Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases; Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases Also called Dbl-homologous (DH) domain. It appears that PH domains invariably occur C-terminal to RhoGEF/DH domains. Improved coverage.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71897169    124 AIYEMSRGEQDLIEDLKLARKAYHDPMLK-LSIMSEEELTHIFGDLDSYIPLHEDLLASLGEATK-PDGTVEQIGPILVK 201
Cdd:smart00325   1 VLKELLQTERNYVRDLKLLVEVFLKPLKKeLKLLSPNELETLFGNIEEIYEFHRDFLDELEERIEeWDDSVERIGDVFLK 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71897169    202 WLPRLHAYKGYCSNQLAAKALLDQKKQDRRVQDFLQRCLESPFSRKLDLWSFLDIPRSRLVKYPLLLKEILRHTPKDHPD 281
Cdd:smart00325  81 LEEFFKIYSEYCSNHPDALELLKKLKKNPRFQKFLKEIESSPQCRRLTLESLLLKPVQRLTKYPLLLKELLKHTPEDHED 160

                          170
                   ....*....|....*....
gi 71897169    282 IQILEEAISIIQGVLSDIN 300
Cdd:smart00325 161 REDLKKALKAIKELANQVN 179

Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases; Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases Also called Dbl-homologous (DH) domain. It appears that PH domains invariably occur C-terminal to RhoGEF/DH domains. Improved coverage.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71897169    124 AIYEMSRGEQDLIEDLKLARKAYHDPMLK-LSIMSEEELTHIFGDLDSYIPLHEDLLASLGEATK-PDGTVEQIGPILVK 201
Cdd:smart00325   1 VLKELLQTERNYVRDLKLLVEVFLKPLKKeLKLLSPNELETLFGNIEEIYEFHRDFLDELEERIEeWDDSVERIGDVFLK 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71897169    202 WLPRLHAYKGYCSNQLAAKALLDQKKQDRRVQDFLQRCLESPFSRKLDLWSFLDIPRSRLVKYPLLLKEILRHTPKDHPD 281
Cdd:smart00325  81 LEEFFKIYSEYCSNHPDALELLKKLKKNPRFQKFLKEIESSPQCRRLTLESLLLKPVQRLTKYPLLLKELLKHTPEDHED 160

                          170
                   ....*....|....*....
gi 71897169    282 IQILEEAISIIQGVLSDIN 300
Cdd:smart00325 161 REDLKKALKAIKELANQVN 179

RhoGEF domain; Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases Also called Dbl-homologous (DH) domain. It appears that pfam00169 domains invariably occur C-terminal to RhoGEF/DH domains.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71897169   124 AIYEMSRGEQDLIEDLKLARKAYHDPMLKLSIMSEEELTHIFGDLDSYIPLHEDLLasLGEATKPDGTVEQIGPILVKWL 203
Cdd:pfam00621   1 VIKELLQTERSYVRDLEILVEVFLPPNSKPLSESEEEIKTIFSNIEEIYELHRQLL--LEELLKEWISIQRIGDIFLKFA 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71897169   204 PRLHAYKGYCSNQLAAKALLDQKKQ-DRRVQDFLQRCLESPFSRKLDLWSFLDIPRSRLVKYPLLLKEILRHTPKDHPDI 282
Cdd:pfam00621  79 PGFKVYSTYCSNYPKALKLLKKLLKkNPKFRAFLEELEANPECRGLDLNSFLIKPVQRIPRYPLLLKELLKHTPPDHPDY 158

                         170
                  ....*....|....*...
gi 71897169   283 QILEEAISIIQGVLSDIN 300
Cdd:pfam00621 159 EDLKKALEAIKEVAKQIN 176

Pleckstrin homology domain; Domain commonly found in eukaryotic signalling proteins. The domain family possesses multiple functions including the abilities to bind inositol phosphates, and various proteins. PH domains have been found to possess inserted domains (such as in PLC gamma, syntrophins) and to be inserted within other domains. Mutations in Brutons tyrosine kinase (Btk) within its PH domain cause X-linked agammaglobulinaemia (XLA) in patients. Point mutations cluster into the positively charged end of the molecule around the predicted binding site for phosphatidylinositol lipids.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71897169    325 PRIEGSkaLLCHGELKNKNGHKLYVFLFQDILVLTRPVTRNERQSYqvyRQPIPVQELLLEDLQDGDvkmggsfrgafgn 404
Cdd:smart00233   1 VIKEGW--LYKKSGGGKKSWKKRYFVLFNSTLLYYKSKKDKKSYKP---KGSIDLSGCTVREAPDPD------------- 62

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|...
gi 71897169    405 SDKAKNIFRVRFQDpspGQSHTLQANDIFHKQQWVNCIRTAIA 447
Cdd:smart00233  63 SSKKPHCFEIKTSD---RKTLLLQAESEEEREKWVEALRKAIA 102

Rho guanine nucleotide exchange factor 3 Pleckstrin homology (PH) domain; RhoGEF3/XPLN, a Rho family GEF, preferentially stimulates guanine nucleotide exchange on RhoA and RhoB, but not RhoC, RhoG, Rac1, or Cdc42 in vitro. It also possesses transforming activity. RhoGEF3/XPLN contains a tandem Dbl homology and PH domain, but lacks homology with other known functional domains or motifs. It is expressed in the brain, skeletal muscle, heart, kidney, platelets, and macrophage and neuronal cell lines. 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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71897169 314 KLEYLDEKQKDPRIEGSKALLCHGELKNKNGHKLYVFLFQDILVLTRPVTRNERQSYQVYRQPIPVQELLLEDLQDGDVK 393
Cdd:cd10572   1 RLEYLDEKQRDPLIDSSRLLLCHGELKNNRGTKLHVFLFEEVLVLTRPVTRNEQLCYQVYRQPIPVADLVLEDLPDGEVR 80

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|...
gi 71897169 394 MGGSFRGAFGNSDKAKNIFRVRFQDPSPGQSHTLQANDIFHKQQWVNCIRTAI 446
Cdd:cd10572  81 LGGSFRGAFSNNERAKNFFRVSFTDRSLGQSHTLQANDEFDKQQWLNCIRQAV 133

Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases; Also called Dbl-homologous (DH) domain. It appears that PH domains invariably occur C-terminal to RhoGEF/DH domains.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71897169 121 RQEAIYEMSRGEQDLIEDLKLARKAYHDPMLKLSI-MSEEELTHIFGDLDSYIPLHEDLLASLGEATK-PDGTVEQIGPI 198
Cdd:cd00160   1 RQEVIKELLQTERNYVRDLKLLVEVFLKPLDKELLpLSPEEVELLFGNIEEIYEFHRIFLKSLEERVEeWDKSGPRIGDV 80

                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71897169 199 LVKWLPRLHAYKGYCSNQLAAKALLDQKKqdrRVQDFLQRCLESPFS--RKLDLWSFLDIPRSRLVKYPLLLKEILRHTP 276
Cdd:cd00160  81 FLKLAPFFKIYSEYCSNHPDALELLKKLK---KFNKFFQEFLEKAESecGRLKLESLLLKPVQRLTKYPLLLKELLKHTP 157

                       170       180
                ....*....|....*....|....
gi 71897169 277 KDHPDIQILEEAISIIQGVLSDIN 300
Cdd:cd00160 158 DGHEDREDLKKALEAIKEVASQVN 181

RhoGEF, Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases [Signal transduction mechanisms];

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71897169  101 LWSEMLDVNMKESLSTKEIKRQEAIYEMSRGEQDLIEDLKLARKAYHDPMLKLSIMSE----EELTHIFGDLDSYIPLHE 176
Cdd:COG5422  465 LWTLSVPKEVWESLPKQEIKRQEAIYEVIYTERDFVKDLEYLRDTWIKPLEESNIIPEnarrNFIKHVFANINEIYAVNS 544

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71897169  177 DLLASLGEATKPDGTVEQIGPILVKWLPRLHAYKGYCSNQLAAKALLD-QKKQDRRVQDFLQRCLESPFSRKLDLWSFLD 255
Cdd:COG5422  545 KLLKALTNRQCLSPIVNGIADIFLDYVPKFEPFIKYGASQPYAKYEFErEKSVNPNFARFDHEVERLDESRKLELDGYLT 624

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71897169  256 IPRSRLVKYPLLLKEILRHTPKDHPDIQILEEAISIIQGVLSDINLKKGESE--------CQYYIDKLEYLDEKQKDPRi 327
Cdd:COG5422  625 KPTTRLARYPLLLEEVLKFTDPDNPDTEDIPKVIDMLREFLSRLNFESGKAEnrgdlfhlNQQLLFKPEYVNLGLNDEY- 703

                        250       260       270       280       290       300       310
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 71897169  328 egsKALLCHGELKNKNGHK--------LYVFLFQDILVLTRPVTRNERQSYQVYRQPIPvqELLLEDLQDGD 391
Cdd:COG5422  704 ---RKIIFKGVLKRKAKSKtdgslrgdIQFFLLDNMLLFCKAKAVNKWRQHKVFQRPIP--LELLFISPDED 770

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71897169   333 LLCHGELKNKNG------HKLYVFLFQDILVLTRPVTRNERQSyqvyrqpiPVQELLLEDLQDGDVKMGgsfrgafgNSD 406
Cdd:pfam00169   1 VVKEGWLLKKGGgkkkswKKRYFVLFDGSLLYYKDDKSGKSKE--------PKGSISLSGCEVVEVVAS--------DSP 64

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|.
gi 71897169   407 KAKNIFRVRFQDPSPGQSHTLQANDIFHKQQWVNCIRTAIA 447
Cdd:pfam00169  65 KRKFCFELRTGERTGKRTYLLQAESEEERKDWIKAIQSAIR 105

Intersectin Pleckstrin homology (PH) domain; ITSNs, an adaptor protein family, play a role in endo- and exocytosis, actin cytoskeleton rearrangement and signal transduction. There are two human ITSN genes: ITSN1 and ITSN2. They share significant sequence identity and a similar domain structure having both short and long isoforms produced by alternative splicing. The short isoform (ITSN-S) consists of two Eps15 homology domains (EH1 and EH2), a coiled-coil region (CCR) and five Src homology 3 domains (SH3A-E). The EH domains bind to Asn-Pro-Phe motifs and are implicated in endocytosis and vesicle transport. The SH3 domains bind to proline-rich sequences and are commonly found in proteins implicated in cell signalling pathways, cytoskeletal organization and membrane traffic. The long isoform (ITSN-L) contains three additional C-terminal domains, a Dbl homology domain (DH), a Pleckstrin homology domain (PH) and a C2 domain. The tandem DH-PH domains are present in all Dbl family of GEFs. ITSN acts specifically on Cdc42 through its DH domain with no portion of the PH domain making contact with Cdc42. This is in contrast to Dbs which requires the PH domain for full catalytic activity. The ITSN PH domain binds phosphoinositides. C2 domains are usually involved in Ca2+-dependent and Ca2+-independent phospholipid binding. There are more than 30 proteins that interact with ITSNs. ITSN-S is present in mammals, frogs, flies and nematodes, while ITSN-L is present only in vertebrates. 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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71897169 329 GSKALLCHGEL-KNKNGHKLYVFLFQDILVLTRPV------------TRNERQSYQVYRQPIPVQELLLEDLQDgdvkmg 395
Cdd:cd13264  12 GPRKFLHSGKLyKAKSNKELYGFLFNDFLLLTQPIkplgssgndfvfDNKANIQYKMYKTPIFLNEVLVKLPTD------ 85

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|
gi 71897169 396 gsfrgafGNSDkaKNIFRVRFQDpspgQSHTLQANDIFHKQQWVNCIRTA 445
Cdd:cd13264  86 -------PSGD--EPIFHISHID----RVYTLRAESINERTAWVQKIKAA 122

Pleckstrin homology domain-containing family G member 5 and 6 pleckstrin homology (PH) domain; PLEKHG5 has a RhoGEF DH/double-homology domain in tandem with a PH domain which is involved in phospholipid binding. PLEKHG5 activates the nuclear factor kappa B (NFKB1) signaling pathway. Mutations in PLEKHG5 are associated with autosomal recessive distal spinal muscular atrophy. PLEKHG6 (also called MyoGEF) has no known function to date. 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.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 71897169 333 LLCHGELKNKNGHK----LYVFLFQDILVLTRPVTRNeRQSYQVYRQPIPVQELLLEDLQDGD 391
Cdd:cd13244   3 LLLEGDLRLKEGKGskvdVHCFLFTDMLLICKPVKRK-KDRLKVIRPPYLVDKLVVQELKDPG 64

Pleckstrin homology domain-containing family G member 7 pleckstrin homology (PH) domain; PLEKHG7 has a RhoGEF DH/double-homology domain in tandem with a PH domain which is involved in phospholipid binding. PLEKHG7 is proposed to functions as a guanine nucleotide exchange factor (GEF) and is involved in the regulation of Rho protein signal transduction. 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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71897169 348 YVFLFQDILVLTR----------------------PVTRNERQSYQVYRQPIPVQELLLEDLQDGDVkmggsfrGAFGns 405
Cdd:cd13245  20 YLFLFDDMLLITKmkknlkkkkssdsensmpslelTPLIKEGGSYTVYKQPIPLDRLCLHDVDPNEA-------TANG-- 90

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*
gi 71897169 406 dkAKNIFRV----RFQdpspgQ---SHTLQANDIFHKQQWVNCIR 443
Cdd:cd13245  91 --LKHAFVLvhlnRYQ-----QvigVYTLQASSENTKQTWMSKLR 128

ArfGAP with coiled-coil, ankyrin repeat and PH domains Pleckstrin homology (PH) domain; ACAP (also called centaurin beta) functions both as a Rab35 effector and as an Arf6-GTPase-activating protein (GAP) by which it controls actin remodeling and membrane trafficking. ACAP contain an NH2-terminal bin/amphiphysin/Rvs (BAR) domain, a phospholipid-binding domain, a PH domain, a GAP domain, and four ankyrin repeats. The AZAPs constitute a family of Arf GAPs that are characterized by an NH2-terminal pleckstrin homology (PH) domain and a central Arf GAP domain followed by two or more ankyrin repeats. On the basis of sequence and domain organization, the AZAP family is further subdivided into four subfamilies: 1) the ACAPs contain an NH2-terminal bin/amphiphysin/Rvs (BAR) domain (a phospholipid-binding domain that is thought to sense membrane curvature), a single PH domain followed by the GAP domain, and four ankyrin repeats; 2) the ASAPs also contain an NH2-terminal BAR domain, the tandem PH domain/GAP domain, three ankyrin repeats, two proline-rich regions, and a COOH-terminal Src homology 3 domain; 3) the AGAPs contain an NH2-terminal GTPase-like domain (GLD), a split PH domain, and the GAP domain followed by four ankyrin repeats; and 4) the ARAPs contain both an Arf GAP domain and a Rho GAP domain, as well as an NH2-terminal sterile-a motif (SAM), a proline-rich region, a GTPase-binding domain, and five PH domains. PMID 18003747 and 19055940 Centaurin can bind to phosphatidlyinositol (3,4,5)P3. 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.

                        10        20
                ....*....|....*....|....*...
gi 71897169 420 SPGQSHTLQANDIFHKQQWVNCIRTAIA 447
Cdd:cd13250  67 SPTKSYMLQAESEEDRQAWIQAIQSAIA 94