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.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034674348  756 AINGYIGNLNELGKMIMQGGFSVWIGHKKGATKmkDLARFKPMQRHLFLYEKAIVFCKRRVESGEGsdryPSYSFKHCWK 835
Cdd:cd01227      1 AITGYDGNLGDLGKLLMQGSFNVWTEHKKGHTK--KLARFKPMQRHIFLYEKAVLFCKKRGENGEA----PSYSYKNSLN 74

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1034674348  836 MDEVGITEYVKGDNRKFEIWYGEKEEVYIVQASNVDVKMTWLKEIRNILLKQ 887
Cdd:cd01227     75 TTAVGLTENVKGDTKKFEIWLNGREEVFIIQAPTPEIKAAWVKAIRQVLLSQ 126

Domain in homologues of a S. cerevisiae phosphatidylinositol transfer protein (Sec14p); Domain in homologues of a S. cerevisiae phosphatidylinositol transfer protein (Sec14p) and in RhoGAPs, RhoGEFs and the RasGAP, neurofibromin (NF1). Lipid-binding domain. The SEC14 domain of Dbl is known to associate with G protein beta/gamma subunits.

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034674348     5 AFLSGGRG--KDNAWIITFP--ENCNFRCIPEEVIAKVLTYLTSIARQNGSD---SRFTIILDRR-----LDTWSSLKIS 72
Cdd:smart00516    7 AYIPGGRGydKDGRPVLIERagRFDLKSVTLEELLRYLVYVLEKILQEEKKTggiEGFTVIFDLKglsmsNPDLSVLRKI 86

                            90       100       110       120       130       140       150
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1034674348    73 LQKISASFPGNLHLVLVLRPTSFLqRTFTDIGFWFSQEDFMLKLPVVMLSSVSDLLTYIDDKQLTPELGGTLQ 145
Cdd:smart00516   87 LKILQDHYPERLGKVYIINPPWFF-RVLWKIIKPFLDEKTREKIRFVGNDSKEELLEYIDKEQLPEELGGTLD 158

DBL's big sister protein pleckstrin homology (PH) domain; Dbs (also called MCF2-transforming sequence-like protein 2) is a guanine nucleotide exchange factor (GEF), which contains spectrin repeats, a rhoGEF (DH) domain and a PH domain. The Dbs PH domain participates in binding to both the Cdc42 and RhoA GTPases. 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 1034674348  756 AINGYIGNLNELGKMIMQGGFSVWIGHKKGATKmkDLARFKPMQRHLFLYEKAIVFCKRRVESGEGsdryPSYSFKHCWK 835
Cdd:cd01227      1 AITGYDGNLGDLGKLLMQGSFNVWTEHKKGHTK--KLARFKPMQRHIFLYEKAVLFCKKRGENGEA----PSYSYKNSLN 74

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1034674348  836 MDEVGITEYVKGDNRKFEIWYGEKEEVYIVQASNVDVKMTWLKEIRNILLKQ 887
Cdd:cd01227     75 TTAVGLTENVKGDTKKFEIWLNGREEVFIIQAPTPEIKAAWVKAIRQVLLSQ 126

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 1034674348   575 VLNELIQTERVYVRELYTVLLGYRAEMDNPEMFdlmppLLRNKKDILFGNMAEIYEFHNdIFLSSLENC----AHAPERV 650
Cdd:smart00325    1 VLKELLQTERNYVRDLKLLVEVFLKPLKKELKL-----LSPNELETLFGNIEEIYEFHR-DFLDELEERieewDDSVERI 74

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034674348   651 GPCFLERKDDFQMYAKYCQNKPRSETIWRKYSEC----AFFQECQRKLKH-RLRLDSYLLKPVQRITKYQLLLKELLKYS 725
Cdd:smart00325   75 GDVFLKLEEFFKIYSEYCSNHPDALELLKKLKKNprfqKFLKEIESSPQCrRLTLESLLLKPVQRLTKYPLLLKELLKHT 154

                           170       180
                    ....*....|....*....|....*.
gi 1034674348   726 K-DCEGSALLKKALDAMLDLLKSVND 750
Cdd:smart00325  155 PeDHEDREDLKKALKAIKELANQVNE 180

Domain in homologues of a S. cerevisiae phosphatidylinositol transfer protein (Sec14p); Domain in homologues of a S. cerevisiae phosphatidylinositol transfer protein (Sec14p) and in RhoGAPs, RhoGEFs and the RasGAP, neurofibromin (NF1). Lipid-binding domain. The SEC14 domain of Dbl is known to associate with G protein beta/gamma subunits.

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034674348     5 AFLSGGRG--KDNAWIITFP--ENCNFRCIPEEVIAKVLTYLTSIARQNGSD---SRFTIILDRR-----LDTWSSLKIS 72
Cdd:smart00516    7 AYIPGGRGydKDGRPVLIERagRFDLKSVTLEELLRYLVYVLEKILQEEKKTggiEGFTVIFDLKglsmsNPDLSVLRKI 86

                            90       100       110       120       130       140       150
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1034674348    73 LQKISASFPGNLHLVLVLRPTSFLqRTFTDIGFWFSQEDFMLKLPVVMLSSVSDLLTYIDDKQLTPELGGTLQ 145
Cdd:smart00516   87 LKILQDHYPERLGKVYIINPPWFF-RVLWKIIKPFLDEKTREKIRFVGNDSKEELLEYIDKEQLPEELGGTLD 158

Spectrin repeats, found in several proteins involved in cytoskeletal structure; family members include spectrin, alpha-actinin and dystrophin; the spectrin repeat forms a three helix bundle with the second helix interrupted by proline in some sequences; the repeats are independent folding units; tandem repeats are found in differing numbers and arrange in an antiparallel manner to form dimers; the repeats are defined by a characteristic tryptophan (W) residue in helix A and a leucine (L) at the carboxyl end of helix C and separated by a linker of 5 residues; two copies of the repeat are present here

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034674348  285 QDFQQLVTEVEFLLNQQAELA---DVTGTIAQVKQKIKKLENLDENSQELLSKAQFVILHGHKLAANHHYALDLICQRCN 361
Cdd:cd00176      3 QQFLRDADELEAWLSEKEELLsstDYGDDLESVEALLKKHEALEAELAAHEERVEALNELGEQLIEEGHPDAEEIQERLE 82

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034674348  362 ELRYLSDILVNEIKAKRIQLSRTFKMHKLLQQARQC---CDEGECLLANQEIDKfqSKEDAQKALQDIENFLEMaLPFIN 438
Cdd:cd00176     83 ELNQRWEELRELAEERRQRLEEALDLQQFFRDADDLeqwLEEKEAALASEDLGK--DLESVEELLKKHKELEEE-LEAHE 159

                          170       180       190
                   ....*....|....*....|....*....|....*...
gi 1034674348  439 YEPETLQYEFDVILSPELKVQMKTIQLKLENIRSIFEN 476
Cdd:cd00176    160 PRLKSLNELAEELLEEGHPDADEEIEEKLEELNERWEE 197

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 1034674348   787 TKMKDLARFKPMQRHLFLYEKAIVFCKRRvesgegsDRYPSYSFKHCWKMDEVGITEYVKGDNRK----FEIWYGEKeEV 862
Cdd:smart00233    8 YKKSGGGKKSWKKRYFVLFNSTLLYYKSK-------KDKKSYKPKGSIDLSGCTVREAPDPDSSKkphcFEIKTSDR-KT 79

                            90       100
                    ....*....|....*....|..
gi 1034674348   863 YIVQASNVDVKMTWLKEIRNIL 884
Cdd:smart00233   80 LLLQAESEEEREKWVEALRKAI 101

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034674348  523 QACKLFSKGKKTWRQNQSNLKIEvvpDCQEKRS---SGPSSSLDNGNSLDVLKNHVLNELIQTERVYVRELYTVLLGYra 599
Cdd:COG5422    436 QQARLHLKLMGGLKRNSSLALDK---FDEEKNLwtlSVPKEVWESLPKQEIKRQEAIYEVIYTERDFVKDLEYLRDTW-- 510

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034674348  600 eMDNPEMFDLMPPllRNKKDIL---FGNMAEIYEFhNDIFLSSL---ENCAHAPERVGPCFLERKDDFQMYAKYCQNKP- 672
Cdd:COG5422    511 -IKPLEESNIIPE--NARRNFIkhvFANINEIYAV-NSKLLKALtnrQCLSPIVNGIADIFLDYVPKFEPFIKYGASQPy 586

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034674348  673 ---RSETiwRKYSECAFF------QECQRKLKHRLrlDSYLLKPVQRITKYQLLLKELLKYSK-DCEGSALLKKALDAML 742
Cdd:COG5422    587 akyEFER--EKSVNPNFArfdhevERLDESRKLEL--DGYLTKPTTRLARYPLLLEEVLKFTDpDNPDTEDIPKVIDMLR 662

                          250       260       270       280       290       300       310       320
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034674348  743 DLLKSVN--------------DSMHQIAINGYI--GNLNELGKMIMQGGFSVWIGHKKGATKMKDLarfkpmqrHLFLYE 806
Cdd:COG5422    663 EFLSRLNfesgkaenrgdlfhLNQQLLFKPEYVnlGLNDEYRKIIFKGVLKRKAKSKTDGSLRGDI--------QFFLLD 734

                   ....*..
gi 1034674348  807 KAIVFCK 813
Cdd:COG5422    735 NMLLFCK 741

DBL's big sister protein pleckstrin homology (PH) domain; Dbs (also called MCF2-transforming sequence-like protein 2) is a guanine nucleotide exchange factor (GEF), which contains spectrin repeats, a rhoGEF (DH) domain and a PH domain. The Dbs PH domain participates in binding to both the Cdc42 and RhoA GTPases. 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 1034674348  756 AINGYIGNLNELGKMIMQGGFSVWIGHKKGATKmkDLARFKPMQRHLFLYEKAIVFCKRRVESGEGsdryPSYSFKHCWK 835
Cdd:cd01227      1 AITGYDGNLGDLGKLLMQGSFNVWTEHKKGHTK--KLARFKPMQRHIFLYEKAVLFCKKRGENGEA----PSYSYKNSLN 74

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1034674348  836 MDEVGITEYVKGDNRKFEIWYGEKEEVYIVQASNVDVKMTWLKEIRNILLKQ 887
Cdd:cd01227     75 TTAVGLTENVKGDTKKFEIWLNGREEVFIIQAPTPEIKAAWVKAIRQVLLSQ 126

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 1034674348   575 VLNELIQTERVYVRELYTVLLGYRAEMDNPEMFdlmppLLRNKKDILFGNMAEIYEFHNdIFLSSLENC----AHAPERV 650
Cdd:smart00325    1 VLKELLQTERNYVRDLKLLVEVFLKPLKKELKL-----LSPNELETLFGNIEEIYEFHR-DFLDELEERieewDDSVERI 74

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034674348   651 GPCFLERKDDFQMYAKYCQNKPRSETIWRKYSEC----AFFQECQRKLKH-RLRLDSYLLKPVQRITKYQLLLKELLKYS 725
Cdd:smart00325   75 GDVFLKLEEFFKIYSEYCSNHPDALELLKKLKKNprfqKFLKEIESSPQCrRLTLESLLLKPVQRLTKYPLLLKELLKHT 154

                           170       180
                    ....*....|....*....|....*.
gi 1034674348   726 K-DCEGSALLKKALDAMLDLLKSVND 750
Cdd:smart00325  155 PeDHEDREDLKKALKAIKELANQVNE 180

Puratrophin-1 pleckstrin homology (PH) domain; Puratrophin-1 (also called Purkinje cell atrophy-associated protein 1 or PLEKHG4/Pleckstrin homology domain-containing family G member 4) contains a spectrin repeat, a RhoGEF (DH) domain, and a PH domain. It is thought to function in intracellular signaling and cytoskeleton dynamics at the Golgi. Puratrophin-1 is expressed in kidney, Leydig cells in the testis, epithelial cells in the prostate gland and Langerhans islet in the pancreas. A single nucleotide substitution in the puratrophin-1 gene were once thought to result in autosomal dominant cerebellar ataxia (ADCA), but now it has been demonstrated that this ataxia is a result of defects in the BEAN gene. Puratrophin contains a domain architecture similar to that of Dbl family members Dbs and Trio. Dbs is a guanine nucleotide exchange factor (GEF), which contains spectrin repeats, a RhoGEF (DH) domain and a PH domain. The Dbs PH domain participates in binding to both the Cdc42 and RhoA GTPases. Trio plays an essential role in regulating the actin cytoskeleton during axonal guidance and branching. Trio is a multidomain signaling protein that contains two RhoGEF(DH)-PH domains in tandem. 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 1034674348  763 NLNELGKMIMQGGFSVWIGHKKGatkmkdlarfkpmQRHLFLYEKAIVFCKRRVESGeGSDrypSYSFKHCWKMDEVGIT 842
Cdd:cd13242     22 NLKEQGQLLRQDEFLVWQGRKKC-------------LRHVFLFEDLILFSKPKKTPG-GKD---VYIYKHSIKTSDIGLT 84

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*..
gi 1034674348  843 EYVKGDNRKFEIWYGEKE--EVYIVQASNVDVKMTWLKEIRNILLKQ 887
Cdd:cd13242     85 ENVGDSGLKFEIWFRRRKarDTYILQATSPEIKQAWTSDIAKLLWKQ 131

Obscurin pleckstrin homology (PH) domain; Obscurin (also called Obscurin-RhoGEF; Obscurin-myosin light chain kinase/Obscurin-MLCK) is a giant muscle protein that is concentrated at the peripheries of Z-disks and M-lines. It binds small ankyrin I, a component of the sarcoplasmic reticulum (SR) membrane. It is associated with the contractile apparatus through binding with titin and sarcomeric myosin. It plays important roles in the organization and assembly of the myofibril and the SR. Obscurin has been observed as alternatively-spliced isoforms. The major isoform in sleletal muscle, approximately 800 kDa in size, is composed of many adhesion modules and signaling domains. It harbors 49 Ig and 2 FNIII repeats at the N-terminues, a complex middle region with additional Ig domains, an IQ motif, and a conserved SH3 domain near RhoGEF and PH domains, and a non-modular C-terminus with phosphorylation motifs. The obscurin gene also encodes two kinase domains, which are not part of the 800 kDa form of the protein, but is part of smaller spliced products that present in heart muscle. 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 1034674348  757 INGYIGNLNELGKMIMQGGFSVWighkKGATKMKDLARfkPMQRHLFLYEKAIVFCKRRVESGEGSDrypSYSFKHCWKM 836
Cdd:cd13239      2 IENYPAPLQALGEPIRQGHFTVW----EEAPEVKTSSR--GHHRHVFLFKNCVVICKPKRDSRTDTV---TYVFKNKMKL 72

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*....
gi 1034674348  837 DEVGITEYVKGDNRKFEIWYGEKEEV--YIVQASNVDVKMTWLKEIRNI 883
Cdd:cd13239     73 SDIDVKDTVEGDDRSFGLWHEHRGSVrkYTLQARSAIIKSSWLKDLRDL 121

p63RhoGEF pleckstrin homology (PH) domain, repeat 2; The guanine nucleotide exchange factor p63RhoGEF is an effector of the heterotrimeric G protein, Galphaq and linking Galphaq-coupled receptors (GPCRs) to the activation of RhoA. The Dbl(DH) and PH domains of p63RhoGEF interact with the effector-binding site and the C-terminal region of Galphaq and appear to relieve autoinhibition of the catalytic DH domain by the PH domain. Trio, Duet, and p63RhoGEF are shown to constitute a family of Galphaq effectors that appear to activate RhoA both in vitro and in intact cells. Dbs is a guanine nucleotide exchange factor (GEF), which contains spectrin repeats, a rhoGEF (DH) domain and a PH domain. The Dbs PH domain participates in binding to both the Cdc42 and RhoA GTPases. Trio plays an essential role in regulating the actin cytoskeleton during axonal guidance and branching. Trio is a multidomain signaling protein that contains two RhoGEF(DH)-PH domains in tandem. 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 1034674348  759 GYIGNLNELGKMIMQGGFSVwighkkgaTKMKDLARFKPMQRHLFLYEKAIVFC-----KRRVESgegsdryPSYSFKHC 833
Cdd:cd13241      6 GFDGKITAQGKLLLQGTLLV--------SEPSAGLLQKGKERRVFLFEQIIIFSeilgkKTQFSN-------PGYIYKNH 70

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1034674348  834 WKMDEVGITEYVKGDNRKFEIW---YGEKEEVYIVQASNVDVKMTWLKEIRNILLKQQELLT 892
Cdd:cd13241     71 IKVNKMSLEENVDGDPLRFALKsrdPNNPSETFILQAASPEVRQEWVDTINQILDTQRDFLK 132

Spectrin repeats, found in several proteins involved in cytoskeletal structure; family members include spectrin, alpha-actinin and dystrophin; the spectrin repeat forms a three helix bundle with the second helix interrupted by proline in some sequences; the repeats are independent folding units; tandem repeats are found in differing numbers and arrange in an antiparallel manner to form dimers; the repeats are defined by a characteristic tryptophan (W) residue in helix A and a leucine (L) at the carboxyl end of helix C and separated by a linker of 5 residues; two copies of the repeat are present here

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034674348  285 QDFQQLVTEVEFLLNQQAELA---DVTGTIAQVKQKIKKLENLDENSQELLSKAQFVILHGHKLAANHHYALDLICQRCN 361
Cdd:cd00176      3 QQFLRDADELEAWLSEKEELLsstDYGDDLESVEALLKKHEALEAELAAHEERVEALNELGEQLIEEGHPDAEEIQERLE 82

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034674348  362 ELRYLSDILVNEIKAKRIQLSRTFKMHKLLQQARQC---CDEGECLLANQEIDKfqSKEDAQKALQDIENFLEMaLPFIN 438
Cdd:cd00176     83 ELNQRWEELRELAEERRQRLEEALDLQQFFRDADDLeqwLEEKEAALASEDLGK--DLESVEELLKKHKELEEE-LEAHE 159

                          170       180       190
                   ....*....|....*....|....*....|....*...
gi 1034674348  439 YEPETLQYEFDVILSPELKVQMKTIQLKLENIRSIFEN 476
Cdd:cd00176    160 PRLKSLNELAEELLEEGHPDADEEIEEKLEELNERWEE 197

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 1034674348   787 TKMKDLARFKPMQRHLFLYEKAIVFCKRRvesgegsDRYPSYSFKHCWKMDEVGITEYVKGDNRK----FEIWYGEKeEV 862
Cdd:smart00233    8 YKKSGGGKKSWKKRYFVLFNSTLLYYKSK-------KDKKSYKPKGSIDLSGCTVREAPDPDSSKkphcFEIKTSDR-KT 79

                            90       100
                    ....*....|....*....|..
gi 1034674348   863 YIVQASNVDVKMTWLKEIRNIL 884
Cdd:smart00233   80 LLLQAESEEEREKWVEALRKAI 101

unc89 pleckstrin homology (PH) domain; unc89 is a myofibrillar protein. unc89-B the largest isoform is composed of 53 immunoglobulin (Ig) domains, 2 Fn3 domains, a triplet of SH3, DH and PH domains at its N-terminus, and 2 protein kinase domains (PK1 and PK2) at its C-terminus. unc-89 mutants display disorganization of muscle A-bands, and usually lack M-lines. The COOH-terminal region of obscurin, the human homolog of unc89, interacts via two specific Ig-like domains with the NH(2)-terminal Z-disk region of titin, a protein that connects the Z line to the M line in the sarcomere and contributes to the contraction of striated muscle. obscurin is also thought to be involved in Ca2+/calmodulin via its IQ domains, as well as G protein-coupled signal transduction in the sarcomere via its RhoGEF/DH domain. The DH-PH region of OBSCN and unc89, the C. elegans homolog, has exchange activity for RhoA and Rho-1 respectively, but not for the small GTPases homologous to Cdc42 or Rac. 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 1034674348  762 GNLNELGKMIMQGGFSVWIGhkkgatkmkdlaRFKPMQRHLFLYEKAIVFCK-RRVesgeGSDRyPSYSFKHCWKMDEVG 840
Cdd:cd13325      1 GNIHKLGRLLRHDWFTVTDG------------EGKAKERYLFLFKSRILITKvRRI----SEDR-SVFILKDIIRLPEVN 63

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*
gi 1034674348  841 ITEYvKGDNRKFEIWYGEKE---EVYIVQASNVDVKMTWLKEIRN 882
Cdd:cd13325     64 VKQH-PDDERTFELQPKLPAfgiLPIDFKAHKDEIKDYWLNEIEE 107

Pleckstrin homology (PH) 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.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034674348  787 TKMKDLARFKPMQRHLFLYEKAIVFCKrrvesgegSDRYPSYSFKHCWKMDE-VGITEYVKGD-NRKFEIWYgEKEEVYI 864
Cdd:cd00821      6 LKRGGGGLKSWKKRWFVLFEGVLLYYK--------SKKDSSYKPKGSIPLSGiLEVEEVSPKErPHCFELVT-PDGRTYY 76

                           90
                   ....*....|....*.
gi 1034674348  865 VQASNVDVKMTWLKEI 880
Cdd:cd00821     77 LQADSEEERQEWLKAL 92

Pleckstrin homology domain-containing family G members 1, 2, and 3 pleckstrin homology (PH) domain; PLEKHG1 (also called ARHGEF41), PLEKHG2 (also called ARHGEF42 or CLG/common-site lymphoma/leukemia guanine nucleotide exchange factor2), and PLEKHG3 (also called ARHGEF43) have RhoGEF DH/double-homology domains in tandem with a PH domain which is involved in phospholipid binding. They function as a guanine nucleotide exchange factor (GEF) and are involved in the regulation of Rho protein signal transduction. Mutations in PLEKHG1 have been associated panic disorder (PD), an anxiety disorder characterized by panic attacks and anticipatory anxiety. 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 1034674348  799 QRHLFLYEKAIVFCKRRVESGegsdrypsYSFKHCWKMDEVGITEYVKGDNRKFEIW-YGEKEEVYIVQASNVDVKMTWL 877
Cdd:cd13243     66 ERLLFLFDKMLLITKKREDGI--------LQYKTHIMCSNLMLSESIPKEPLSFQVLpFDNPKLQYTLQAKNQEQKRLWT 137

                   ....*....
gi 1034674348  878 KEIRNILLK 886
Cdd:cd13243    138 QEIKRLILE 146