HEPL (HEF1-EFS-p130Cas-like), localizes to focal adhesions and plays a role in regulating FAK activity, focal adhesion integrity, and cell spreading. It is most abundant in blood cells and lung tissue, and is also found in high levels in leukemia and ovarian cell lines. CAS proteins function as molecular scaffolds to regulate protein complexes that are involved in many cellular processes. They share a common domain structure that includes an N-terminal SH3 domain, an unstructured substrate domain that contains many YxxP motifs, a serine-rich four-helix bundle, and a FAT-like C-terminal domain. The SH3 domain of CAS proteins binds to diverse partners including FAK, FRNK, Pyk2, PTP-PEST, DOCK180, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212933 Cd Length: 57 Bit Score: 41.02 E-value: 1.43e-04

                         10        20        30
                 ....*....|....*....|....*....|....*..
gi 190036    775 KALYDYKAKRSDELSFCRGALIHNVSKE-PG--GWWK 808
Cdd:cd12000    4 RALYDNKADCSDELAFRRGDILTVLEQNvPGseGWWK 40

SH3_SH3RF_3

cd11783

Third Src Homology 3 domain of SH3 domain containing ring finger 1 (SH3RF1), SH3RF3, and ...

776-824

1.58e-04

Third Src Homology 3 domain of SH3 domain containing ring finger 1 (SH3RF1), SH3RF3, and similar domains; SH3RF1 (or POSH) and SH3RF3 (or POSH2) are scaffold proteins that function as E3 ubiquitin-protein ligases. They contain an N-terminal RING finger domain and four SH3 domains. This model represents the third SH3 domain, located in the middle of SH3RF1 and SH3RF3, and similar domains. SH3RF1 plays a role in calcium homeostasis through the control of the ubiquitin domain protein Herp. It may also have a role in regulating death receptor mediated and JNK mediated apoptosis. SH3RF3 interacts with p21-activated kinase 2 (PAK2) and GTP-loaded Rac1. It may play a role in regulating JNK mediated apoptosis in certain conditions. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212717 [Multi-domain] Cd Length: 55 Bit Score: 40.84 E-value: 1.58e-04

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|
gi 190036    776 ALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKG-DYGTRIQQYFPSNYV 824
Cdd:cd11783    4 ALYPYKPQKPDELELRKGEMYTVTEKCQDGWFKGtSLRTGQSGVFPGNYV 53

SH3_ASAP

cd11821

Src homology 3 domain of ArfGAP with SH3 domain, ankyrin repeat and PH domain containing ...

774-809

1.70e-04

Src homology 3 domain of ArfGAP with SH3 domain, ankyrin repeat and PH domain containing proteins; ASAPs are Arf GTPase activating proteins (GAPs) and they function in regulating cell growth, migration, and invasion. They contain an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, an Arf GAP domain, ankyrin (ANK) repeats, and a C-terminal SH3 domain. Vertebrates contain at least three members, ASAP1, ASAP2, and ASAP3, but some ASAP3 proteins do not seem to harbor a C-terminal SH3 domain. ASAP1 and ASAP2 show GTPase activating protein (GAP) activity towards Arf1 and Arf5. They do not show GAP activity towards Arf6, but are able to mediate Arf6 signaling by binding stably to GTP-Arf6. ASAP3 is an Arf6-specific GAP. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212755 [Multi-domain] Cd Length: 53 Bit Score: 40.38 E-value: 1.70e-04

                         10        20        30
                 ....*....|....*....|....*....|....*.
gi 190036    774 VKALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKG 809
Cdd:cd11821    2 VRALYDCQADNDDELTFSEGEIIVVTGEEDDEWWEG 37

SH3_Intersectin2_1

cd11988

First Src homology 3 domain (or SH3A) of Intersectin-2; Intersectin-2 (ITSN2) is an adaptor ...

773-825

1.82e-04

First Src homology 3 domain (or SH3A) of Intersectin-2; Intersectin-2 (ITSN2) is an adaptor protein that functions in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. It plays a role in clathrin-coated pit (CCP) formation. It binds to many proteins through its multidomain structure and facilitate the assembly of multimeric complexes. ITSN2 also functions as a specific GEF for Cdc42 activation in epithelial morphogenesis, and is required in mitotic spindle orientation. It exists in alternatively spliced short and long isoforms. The short isoform contains two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoform, in addition, contains RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. The first SH3 domain (or SH3A) of ITSN2 is expected to bind many protein partners, similar to ITSN1 which has been shown to bind Sos1, dynamin1/2, CIN85, c-Cbl, PI3K-C2, SHIP2, N-WASP, and CdGAP, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212921 [Multi-domain] Cd Length: 57 Bit Score: 40.63 E-value: 1.82e-04

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 190036    773 TVKALYDYKAKRSDELSFCRGALIH---NVSKEPG---GWWKGDYGtriqqYFPSNYVE 825
Cdd:cd11988    3 NYRALYPFEARNHDEMSFNAGDIIQvdeKTVGEPGwlyGSFQGNFG-----WFPCNYVE 56

SH3_SH3RF3_3

cd11925

Third Src Homology 3 domain of SH3 domain containing ring finger 3, an E3 ubiquitin-protein ...

776-824

1.82e-04

Third Src Homology 3 domain of SH3 domain containing ring finger 3, an E3 ubiquitin-protein ligase; SH3RF3 is also called POSH2 (Plenty of SH3s 2) or SH3MD4 (SH3 multiple domains protein 4). It is a scaffold protein with E3 ubiquitin-protein ligase activity. It was identified in the screen for interacting partners of p21-activated kinase 2 (PAK2). It may play a role in regulating JNK mediated apoptosis in certain conditions. It also interacts with GTP-loaded Rac1. SH3RF3 is highly homologous to SH3RF1; it also contains an N-terminal RING finger domain and four SH3 domains. This model represents the third SH3 domain, located in the middle, of SH3RF3. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212858 Cd Length: 57 Bit Score: 40.75 E-value: 1.82e-04

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|
gi 190036    776 ALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKG-DYGTRIQQYFPSNYV 824
Cdd:cd11925    5 ALYAYKPQKNDELELRKGEMYRVIEKCQDGWFKGtSLRTGVSGVFPGNYV 54

SH3_Stac_1

cd11833

First C-terminal Src homology 3 domain of SH3 and cysteine-rich domain-containing (Stac) ...

776-824

1.93e-04

First C-terminal Src homology 3 domain of SH3 and cysteine-rich domain-containing (Stac) proteins; Stac proteins are putative adaptor proteins that contain a cysteine-rich C1 domain and one or two SH3 domains at the C-terminus. There are three mammalian members (Stac1, Stac2, and Stac3) of this family. Stac1 and Stac3 contain two SH3 domains while Stac2 contains a single SH3 domain at the C-terminus. This model represents the first C-terminal SH3 domain of Stac1 and Stac3, and the single C-terminal SH3 domain of Stac2. Stac1 and Stac2 have been found to be expressed differently in mature dorsal root ganglia (DRG) neurons. Stac1 is mainly expressed in peptidergic neurons while Stac2 is found in a subset of nonpeptidergic and all trkB+ neurons. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212767 [Multi-domain] Cd Length: 53 Bit Score: 40.18 E-value: 1.93e-04

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*....
gi 190036    776 ALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRIqQYFPSNYV 824
Cdd:cd11833    4 ALYKFKPQENEDLEMRPGDKITLLDDSNEDWWKGKIEDRV-GFFPANFV 51

SH3_Intersectin_1

cd11836

First Src homology 3 domain (or SH3A) of Intersectin; Intersectins (ITSNs) are adaptor ...

775-825

2.01e-04

First Src homology 3 domain (or SH3A) of Intersectin; Intersectins (ITSNs) are adaptor proteins that function in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. They are essential for initiating clathrin-coated pit formation. They bind to many proteins through their multidomain structure and facilitate the assembly of multimeric complexes. Vertebrates contain two ITSN proteins, ITSN1 and ITSN2, which exist in alternatively spliced short and long isoforms. The short isoforms contain two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoforms, in addition, contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. ITSN1 and ITSN2 are both widely expressed, with variations depending on tissue type and stage of development. The first SH3 domain (or SH3A) of ITSN1 has been shown to bind many proteins including Sos1, dynamin1/2, CIN85, c-Cbl, PI3K-C2, SHIP2, N-WASP, and CdGAP, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212770 [Multi-domain] Cd Length: 55 Bit Score: 40.42 E-value: 2.01e-04

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....
gi 190036    775 KALYDYKAKRSDELSFCRGALI---HNVSKEPgGWWKGDYGTRIqQYFPSNYVE 825
Cdd:cd11836    3 RALYAFEARNPDEISFQPGDIIqvdESQVAEP-GWLAGELKGKT-GWFPANYVE 54

C2B_Synaptotagmin

cd00276

C2 domain second repeat present in Synaptotagmin; Synaptotagmin is a membrane-trafficking ...

1053-1150

2.01e-04

C2 domain second repeat present in Synaptotagmin; Synaptotagmin is a membrane-trafficking protein characterized by a N-terminal transmembrane region, a linker, and 2 C-terminal C2 domains. There are several classes of Synaptotagmins. Previously all synaptotagmins were thought to be calcium sensors in the regulation of neurotransmitter release and hormone secretion, but it has been shown that not all of them bind calcium. Of the 17 identified synaptotagmins only 8 bind calcium (1-3, 5-7, 9, 10). The function of the two C2 domains that bind calcium are: regulating the fusion step of synaptic vesicle exocytosis (C2A) and binding to phosphatidyl-inositol-3,4,5-triphosphate (PIP3) in the absence of calcium ions and to phosphatidylinositol bisphosphate (PIP2) in their presence (C2B). C2B also regulates also the recycling step of synaptic vesicles. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the second C2 repeat, C2B, and has a type-I topology.

Pssm-ID: 175975 [Multi-domain] Cd Length: 134 Bit Score: 42.57 E-value: 2.01e-04

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036   1053 PESQRkilmtLTVKVLGARHLPKL-GRSIACPFVEVEICGAEYGNNKFKTTVVNDNgLSPIWaptQEKVTFEIYDPNL-- 1129
Cdd:cd00276   11 PTAER-----LTVVVLKARNLPPSdGKGLSDPYVKVSLLQGGKKLKKKKTSVKKGT-LNPVF---NEAFSFDVPAEQLee 81

                         90       100
                 ....*....|....*....|.
gi 190036   1130 AFLRFVVYEEDMFSDPNFLAH 1150
Cdd:cd00276   82 VSLVITVVDKDSVGRNEVIGQ 102

SH2_STAP1

cd10403

Src homology 2 domain found in Signal-transducing adaptor protein 1 (STAP1); STAP1 is a ...

645-704

2.14e-04

Src homology 2 domain found in Signal-transducing adaptor protein 1 (STAP1); STAP1 is a signal-transducing adaptor protein. It is composed of a Pleckstrin homology (PH) and SH2 domains along with several tyrosine phosphorylation sites. STAP-1 is an ortholog of BRDG1 (BCR downstream signaling 1). STAP1 protein functions as a docking protein acting downstream of Tec tyrosine kinase in B cell antigen receptor signaling. The protein is phosphorylated by Tec and participates in a positive feedback loop, increasing Tec activity. STAP1 has been shown to interact with C19orf2, an unconventional prefoldin RPB5 interactor. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198266 Cd Length: 94 Bit Score: 41.63 E-value: 2.14e-04

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 190036    645 PWYYDSLSRGEAEDMLMRIPRDGAFLIRKREGSDSYAITFRA---RGKVKHCRINRDGRHFVL 704
Cdd:cd10403    1 PACFYKVSRKEAEELLERNPSCGNMLLRPGSDSSNYSITTRQeinKPRIKHYRVMSRGQGYTI 63

SH3_p67phox_C

cd12046

C-terminal (or second) Src Homology 3 domain of the p67phox subunit of NADPH oxidase; p67phox, ...

774-826

2.41e-04

C-terminal (or second) Src Homology 3 domain of the p67phox subunit of NADPH oxidase; p67phox, also called Neutrophil cytosol factor 2 (NCF-2), is a cytosolic subunit of the phagocytic NADPH oxidase complex (also called Nox2 or gp91phox) which plays a crucial role in the cellular response to bacterial infection. NADPH oxidase catalyzes the transfer of electrons from NADPH to oxygen during phagocytosis forming superoxide and reactive oxygen species. p67phox plays a regulatory role and contains N-terminal TPR, first SH3 (or N-terminal or central SH3), PB1, and C-terminal SH3 domains. It binds, via its C-terminal SH3 domain, to a proline-rich region of p47phox and upon activation, this complex assembles with flavocytochrome b558, the Nox2-p22phox heterodimer. Concurrently, RacGTP translocates to the membrane and interacts with the TPR domain of p67phox, which leads to the activation of NADPH oxidase. The PB1 domain of p67phox binds to its partner PB1 domain in p40phox, and this facilitates the assembly of p47phox-p67phox at the membrane. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212979 [Multi-domain] Cd Length: 53 Bit Score: 40.17 E-value: 2.41e-04

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|...
gi 190036    774 VKALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRIqQYFPSNYVED 826
Cdd:cd12046    2 VVALFSYEASQPEDLEFQKGDVILVLSKVNEDWLEGQCKGKI-GIFPSAFVED 53

C2D_Tricalbin-like

cd04040

C2 domain fourth repeat present in Tricalbin-like proteins; 5 to 6 copies of the C2 domain are ...

1063-1167

2.64e-04

C2 domain fourth repeat present in Tricalbin-like proteins; 5 to 6 copies of the C2 domain are present in Tricalbin, a yeast homolog of Synaptotagmin, which is involved in membrane trafficking and sorting. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the fifth C2 repeat, C2E, and has a type-II topology.

Pssm-ID: 176005 [Multi-domain] Cd Length: 115 Bit Score: 41.78 E-value: 2.64e-04

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036   1063 LTVKVLGARHLPKL---GRSIacPFVEVEICGAEYgnnkFKTTVVNDNgLSPIWaptQEKVTFEIydPNL--AFLRFVVY 1137
Cdd:cd04040    1 LTVDVISAENLPSAdrnGKSD--PFVKFYLNGEKV----FKTKTIKKT-LNPVW---NESFEVPV--PSRvrAVLKVEVY 68

                         90       100       110
                 ....*....|....*....|....*....|...
gi 190036   1138 EEDMFSDPNFLAHATYPIKAV---KSGFRSVPL 1167
Cdd:cd04040   69 DWDRGGKDDLLGSAYIDLSDLepeETTELTLPL 101

SH3_Src

cd12008

Src homology 3 domain of Src Protein Tyrosine Kinase; Src (or c-Src) is a cytoplasmic (or ...

776-824

2.68e-04

Src homology 3 domain of Src Protein Tyrosine Kinase; Src (or c-Src) is a cytoplasmic (or non-receptor) PTK and is the vertebrate homolog of the oncogenic protein (v-Src) from Rous sarcoma virus. Together with other Src subfamily proteins, it is involved in signaling pathways that regulate cytokine and growth factor responses, cytoskeleton dynamics, cell proliferation, survival, and differentiation. Src also play a role in regulating cell adhesion, invasion, and motility in cancer cells, and tumor vasculature, contributing to cancer progression and metastasis. Elevated levels of Src kinase activity have been reported in a variety of human cancers. Several inhibitors of Src have been developed as anti-cancer drugs. Src is also implicated in acute inflammatory responses and osteoclast function. Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212941 [Multi-domain] Cd Length: 56 Bit Score: 40.09 E-value: 2.68e-04

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|
gi 190036    776 ALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRIQQ-YFPSNYV 824
Cdd:cd12008    4 ALYDYESRTETDLSFKKGERLQIVNNTEGDWWLAHSLTTGQTgYIPSNYV 53

SH2_Src_Yes

cd10366

Src homology 2 (SH2) domain found in Yes; Yes is a member of the Src non-receptor type ...

642-724

2.86e-04

Pssm-ID: 198229 Cd Length: 101 Bit Score: 41.54 E-value: 2.86e-04

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    642 ESKPWYYDSLSRGEAEDMLMRI-PRDGAFLIRKREGSD-SYAITFR----ARG-KVKHCRINR-DGRHFVLGTSAYFESL 713
Cdd:cd10366    1 QAEEWYFGKMGRKDAERLLLNPgNQRGIFLVRESETTKgAYSLSIRdwdeVRGdNVKHYKIRKlDNGGYYITTRAQFDTL 80

                         90
                 ....*....|.
gi 190036    714 VELVSYYEKHS 724
Cdd:cd10366   81 QKLVKHYTEHA 91

SH3_CD2AP_2

cd12054

Second Src Homology 3 domain (SH3B) of CD2-associated protein; CD2AP, also called CMS (Cas ...

772-827

3.12e-04

Second Src Homology 3 domain (SH3B) of CD2-associated protein; CD2AP, also called CMS (Cas ligand with Multiple SH3 domains) or METS1 (Mesenchyme-to-Epithelium Transition protein with SH3 domains), is a cytosolic adaptor protein that plays a role in regulating the cytoskeleton. It is critical in cell-to-cell union necessary for kidney function. It also stabilizes the contact between a T cell and antigen-presenting cells. It is primarily expressed in podocytes at the cytoplasmic face of the slit diaphragm and serves as a linker anchoring podocin and nephrin to the actin cytoskeleton. CD2AP contains three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP to bind various protein partners and assemble complexes that have been implicated in many different functions. This alignment model represents the second SH3 domain (SH3B) of CD2AP. SH3B binds to c-Cbl in a site (TPSSRPLR is the core binding motif) distinct from the c-Cbl/SH3A binding site. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212987 [Multi-domain] Cd Length: 55 Bit Score: 39.95 E-value: 3.12e-04

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 190036    772 RTVKALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRiQQYFPSNYVEDI 827
Cdd:cd12054    1 RQCKVLFEYVPQNEDELELKVGDIIDINEEVEEGWWSGTLNGK-SGLFPSNFVKEL 55

SH3_SKAP1

cd12044

Src Homology 3 domain of Src Kinase-Associated Phosphoprotein 1; SKAP1, also called SKAP55 ...

775-810

3.17e-04

Src Homology 3 domain of Src Kinase-Associated Phosphoprotein 1; SKAP1, also called SKAP55 (Src kinase-associated protein of 55kDa), is an immune cell-specific adaptor protein that plays an important role in T-cell adhesion, migration, and integrin clustering. It is expressed exclusively in T-lymphocytes, mast cells, and macrophages. Binding partners include ADAP (adhesion and degranulation-promoting adaptor protein), Fyn, Riam, RapL, and RasGRP. It contains a pleckstrin homology (PH) domain, a C-terminal SH3 domain, and several tyrosine phosphorylation sites. The SH3 domain of SKAP1 is necessary for its ability to regulate T-cell conjugation with antigen-presenting cells and the formation of LFA-1 clusters. SKAP1 binds primarily to a proline-rich region of ADAP through its SH3 domain; its degradation is regulated by ADAP. A secondary interaction occurs via the ADAP SH3 domain and the RKxxYxxY motif in SKAP1. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212977 Cd Length: 53 Bit Score: 39.84 E-value: 3.17e-04

                         10        20        30
                 ....*....|....*....|....*....|....*...
gi 190036    775 KALYDYKAKRSDELSFCRGALIHNVSKEPG--GWWKGD 810
Cdd:cd12044    3 QGLWDCFGDNPDELSFQRGDLIYILSKEYNmyGWWVGE 40

SH3_GAS7

cd11829

Src homology 3 domain of Growth Arrest Specific protein 7; GAS7 is mainly expressed in the ...

775-824

3.30e-04

Src homology 3 domain of Growth Arrest Specific protein 7; GAS7 is mainly expressed in the brain and is required for neurite outgrowth. It may also play a role in the protection and migration of embryonic stem cells. Treatment-related acute myeloid leukemia (AML) has been reported resulting from mixed-lineage leukemia (MLL)-GAS7 translocations as a complication of primary cancer treatment. GAS7 contains an N-terminal SH3 domain, followed by a WW domain, and a central F-BAR domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212763 [Multi-domain] Cd Length: 52 Bit Score: 39.80 E-value: 3.30e-04

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 190036    775 KALYDYKAKRSDE-LSFCRGALIHNVSKEPGGWWKGDY-GTRiqQYFPSNYV 824
Cdd:cd11829    3 RTLYAFTGEQHQQgLSFEAGELIRVLQAPDGGWWEGEKdGLR--GWFPASYV 52

SH3_GRAF

cd12064

Src Homology 3 domain of GTPase Regulator Associated with Focal adhesion kinase; GRAF, also ...

772-825

3.35e-04

Src Homology 3 domain of GTPase Regulator Associated with Focal adhesion kinase; GRAF, also called Rho GTPase activating protein 26 (ARHGAP26), Oligophrenin-1-like (OPHN1L) or GRAF1, is a GAP with activity towards RhoA and Cdc42 and is only weakly active towards Rac1. It influences Rho-mediated cytoskeletal rearrangements and binds focal adhesion kinase (FAK), which is a critical component of integrin signaling. It is essential for the major clathrin-independent endocytic pathway mediated by pleiomorphic membranes. GRAF contains an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, a Rho GAP domain, and a C-terminal SH3 domain. The SH3 domain of GRAF binds PKNbeta, a target of the small GTPase Rho. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212997 Cd Length: 56 Bit Score: 39.71 E-value: 3.35e-04

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 190036    772 RTVKALYDYKAKRSDELSFCRGALIHNV--SKEPgGWWKGDYGTRiQQYFPSNYVE 825
Cdd:cd12064    1 RKAKALYACKAEHDSELSFTAGTVFDNVhpSQEP-GWLEGTLNGK-TGLIPENYVE 54

SH3_NoxO1_2

cd12024

Second or C-terminal Src homology 3 domain of NADPH oxidase (Nox) Organizing protein 1; Nox ...

780-823

3.61e-04

Second or C-terminal Src homology 3 domain of NADPH oxidase (Nox) Organizing protein 1; Nox Organizing protein 1 (NoxO1) is a critical regulator of enzyme kinetics of the nonphagocytic NADPH oxidase Nox1, which catalyzes the transfer of electrons from NADPH to molecular oxygen to form superoxide. Nox1 is expressed in colon, stomach, uterus, prostate, and vascular smooth muscle cells. NoxO1 is involved in targeting activator subunits (such as NoxA1) to Nox1. It is co-localized with Nox1 in the membranes of resting cells and directs the subcellular localization of Nox1. NoxO1 contains an N-terminal Phox homology (PX) domain, tandem SH3 domains (N-SH3 and C-SH3), and a C-terminal proline-rich region (PRR). This model characterizes the second SH3 domain (or C-SH3) of NoxO1. The tandem SH3 domains of NoxO1 interact with the PRR of p22phox, which also complexes with Nox1. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212957 Cd Length: 53 Bit Score: 39.63 E-value: 3.61e-04

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....
gi 190036    780 YKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRiQQYFPSNY 823
Cdd:cd12024    8 YEAQKEDELSVPAGVVVEVLQKSDNGWWLIRYNGR-AGYVPSMY 50

PH_PLC_delta

cd13363

Phospholipase C-delta (PLC-delta) pleckstrin homology (PH) domain; The PLC-delta (PLCdelta) ...

67-135

3.62e-04

Phospholipase C-delta (PLC-delta) pleckstrin homology (PH) domain; The PLC-delta (PLCdelta) consists of three family members, delta 1, 2, and 3. PLC-delta1 is the most well studied. PLC-delta is activated by high calcium levels generated by other PLC family members, and functions as a calcium amplifier within the cell. PLC-delta consists of an N-terminal PH domain, a EF hand domain, a catalytic domain split into X and Y halves, and a C-terminal C2 domain. The PH domain binds PIP2 and promotes activation of the catalytic core as well as tethering the enzyme to the plasma membrane. The C2 domain has been shown to mediate calcium-dependent phospholipid binding as well. The PH and C2 domains operate in concert as a "tether and fix" apparatus necessary for processive catalysis by the enzyme. Its leucine-rich nuclear export signal (NES) in its EF hand motif, as well as a Nuclear localization signal within its linker region allow PLC-delta 1 to actively translocate into and out of the nucleus. PLCs (EC 3.1.4.3) play a role in the initiation of cellular activation, proliferation, differentiation and apoptosis. They are central to inositol lipid signalling pathways, facilitating intracellular Ca2+ release and protein kinase C (PKC) activation. Specificaly, PLCs catalyze the cleavage of phosphatidylinositol-4,5-bisphosphate (PIP2) and result in the release of 1,2-diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3). These products trigger the activation of protein kinase C (PKC) and the release of Ca2+ from intracellular stores. There are fourteen kinds of mammalian phospholipase C proteins which are are classified into six isotypes (beta, gamma, delta, epsilon, zeta, eta). PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

Pssm-ID: 270169 Cd Length: 117 Bit Score: 41.54 E-value: 3.62e-04

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 190036     67 IMEIKEIRPGKNSKDFER-AKAVrqKEDCCFTILYGTQfvLSTLSLAADSKEDAVNWLSGLK--ILHQEAMN 135
Cdd:cd13363   47 IEDIESVREGHQSEGLRKyAEAF--PEDRCFSIVFKGR--RKNLDLIAPSEEEAQRWVRGLEklIARLTNMS 114

SH2_Src_Blk

cd10371

Src homology 2 (SH2) domain found in B lymphoid kinase (Blk); Blk is a member of the Src ...

642-734

3.63e-04

Pssm-ID: 198234 [Multi-domain] Cd Length: 100 Bit Score: 41.16 E-value: 3.63e-04

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    642 ESKPWYYDSLSRGEAE-DMLMRIPRDGAFLIRKREGSD-SYAITFR---ARGKV-KHCRINR-DGRHFVLGTSAYFESLV 714
Cdd:cd10371    1 EVEKWFFRTISRKDAErQLLAPMNKAGSFLIRESESNKgAFSLSVKdvtTQGEVvKHYKIRSlDNGGYYISPRITFPTLQ 80

                         90       100
                 ....*....|....*....|
gi 190036    715 ELVSYYEKHSLYRKMRLRYP 734
Cdd:cd10371   81 ALVQHYSKKGDGLCQKLTLP 100

SH2_Tec_Btk

cd10397

Src homology 2 (SH2) domain found in Tec protein, Bruton's tyrosine kinase (Btk); A member of ...

532-618

3.90e-04

Pssm-ID: 198260 [Multi-domain] Cd Length: 106 Bit Score: 40.97 E-value: 3.90e-04

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    532 WFHKKVeKRTSAEKLLQeycmeTGGKDGTFLVRESeTFPNDYTLSFW------RSGRVQHCRIRSTMEGgtlKYYLTDNL 605
Cdd:cd10397    8 WYSKNM-TRSQAEQLLK-----QEGKEGGFIVRDS-SKAGKYTVSVFaksagdPQGVIRHYVVCSTPQS---QYYLAEKH 77

                         90
                 ....*....|...
gi 190036    606 RFRRMYALIQHYR 618
Cdd:cd10397   78 LFSTIPELINYHQ 90

SH2_SAP1a

cd10400

Src homology 2 (SH2) domain found in SLAM-associated protein (SAP) 1a; The X-linked ...

533-619

3.91e-04

Src homology 2 (SH2) domain found in SLAM-associated protein (SAP) 1a; The X-linked lymphoproliferative syndrome (XLP) gene encodes SAP (also called SH2D1A/DSHP) a protein that consists of a 5 residue N-terminus, a single SH2 domain, and a short 25 residue C-terminal tail. XLP is characterized by an extreme sensitivity to Epstein-Barr virus. Both T and natural killer (NK) cell dysfunctions have been seen in XLP patients. SAP binds the cytoplasmic tail of Signaling lymphocytic activation molecule (SLAM), 2B4, Ly-9, and CD84. SAP is believed to function as a signaling inhibitor, by blocking or regulating binding of other signaling proteins. SAP and the SAP-like protein EAT-2 recognize the sequence motif TIpYXX[VI], which is found in the cytoplasmic domains of a restricted number of T, B, and NK cell surface receptors and are proposed to be natural inhibitors or regulators of the physiological role of a small family of receptors on the surface of these cells. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198263 Cd Length: 103 Bit Score: 40.98 E-value: 3.91e-04

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    533 FHKKVEKRTsAEKLLQeycmeTGGKDGTFLVRESETFPNDYTLSFWRSGRVQHCRIRSTMEG--------GTLKYYltdn 604
Cdd:cd10400    6 YHGKISRET-GEKLLL-----AAGLDGSYLLRDSESVPGVYCLCVLYKGYVYTYRVSQTETGswsaetapGVHKRL---- 75

                         90
                 ....*....|....*
gi 190036    605 lrFRRMYALIQHYRE 619
Cdd:cd10400   76 --FRKVKNLISAFQK 88

SH3_srGAP4

cd11956

Src homology 3 domain of Slit-Robo GTPase Activating Protein 4; srGAP4, also called ARHGAP4, ...

776-812

4.20e-04

Src homology 3 domain of Slit-Robo GTPase Activating Protein 4; srGAP4, also called ARHGAP4, is highly expressed in hematopoietic cells and may play a role in lymphocyte differentiation. It is able to stimulate the GTPase activity of Rac1, Cdc42, and RhoA. In the nervous system, srGAP4 has been detected in differentiating neurites and may be involved in axon and dendritic growth. srGAPs are Rho GAPs that interact with Robo1, the transmembrane receptor of Slit proteins. Slit proteins are secreted proteins that control axon guidance and the migration of neurons and leukocytes. srGAPs contain an N-terminal F-BAR domain, a Rho GAP domain, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212889 [Multi-domain] Cd Length: 55 Bit Score: 39.44 E-value: 4.20e-04

                         10        20        30
                 ....*....|....*....|....*....|....*..
gi 190036    776 ALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYG 812
Cdd:cd11956    6 ACFDYTGRTAQELSFKRGDVLLLHSKASSDWWRGEHN 42

SH2_Fps_family

cd10361

Src homology 2 (SH2) domain found in feline sarcoma, Fujinami poultry sarcoma, and fes-related ...

527-623

4.61e-04

Pssm-ID: 198224 Cd Length: 90 Bit Score: 40.20 E-value: 4.61e-04

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    527 HFGEKWFHKKVeKRTSAEKLLQeycmetggKDGTFLVRESE---TFPNDYTLSFWRSGRVQHCRIRSTMEGgtlKYYLtD 603
Cdd:cd10361    3 LENEPYYHGLL-PREDAEELLK--------NDGDFLVRKTEpkgGGKRKLVLSVRWDGKIRHFVINRDDGG---KYYI-E 69

                         90       100
                 ....*....|....*....|
gi 190036    604 NLRFRRMYALIQHYRETHLP 623
Cdd:cd10361   70 GKSFKSISELINYYQKTKEP 89

SH3_GRB2_N

cd11946

N-terminal Src homology 3 domain of Growth factor receptor-bound protein 2; GRB2 is a critical ...

776-825

5.03e-04

N-terminal Src homology 3 domain of Growth factor receptor-bound protein 2; GRB2 is a critical signaling molecule that regulates the Ras pathway by linking tyrosine kinases to the Ras guanine nucleotide releasing protein Sos (son of sevenless), which converts Ras to the active GTP-bound state. It is ubiquitously expressed in all tissues throughout development and is important in cell cycle progression, motility, morphogenesis, and angiogenesis. In lymphocytes, GRB2 is associated with antigen receptor signaling components. GRB2 contains an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. Its N-terminal SH3 domain binds to Sos and Sos-derived proline-rich peptides. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212879 [Multi-domain] Cd Length: 56 Bit Score: 39.24 E-value: 5.03e-04

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 190036    776 ALYDYKAKRSDELSFCRGALIHNVSKE-PGGWWKGDYGTRiQQYFPSNYVE 825
Cdd:cd11946    5 AKYDFKATADDELSFKRGDILKVLNEEcDQNWYKAELNGK-DGFIPKNYIE 54

SH2_SHIP

cd10343

Src homology 2 (SH2) domain found in SH2-containing inositol-5'-phosphatase (SHIP) and ...

532-575

5.13e-04

Pssm-ID: 198206 Cd Length: 103 Bit Score: 40.50 E-value: 5.13e-04

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....
gi 190036    532 WFHKKVeKRTSAEKLLQEycmetGGKDGTFLVRESETFPNDYTL 575
Cdd:cd10343    5 WYHGNI-TRSKAEELLSK-----AGKDGSFLVRDSESVSGAYAL 42

SH2_SH2B3

cd10412

Src homology 2 (SH2) domain found in SH2B adapter proteins (SH2B1, SH2B2, SH2B3); SH2B3 (Lnk), ...

643-722

5.36e-04

Pssm-ID: 198275 Cd Length: 97 Bit Score: 40.65 E-value: 5.36e-04

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    643 SKPWYYDSLSRGEAEDM--LMRIPRDGAFLIRKREGS-DSYAITFRARGKVKHCRINRDGRHFVLGTSAYFESLVELVSY 719
Cdd:cd10412    7 CYPWFHGPISRVKAAQLvqLQGPDAHGVFLVRQSETRrGEYVLTFNFQGRAKHLRLSLTERGQCRVQHLHFPSVVDMLHH 86


                 ...
gi 190036    720 YEK 722
Cdd:cd10412   87 FQR 89

SH2_Nterm_RasGAP

cd10353

N-terminal Src homology 2 (SH2) domain found in Ras GTPase-activating protein 1 (GAP); RasGAP ...

646-720

6.05e-04

Pssm-ID: 198216 Cd Length: 103 Bit Score: 40.59 E-value: 6.05e-04

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 190036    646 WYYDSLSRGEAEDMLMRIPRDGAFLIR---KREGsdSYAITFRARGKVKHCRINRDGRHFVLGtSAYFESLVELVSYY 720
Cdd:cd10353   21 WYHGRLDRTIAEERLRQAGKLGSYLIResdRRPG--SFVLSFLSRTGVNHFRIIAMCGDYYIG-GRRFSSLSDLIGYY 95

SH2_N-SH2_Zap70_Syk_like

cd09938

N-terminal Src homology 2 (SH2) domain found in Zeta-chain-associated protein kinase 70 ...

532-617

6.15e-04

Pssm-ID: 198191 Cd Length: 104 Bit Score: 40.46 E-value: 6.15e-04

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    532 WFHKKVeKRTSAEkllqEYCMETGGKDGTFLVRESETFPNDYTLSFWRSGRVQHCRIRSTMEGgtlKYYLTDNLRFRRMY 611
Cdd:cd09938    3 FFYGSI-TREEAE----EYLKLAGMSDGLFLLRQSLRSLGGYVLSVCHGRKFHHYTIERQLNG---TYAIAGGKAHCGPA 74


                 ....*.
gi 190036    612 ALIQHY 617
Cdd:cd09938   75 ELCEYH 80

SH3_iASPP

cd11952

Src Homology 3 (SH3) domain of Inhibitor of ASPP protein (iASPP); iASPP, also called ...

774-823

6.24e-04

Src Homology 3 (SH3) domain of Inhibitor of ASPP protein (iASPP); iASPP, also called RelA-associated inhibitor (RAI), is an oncoprotein that inhibits the apoptotic transactivation potential of p53. It is upregulated in human breast cancers expressing wild-type p53, in acute leukemias regardless of the p53 mutation status, as well as in ovarian cancer where it is associated with poor patient outcome and chemoresistance. iASPP is also a binding partner and negative regulator of p65RelA, which promotes cell proliferation and inhibits apoptosis; p65RelA has the opposite effect on cell growth compared to the p53 family. It contains a proline-rich region, four ankyrin (ANK) repeats, and an SH3 domain at its C-terminal half. The SH3 domain and the ANK repeats of iASPP contribute to the p53 binding site; they bind to the DNA binding domain of p53. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212885 [Multi-domain] Cd Length: 56 Bit Score: 39.14 E-value: 6.24e-04

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 190036    774 VKALYDYKAKRSDELSFCRGALIHNVSK--EPGGWWKGDYGTRiQQYFPSNY 823
Cdd:cd11952    3 VYALWDYSAEFPDELSFKEGDMVTVLRKdgEGTDWWWASLCGR-EGYVPRNY 53

SH2_C-SH2_Syk_like

cd10401

C-terminal Src homology 2 (SH2) domain found in Spleen tyrosine kinase (Syk) proteins; ZAP-70 ...

532-638

6.51e-04

Pssm-ID: 198264 Cd Length: 99 Bit Score: 40.26 E-value: 6.51e-04

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    532 WFHKKVEKRTSAEKLLQeycmeTGGKDGTFLVRESETfPNDYTLSFWRSGRVQHCRIRSTMEGgtlKYYLTDNLRFRRMY 611
Cdd:cd10401    5 WFHGKISREESEQILLI-----GSKTNGKFLIRERDN-NGSYALCLLHDGKVLHYRIDKDKTG---KLSIPDGKKFDTLW 75

                         90       100
                 ....*....|....*....|....*...
gi 190036    612 ALIQHYREThlpcAEFELR-LTDPVPNP 638
Cdd:cd10401   76 QLVEHYSYK----PDGLLRvLTEPCPRI 99

SH3_SKAP1-like

cd11866

Src Homology 3 domain of Src Kinase-Associated Phosphoprotein 1 and similar proteins; This ...

776-809

6.86e-04

Src Homology 3 domain of Src Kinase-Associated Phosphoprotein 1 and similar proteins; This subfamily is composed of SKAP1, SKAP2, and similar proteins. SKAP1 and SKAP2 are immune cell-specific adaptor proteins that play roles in T- and B-cell adhesion, respectively, and are thus important in the migration of T- and B-cells to sites of inflammation and for movement during T-cell conjugation with antigen-presenting cells. Both SKAP1 and SKAP2 bind to ADAP (adhesion and degranulation-promoting adaptor protein), among many other binding partners. They contain a pleckstrin homology (PH) domain, a C-terminal SH3 domain, and several tyrosine phosphorylation sites. The SH3 domain of SKAP1 is necessary for its ability to regulate T-cell conjugation with antigen-presenting cells and the formation of LFA-1 clusters. SKAP1 binds primarily to a proline-rich region of ADAP through its SH3 domain; its degradation is regulated by ADAP. A secondary interaction occurs via the ADAP SH3 domain and the RKxxYxxY motif in SKAP1. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212800 Cd Length: 53 Bit Score: 38.95 E-value: 6.86e-04

                         10        20        30
                 ....*....|....*....|....*....|....*.
gi 190036    776 ALYDYKAKRSDELSFCRGALIHNVSKEPG--GWWKG 809
Cdd:cd11866    4 GLWDCSGNEPDELSFKRGDLIYIISKEYDsfGWWVG 39

SH3_FCHSD_1

cd11761

First Src Homology 3 domain of FCH and double SH3 domains proteins; This group is composed of ...

773-825

7.58e-04

First Src Homology 3 domain of FCH and double SH3 domains proteins; This group is composed of FCH and double SH3 domains protein 1 (FCHSD1) and FCHSD2. These proteins have a common domain structure consisting of an N-terminal F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs), two SH3, and C-terminal proline-rich domains. They have only been characterized in silico and their functions remain unknown. This group also includes the insect protein, nervous wreck, which acts as a regulator of synaptic growth signaling. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212695 [Multi-domain] Cd Length: 57 Bit Score: 38.88 E-value: 7.58e-04

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....
gi 190036    773 TVKALYDYKAKRSDELSFCRGALIHNVSKEPG-GWWKGDYGTRIQQYFPSNYVE 825
Cdd:cd11761    3 TCKVLYSYEAQRPDELTITEGEELEVIEDGDGdGWVKARNKSGEVGYVPENYLQ 56

SH3_Abp1_fungi_C1

cd11962

First C-terminal Src homology 3 domain of Fungal Actin-binding protein 1; Abp1 is an adaptor ...

777-825

7.61e-04

First C-terminal Src homology 3 domain of Fungal Actin-binding protein 1; Abp1 is an adaptor protein that functions in receptor-mediated endocytosis and vesicle trafficking. It contains an N-terminal actin-binding module, the actin-depolymerizing factor (ADF) homology domain, a central proline-rich region, and a C-terminal SH3 domain (many yeast Abp1 proteins contain two C-terminal SH3 domains). Yeast Abp1 also contains two acidic domains that bind directly to the Arp2/3 complex, which is required to initiate actin polymerization. The SH3 domain of yeast Abp1 binds and localizes the kinases, Ark1p and Prk1p, which facilitate actin patch disassembly following vesicle internalization. It also mediates the localization to the actin patch of the synaptojanin-like protein, Sjl2p, which plays a key role in endocytosis. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212895 [Multi-domain] Cd Length: 54 Bit Score: 38.62 E-value: 7.61e-04

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*....
gi 190036    777 LYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRIQQYFPSNYVE 825
Cdd:cd11962    5 LYDYEKDEDNEIELVEGEIVTNIEMVDEDWWMGTNSKGESGLFPSNYVE 53

SH2_a2chimerin_b2chimerin

cd10352

Src homology 2 (SH2) domain found in alpha2-chimerin and beta2-chimerin proteins; Chimerins ...

533-614

8.18e-04

Pssm-ID: 198215 Cd Length: 91 Bit Score: 39.66 E-value: 8.18e-04

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    533 FHKKVEkRTSAEKLLQeycmetGGKDGTFLVRESETFPNDYTLSFWRSGRVQHCRIRStmEGGTLKYYLTDnLRFRRMYA 612
Cdd:cd10352    9 YHGLIS-REEAEQLLS------GASDGSYLIRESSRDDGYYTLSLRFNGKVKNYKLYY--DGKNHYHYVGE-KRFDTIHD 78


                 ..
gi 190036    613 LI 614
Cdd:cd10352   79 LV 80

SH3_Tks4_2

cd12076

Second Src homology 3 domain of Tyrosine kinase substrate with four SH3 domains; Tks4, also ...

776-825

8.35e-04

Second Src homology 3 domain of Tyrosine kinase substrate with four SH3 domains; Tks4, also called SH3 and PX domain-containing protein 2B (SH3PXD2B) or HOFI, is a Src substrate and scaffolding protein that plays an important role in the formation of podosomes and invadopodia, the dynamic actin-rich structures that are related to cell migration and cancer cell invasion. It is required in the formation of functional podosomes, EGF-induced membrane ruffling, and lamellipodia generation. It plays an important role in cellular attachment and cell spreading. Tks4 is essential for the localization of MT1-MMP (membrane-type 1 matrix metalloproteinase) to invadopodia. It contains an N-terminal Phox homology (PX) domain and four SH3 domains. This model characterizes the second SH3 domain of Tks4. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 213009 [Multi-domain] Cd Length: 54 Bit Score: 38.47 E-value: 8.35e-04

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|
gi 190036    776 ALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRiQQYFPSNYVE 825
Cdd:cd12076    5 VIYPYTARDQDEINLEKGAVVEVIQKNLEGWWKIRYQGK-EGWAPASYLK 53

SH3_CD2AP_1

cd12053

First Src Homology 3 domain (SH3A) of CD2-associated protein; CD2AP, also called CMS (Cas ...

778-827

8.65e-04

First Src Homology 3 domain (SH3A) of CD2-associated protein; CD2AP, also called CMS (Cas ligand with Multiple SH3 domains) or METS1 (Mesenchyme-to-Epithelium Transition protein with SH3 domains), is a cytosolic adaptor protein that plays a role in regulating the cytoskeleton. It is critical in cell-to-cell union necessary for kidney function. It also stabilizes the contact between a T cell and antigen-presenting cells. It is primarily expressed in podocytes at the cytoplasmic face of the slit diaphragm and serves as a linker anchoring podocin and nephrin to the actin cytoskeleton. CD2AP contains three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP to bind various protein partners and assemble complexes that have been implicated in many different functions. This alignment model represents the first SH3 domain (SH3A) of CD2AP. SH3A binds to the PXXXPR motif present in c-Cbl and the cytoplasmic domain of cell adhesion protein CD2. Its interaction with CD2 anchors CD2 at sites of cell contact. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212986 Cd Length: 56 Bit Score: 38.67 E-value: 8.65e-04

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 190036    778 YDYKAKRSDELSFCRGALIHNVSK-EPGGWWKGDYGTRiQQYFPSNYVEDI 827
Cdd:cd12053    6 YDYDAVHEDELTIRVGEIIRNVKKlEEEGWLEGELNGR-RGMFPDNFVKEI 55

SH3_SH3YL1_like

cd11841

Src homology 3 domain of SH3 domain containing Ysc84-like 1 (SH3YL1) protein; SH3YL1 localizes ...

773-824

8.80e-04

Src homology 3 domain of SH3 domain containing Ysc84-like 1 (SH3YL1) protein; SH3YL1 localizes to the plasma membrane and is required for dorsal ruffle formation. It binds phosphoinositides (PIs) with high affinity through its N-terminal SYLF domain (also called DUF500). In addition, SH3YL1 contains a C-terminal SH3 domain which has been reported to bind to N-WASP, dynamin 2, and SHIP2 (a PI 5-phosphatase). SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212775 Cd Length: 54 Bit Score: 38.53 E-value: 8.80e-04

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....
gi 190036    773 TVKALYDYKAKRSDELSFCRGALIHNVSKEPG--GWWKGDYGTRIqQYFPSNYV 824
Cdd:cd11841    1 EVTALYSFEGQQPCDLSFQAGDRITVLTRTDSqfDWWEGRLRGRV-GIFPANYV 53

SH3_Nephrocystin

cd11770

Src Homology 3 domain of Nephrocystin (or Nephrocystin-1); Nephrocystin contains an SH3 domain ...

774-812

9.30e-04

Src Homology 3 domain of Nephrocystin (or Nephrocystin-1); Nephrocystin contains an SH3 domain involved in signaling pathways that regulate cell adhesion and cytoskeletal organization. It is a protein that in humans is associated with juvenile nephronophthisis, an inherited kidney disease characterized by renal fibrosis that lead to chronic renal failure in children. It is localized in cell-cell junctions in renal duct cells, and is known to interact with Ack1, an activated Cdc42-associated kinase. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212704 [Multi-domain] Cd Length: 54 Bit Score: 38.45 E-value: 9.30e-04

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....
gi 190036    774 VKALYDYKAKRSDELSFCRGALIHNVSKEPGGWW-----KGDYG 812
Cdd:cd11770    2 YEALSDFQAEQEGDLSFKKGEVLRIISKRADGWWlaensKGNRG 45

SH3_GRB2_like_N

cd11804

N-terminal Src homology 3 domain of Growth factor receptor-bound protein 2 (GRB2) and related ...

776-824

9.46e-04

N-terminal Src homology 3 domain of Growth factor receptor-bound protein 2 (GRB2) and related proteins; This family includes the adaptor protein GRB2 and related proteins including Drosophila melanogaster Downstream of receptor kinase (DRK), Caenorhabditis elegans Sex muscle abnormal protein 5 (Sem-5), GRB2-related adaptor protein (GRAP), GRAP2, and similar proteins. Family members contain an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. GRB2/Sem-5/DRK is a critical signaling molecule that regulates the Ras pathway by linking tyrosine kinases to the Ras guanine nucleotide releasing protein Sos (son of sevenless), which converts Ras to the active GTP-bound state. GRAP2 plays an important role in T cell receptor (TCR) signaling by promoting the formation of the SLP-76:LAT complex, which couples the TCR to the Ras pathway. GRAP acts as a negative regulator of T cell receptor (TCR)-induced lymphocyte proliferation by downregulating the signaling to the Ras/ERK pathway. The N-terminal SH3 domain of GRB2 binds to Sos and Sos-derived proline-rich peptides. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212738 [Multi-domain] Cd Length: 52 Bit Score: 38.49 E-value: 9.46e-04

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|
gi 190036    776 ALYDYKAKRSDELSFCRGALIHNVSKEPG-GWWKGDYGTRiQQYFPSNYV 824
Cdd:cd11804    4 AKHDFKATAEDELSFKKGSILKVLNMEDDpNWYKAELDGK-EGLIPKNYI 52

SH3_Endophilin_A

cd11803

Src homology 3 domain of Endophilin-A; Endophilins play roles in synaptic vesicle formation, ...

775-825

9.61e-04

Src homology 3 domain of Endophilin-A; Endophilins play roles in synaptic vesicle formation, virus budding, mitochondrial morphology maintenance, receptor-mediated endocytosis inhibition, and endosomal sorting. They are classified into two types, A and B. Vertebrates contain three endophilin-A isoforms (A1, A2, and A3). Endophilin-A proteins are enriched in the brain and play multiple roles in receptor-mediated endocytosis. They tubulate membranes and regulate calcium influx into neurons to trigger the activation of the endocytic machinery. They are also involved in the sorting of plasma membrane proteins, actin filament assembly, and the uncoating of clathrin-coated vesicles for fusion with endosomes. Endophilins contain an N-terminal N-BAR domain (BAR domain with an additional N-terminal amphipathic helix), followed by a variable region containing proline clusters, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212737 [Multi-domain] Cd Length: 55 Bit Score: 38.39 E-value: 9.61e-04

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 190036    775 KALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRiQQYFPSNYVE 825
Cdd:cd11803    4 RALYDFEPENEGELGFKEGDIITLTNQIDENWYEGMVNGQ-SGFFPVNYVE 53

SH2_SH2D4A

cd10350

Src homology 2 domain found in the SH2 domain containing protein 4A (SH2D4A); SH2D4A contains ...

645-734

1.08e-03

Src homology 2 domain found in the SH2 domain containing protein 4A (SH2D4A); SH2D4A contains a single SH2 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198213 Cd Length: 103 Bit Score: 39.91 E-value: 1.08e-03

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    645 PWYYDSLSRGEAEDMLMRIpRDGAFLIRKREGSDSYAITFRARGKVKHCRINRDGRHF-VLGTSAY-FESLVELVSYYEK 722
Cdd:cd10350    8 PWFHGILTLKKANELLLST-MPGSFLIRVSEKIKGYALSYLSEEGCKHFLIDASADSYsFLGVDQLqHATLADLVEYHKE 86

                         90
                 ....*....|....*
gi 190036    723 H---SLYRKMrLRYP 734
Cdd:cd10350   87 EpitSLGKEL-LLYP 100

SH3_Bem1p_1

cd11878

First Src Homology 3 domain of Bud emergence protein 1 and similar domains; Members of this ...

774-807

1.13e-03

First Src Homology 3 domain of Bud emergence protein 1 and similar domains; Members of this subfamily bear similarity to Saccharomyces cerevisiae Bem1p, containing two Src Homology 3 (SH3) domains at the N-terminus, a central PX domain, and a C-terminal PB1 domain. Bem1p is a scaffolding protein that is critical for proper Cdc42p activation during bud formation in yeast. During budding and mating, Bem1p migrates to the plasma membrane where it can serve as an adaptor for Cdc42p and some other proteins. Bem1p also functions as an effector of the G1 cyclin Cln3p and the cyclin-dependent kinase Cdc28p in promoting vacuolar fusion. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

Pssm-ID: 212811 [Multi-domain] Cd Length: 54 Bit Score: 38.04 E-value: 1.13e-03

                         10        20        30
                 ....*....|....*....|....*....|....
gi 190036    774 VKALYDYKAKRSDELSFCRGALIHNVSKEPGGWW 807
Cdd:cd11878    2 IRALYDYRAQTPGELSFSKGDFFHVIGEEDQGEW 35

SH2_STAP_family

cd09939

Src homology 2 domain found in Signal-transducing adaptor protein (STAP) family; STAP1 and ...

645-724

1.17e-03

Src homology 2 domain found in Signal-transducing adaptor protein (STAP) family; STAP1 and STAP2 are signal-transducing adaptor proteins. They are composed of a Pleckstrin homology (PH) and SH2 domains along with several tyrosine phosphorylation sites. STAP-1 is an ortholog of BRDG1 (BCR downstream signaling 1). STAP1 protein functions as a docking protein acting downstream of Tec tyrosine kinase in B cell antigen receptor signaling. The protein is phosphorylated by Tec and participates in a positive feedback loop, increasing Tec activity. STAP1 has been shown to interact with C19orf2, an unconventional prefoldin RPB5 interactor. The STAP2 protein is the substrate of breast tumor kinase, an Src-type non-receptor tyrosine kinase that mediates the interactions linking proteins involved in signal transduction pathways. STAP2 has alternative splicing variants. STAP2 has been shown to interact with tyrosine-protein kinase 6 (PTK6). In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

Pssm-ID: 198192 Cd Length: 94 Bit Score: 39.45 E-value: 1.17e-03

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036    645 PWYYDSLSRGEAEDMLMRIPRDGAFLIRKREGSDSYAITFRAR---GKVKHCRINRDGRHFVLGTSAYFE--SLVELVSY 719
Cdd:cd09939    1 PACFYTVSRKEATELLERNPSCGNMLLRPGSDSRNYSVTTRQEiniPVIRHYKVMSVGQNYTIELEKPVTcpNLFSVINY 80


                 ....*
gi 190036    720 YEKHS 724
Cdd:cd09939   81 FVKET 85

SH3_Sorbs_2

cd11782

Second Src Homology 3 domain of Sorbin and SH3 domain containing (Sorbs) proteins and similar ...

775-825

1.73e-03

Second Src Homology 3 domain of Sorbin and SH3 domain containing (Sorbs) proteins and similar domains; This family, also called the vinexin family, is composed predominantly of adaptor proteins containing one sorbin homology (SoHo) and three SH3 domains. Members include the second SH3 domains of Sorbs1 (or ponsin), Sorbs2 (or ArgBP2), Vinexin (or Sorbs3), and similar domains. They are involved in the regulation of cytoskeletal organization, cell adhesion, and growth factor signaling. Members of this family bind multiple partners including signaling molecules like c-Abl, c-Arg, Sos, and c-Cbl, as well as cytoskeletal molecules such as vinculin and afadin. They may have overlapping functions. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

Pssm-ID: 212716 [Multi-domain] Cd Length: 53 Bit Score: 37.71 E-value: 1.73e-03

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 190036    775 KALYDYKAKRSDELSFCRGALIHNVSKEPGGWWKGDYGTRiQQYFPSNYVE 825
Cdd:cd11782    3 RAKYNFNADTGVELSFRKGDVITLTRRVDENWYEGRIGGR-QGIFPVSYVQ 52

C2B_RasA1_RasA4

cd04025

C2 domain second repeat present in RasA1 and RasA4; RasA1 and RasA4 are GAP1s (GTPase ...

1062-1174

1.84e-03

C2 domain second repeat present in RasA1 and RasA4; RasA1 and RasA4 are GAP1s (GTPase activating protein 1s ), Ras-specific GAP members, which suppresses Ras function by enhancing the GTPase activity of Ras proteins resulting in the inactive GDP-bound form of Ras. In this way it can control cellular proliferation and differentiation. Both proteins contain two C2 domains, a Ras-GAP domain, a plextrin homology (PH)-like domain, and a Bruton's Tyrosine Kinase (BTK) zinc binding domain. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions. This cd contains the second C2 repeat, C2B, and has a type-I topology.

Pssm-ID: 175991 [Multi-domain] Cd Length: 123 Bit Score: 39.78 E-value: 1.84e-03

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036   1062 TLTVKVLGARHLPKLGRSIAC-PFVEVEicgaeYGNNKFKTTVVNDNGLsPIWaptQEKVTFEIYDPNLAFLRFVVYEED 1140
Cdd:cd04025    1 RLRCHVLEARDLAPKDRNGTSdPFVRVF-----YNGQTLETSVVKKSCY-PRW---NEVFEFELMEGADSPLSVEVWDWD 71

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|
gi 190036   1141 MFSDPNFLAHATYPIK------AVKSGFRSVPLKNGYSED 1174
Cdd:cd04025   72 LVSKNDFLGKVVFSIQtlqqakQEEGWFRLLPDPRAEEES 111

C2_C21orf25-like

cd08678

C2 domain found in the Human chromosome 21 open reading frame 25 (C21orf25) protein; The ...

1063-1174

2.22e-03

C2 domain found in the Human chromosome 21 open reading frame 25 (C21orf25) protein; The members in this cd are named after the Human C21orf25 which contains a single C2 domain. Several other members contain a C1 domain downstream of the C2 domain. No other information on this protein is currently known. The C2 domain was first identified in PKC. C2 domains fold into an 8-standed beta-sandwich that can adopt 2 structural arrangements: Type I and Type II, distinguished by a circular permutation involving their N- and C-terminal beta strands. Many C2 domains are Ca2+-dependent membrane-targeting modules that bind a wide variety of substances including bind phospholipids, inositol polyphosphates, and intracellular proteins. Most C2 domain proteins are either signal transduction enzymes that contain a single C2 domain, such as protein kinase C, or membrane trafficking proteins which contain at least two C2 domains, such as synaptotagmin 1. However, there are a few exceptions to this including RIM isoforms and some splice variants of piccolo/aczonin and intersectin which only have a single C2 domain. C2 domains with a calcium binding region have negatively charged residues, primarily aspartates, that serve as ligands for calcium ions.

Pssm-ID: 176060 [Multi-domain] Cd Length: 126 Bit Score: 39.27 E-value: 2.22e-03

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 190036   1063 LTVKVLgarHLPKLGRSIAC--PFVEVEIcgaEYGNNKFKTTVVNdNGLSPIWaptQEKVTFEIyDPNLAFLRFVVYEED 1140
Cdd:cd08678    1 LLVKNI---KANGLSEAAGSsnPYCVLEM---DEPPQKYQSSTQK-NTSNPFW---DEHFLFEL-SPNSKELLFEVYDNG 69

                         90       100       110
                 ....*....|....*....|....*....|....*..
gi 190036   1141 MFSDPNFLAHATYPIKAVK---SGFRSVPLKNGYSED 1174
Cdd:cd08678   70 KKSDSKFLGLAIVPFDELRknpSGRQIFPLQGRPYEG 106

PHsplit_PLC_gamma