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 1622884774  845 AITGYDGNLGDLGKLLMQGSFSVWTDHKRGHTKvkELARFKPMQRHLFLHEKAVLFCKKREENGEgyekAPSYSYKQSLN 924
Cdd:cd01227      1 AITGYDGNLGDLGKLLMQGSFNVWTEHKKGHTK--KLARFKPMQRHIFLYEKAVLFCKKRGENGE----APSYSYKNSLN 74

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1622884774  925 MAAVGITENVKGDAKKFEIWYNAREEVYIVQAPTPEIKAAWVNEIRKVLTSQ 976
Cdd:cd01227     75 TTAVGLTENVKGDTKKFEIWLNGREEVFIIQAPTPEIKAAWVKAIRQVLLSQ 126

Src homology 3 domain of DBL's Big Sister (DBS), a guanine nucleotide exchange factor; DBS, also called MCF2L (MCF2-transforming sequence-like protein) or OST, is a Rho GTPase guanine nucleotide exchange factor (RhoGEF), facilitating the exchange of GDP and GTP. It was originally isolated from a cDNA screen for sequences that cause malignant growth. It plays roles in regulating clathrin-mediated endocytosis and cell migration through its activation of Rac1 and Cdc42. Depending on cell type, DBS can also activate RhoA and RhoG. DBS contains a Sec14-like domain, spectrin-like repeats, a RhoGEF [or Dbl homology (DH)] domain, a Pleckstrin homology (PH) domain, and an 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.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....
gi 1622884774 1144 KYTVVADHEKGGPDALVVRSGDVVELVQQGDEGLWYVRDPTTGKEGWVPASSLS 1197
Cdd:cd11857      1 KYTVVADYEKGGPDDLTVKSGDLVQLIHEGDEGQWLVKNLSTRKEGWVPAANLQ 54

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 1622884774   139 LKKRFAYLSGGRGQD--GSPVITFPDY--PAFSEIPDKEFQNVMTYLTSIPSLQDAGI---GFILVIDRRRDKWTSVKAS 211
Cdd:smart00516    2 LELLKAYIPGGRGYDkdGRPVLIERAGrfDLKSVTLEELLRYLVYVLEKILQEEKKTGgieGFTVIFDLKGLSMSNPDLS 81

                            90       100       110       120       130       140       150
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1622884774   212 VLRIA--------------------------------------------VIMLSSVPDLHGYIDKSQLTEDLGGTLD 244
Cdd:smart00516   82 VLRKIlkilqdhyperlgkvyiinppwffrvlwkiikpfldektrekirFVGNDSKEELLEYIDKEQLPEELGGTLD 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 1622884774  845 AITGYDGNLGDLGKLLMQGSFSVWTDHKRGHTKvkELARFKPMQRHLFLHEKAVLFCKKREENGEgyekAPSYSYKQSLN 924
Cdd:cd01227      1 AITGYDGNLGDLGKLLMQGSFNVWTEHKKGHTK--KLARFKPMQRHIFLYEKAVLFCKKRGENGE----APSYSYKNSLN 74

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1622884774  925 MAAVGITENVKGDAKKFEIWYNAREEVYIVQAPTPEIKAAWVNEIRKVLTSQ 976
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 1622884774   658 VMSELLDTERAYVEELLCVLEGYAAEMDNPLMahLLStglHNKKDVLFGNMEEIYHFHnRIFLRELENYIDC----PELV 733
Cdd:smart00325    1 VLKELLQTERNYVRDLKLLVEVFLKPLKKELK--LLS---PNELETLFGNIEEIYEFH-RDFLDELEERIEEwddsVERI 74

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622884774   734 GRCFLERMEDFQIYEKYCQNKPRSESLWRQCSDCPFFQvlAWFQECQRKLDH-KLSLDSYLLKPVQRITKYQLLLKEMLK 812
Cdd:smart00325   75 GDVFLKLEEFFKIYSEYCSNHPDALELLKKLKKNPRFQ--KFLKEIESSPQCrRLTLESLLLKPVQRLTKYPLLLKELLK 152

                           170       180
                    ....*....|....*....|....*...
gi 1622884774   813 YSK-NCEGAEDLQEALSSILGILKAVND 839
Cdd:smart00325  153 HTPeDHEDREDLKKALKAIKELANQVNE 180

Src homology 3 domain of DBL's Big Sister (DBS), a guanine nucleotide exchange factor; DBS, also called MCF2L (MCF2-transforming sequence-like protein) or OST, is a Rho GTPase guanine nucleotide exchange factor (RhoGEF), facilitating the exchange of GDP and GTP. It was originally isolated from a cDNA screen for sequences that cause malignant growth. It plays roles in regulating clathrin-mediated endocytosis and cell migration through its activation of Rac1 and Cdc42. Depending on cell type, DBS can also activate RhoA and RhoG. DBS contains a Sec14-like domain, spectrin-like repeats, a RhoGEF [or Dbl homology (DH)] domain, a Pleckstrin homology (PH) domain, and an 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.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....
gi 1622884774 1144 KYTVVADHEKGGPDALVVRSGDVVELVQQGDEGLWYVRDPTTGKEGWVPASSLS 1197
Cdd:cd11857      1 KYTVVADYEKGGPDDLTVKSGDLVQLIHEGDEGQWLVKNLSTRKEGWVPAANLQ 54

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 1622884774   859 LLMQGSFSVWTDHKRGHTKvkelarfkpmQRHLFLHEKAVLFCKKREENgegyekaPSYSYKQSLNMAAVGITENVKGDA 938
Cdd:smart00233    1 VIKEGWLYKKSGGGKKSWK----------KRYFVLFNSTLLYYKSKKDK-------KSYKPKGSIDLSGCTVREAPDPDS 63

                            90       100       110
                    ....*....|....*....|....*....|....*....
gi 1622884774   939 KK----FEIWYNAREeVYIVQAPTPEIKAAWVNEIRKVL 973
Cdd:smart00233   64 SKkphcFEIKTSDRK-TLLLQAESEEEREKWVEALRKAI 101

Spectrin repeats;

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622884774   377 RHFEQGFREVKAILDAVcQKIATFTDIGNSLAHVEHLLRDLASFEEKSGVSVERARALSLDGEQLIENKHYAVDSIRPKC 456
Cdd:smart00150    1 QQFLRDADELEAWLEEK-EQLLASEDLGKDLESVEALLKKHEAFEAELEAHEERVEALNELGEQLIEEGHPDAEEIEERL 79

                            90       100
                    ....*....|....*....|.
gi 1622884774   457 QELRHLCDQFSSEIVRRRGLL 477
Cdd:smart00150   80 EELNERWEELKELAEERRQKL 100

PH domain; PH stands for pleckstrin homology.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622884774  859 LLMQGSFSVWTDHKRGHTKvkelarfkpmQRHLFLHEKAVLFCKKREengegyeKAPSYSYKQSLNMAAVGITENVKGDA 938
Cdd:pfam00169    1 VVKEGWLLKKGGGKKKSWK----------KRYFVLFDGSLLYYKDDK-------SGKSKEPKGSISLSGCEVVEVVASDS 63

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|.
gi 1622884774  939 KK----FEIWYNAR--EEVYIVQAPTPEIKAAWVNEIRKVL 973
Cdd:pfam00169   64 PKrkfcFELRTGERtgKRTYLLQAESEEERKDWIKAIQSAI 104

Spectrin repeat; Spectrin repeat-domains are found in several proteins involved in cytoskeletal structure. These include spectrin, alpha-actinin and dystrophin. The sequence repeat used in this family is taken from the structural repeat in reference. The spectrin domain- repeat forms a three helix bundle. The second helix is interrupted by proline in some sequences. The repeats are defined by a characteriztic tryptophan (W) residue at position 17 in helix A and a leucine (L) at 2 residues from the carboxyl end of helix C. Although the domain occurs in multiple repeats along sequences, the domains are actually stable on their own - ie they act, biophysically, like domains rather than repeats that along function when aggregated.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622884774  365 KHQQKLEQclQLRHFEQGFREVKAILDAvcqkiatfTDIGNSLAHVEHLLRDLASFEEKSGVSVERARALSLDGEQLIEN 444
Cdd:pfam00435    1 LLLQQFFR--DADDLESWIEEKEALLSS--------EDYGKDLESVQALLKKHKALEAELAAHQDRVEALNELAEKLIDE 70

                           90       100       110
                   ....*....|....*....|....*....|...
gi 1622884774  445 KHYAVDSIRPKCQELRHLCDQFSSEIVRRRGLL 477
Cdd:pfam00435   71 GHYASEEIQERLEELNERWEQLLELAAERKQKL 103

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.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*.
gi 1622884774 1144 KYTVVADHEKGGPDALVVRSGDVVELVQQGDEGLWYVRdpTTGKEGWVPASSLSVQ 1199
Cdd:pfam07653    1 YGRVIFDYVGTDKNGLTLKKGDVVKVLGKDNDGWWEGE--TGGRVGLVPSTAVEEI 54

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 1622884774  845 AITGYDGNLGDLGKLLMQGSFSVWTDHKRGHTKvkELARFKPMQRHLFLHEKAVLFCKKREENGEgyekAPSYSYKQSLN 924
Cdd:cd01227      1 AITGYDGNLGDLGKLLMQGSFNVWTEHKKGHTK--KLARFKPMQRHIFLYEKAVLFCKKRGENGE----APSYSYKNSLN 74

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1622884774  925 MAAVGITENVKGDAKKFEIWYNAREEVYIVQAPTPEIKAAWVNEIRKVLTSQ 976
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 1622884774   658 VMSELLDTERAYVEELLCVLEGYAAEMDNPLMahLLStglHNKKDVLFGNMEEIYHFHnRIFLRELENYIDC----PELV 733
Cdd:smart00325    1 VLKELLQTERNYVRDLKLLVEVFLKPLKKELK--LLS---PNELETLFGNIEEIYEFH-RDFLDELEERIEEwddsVERI 74

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622884774   734 GRCFLERMEDFQIYEKYCQNKPRSESLWRQCSDCPFFQvlAWFQECQRKLDH-KLSLDSYLLKPVQRITKYQLLLKEMLK 812
Cdd:smart00325   75 GDVFLKLEEFFKIYSEYCSNHPDALELLKKLKKNPRFQ--KFLKEIESSPQCrRLTLESLLLKPVQRLTKYPLLLKELLK 152

                           170       180
                    ....*....|....*....|....*...
gi 1622884774   813 YSK-NCEGAEDLQEALSSILGILKAVND 839
Cdd:smart00325  153 HTPeDHEDREDLKKALKAIKELANQVNE 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 1622884774  838 NDSMHLIAITGYDGNLGDLGKLLMQGSFSVWTDHKRGhtkvkelarfkpmQRHLFLHEKAVLFCKKReengegyeKAPS- 916
Cdd:cd13242      8 NDLLAMDSIRGCDVNLKEQGQLLRQDEFLVWQGRKKC-------------LRHVFLFEDLILFSKPK--------KTPGg 66

                           90       100       110       120       130       140       150
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622884774  917 ---YSYKQSLNMAAVGITENVKGDAKKFEIWYNARE--EVYIVQAPTPEIKAAWVNEIRKVLTSqlQACR 981
Cdd:cd13242     67 kdvYIYKHSIKTSDIGLTENVGDSGLKFEIWFRRRKarDTYILQATSPEIKQAWTSDIAKLLWK--QAIR 134

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 1622884774  848 GYDGNLGDLGKLLMQGSFSVwtdhkrghTKVKELARFKPMQRHLFLHEKAVLFC----KKREENGegyekaPSYSYKQSL 923
Cdd:cd13241      6 GFDGKITAQGKLLLQGTLLV--------SEPSAGLLQKGKERRVFLFEQIIIFSeilgKKTQFSN------PGYIYKNHI 71

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 1622884774  924 NMAAVGITENVKGDAKKFEIW---YNAREEVYIVQAPTPEIKAAWVNEIRKVLTSQL 977
Cdd:cd13241     72 KVNKMSLEENVDGDPLRFALKsrdPNNPSETFILQAASPEVRQEWVDTINQILDTQR 128

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 1622884774  375 QLRHFEQGFREVKAILDAVCQKIATfTDIGNSLAHVEHLLRDLASFEEKSGVSVERARALSLDGEQLIENKHYAVDSIRP 454
Cdd:cd00176      1 KLQQFLRDADELEAWLSEKEELLSS-TDYGDDLESVEALLKKHEALEAELAAHEERVEALNELGEQLIEEGHPDAEEIQE 79

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622884774  455 KCQELRHLCDQFSSEIVRRRGLLSKSLELHRRLETS---LKWCDEGIYLLASQPVDKcqSQDGAEAALQEIEKFLET--S 529
Cdd:cd00176     80 RLEELNQRWEELRELAEERRQRLEEALDLQQFFRDAddlEQWLEEKEAALASEDLGK--DLESVEELLKKHKELEEEleA 157

                          170       180       190       200       210
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 1622884774  530 AENKIQELNTIYKEYESILNQDLMEHVrkvfqkQASMEEVFHRRQASLKKLAARQTR 586
Cdd:cd00176    158 HEPRLKSLNELAEELLEEGHPDADEEI------EEKLEELNERWEELLELAEERQKK 208

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 1622884774   859 LLMQGSFSVWTDHKRGHTKvkelarfkpmQRHLFLHEKAVLFCKKREENgegyekaPSYSYKQSLNMAAVGITENVKGDA 938
Cdd:smart00233    1 VIKEGWLYKKSGGGKKSWK----------KRYFVLFNSTLLYYKSKKDK-------KSYKPKGSIDLSGCTVREAPDPDS 63

                            90       100       110
                    ....*....|....*....|....*....|....*....
gi 1622884774   939 KK----FEIWYNAREeVYIVQAPTPEIKAAWVNEIRKVL 973
Cdd:smart00233   64 SKkphcFEIKTSDRK-TLLLQAESEEEREKWVEALRKAI 101

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 1622884774   139 LKKRFAYLSGGRGQD--GSPVITFPDY--PAFSEIPDKEFQNVMTYLTSIPSLQDAGI---GFILVIDRRRDKWTSVKAS 211
Cdd:smart00516    2 LELLKAYIPGGRGYDkdGRPVLIERAGrfDLKSVTLEELLRYLVYVLEKILQEEKKTGgieGFTVIFDLKGLSMSNPDLS 81

                            90       100       110       120       130       140       150
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1622884774   212 VLRIA--------------------------------------------VIMLSSVPDLHGYIDKSQLTEDLGGTLD 244
Cdd:smart00516   82 VLRKIlkilqdhyperlgkvyiinppwffrvlwkiikpfldektrekirFVGNDSKEELLEYIDKEQLPEELGGTLD 158

First Src homology 3 domain of Tyrosine kinase substrate (Tks) proteins; 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. Vertebrates contain two Tks proteins, Tks4 (Tyr kinase substrate with four SH3 domains) and Tks5 (Tyr kinase substrate with five SH3 domains), which display partially overlapping but non-redundant functions. Both associate with the ADAMs family of transmembrane metalloproteases, which function as sheddases and mediators of cell and matrix interactions. Tks5 interacts with N-WASP and Nck, while Tks4 is essential for the localization of MT1-MMP (membrane-type 1 matrix metalloproteinase) to invadopodia. Tks proteins contain an N-terminal Phox homology (PX) domain and four or five SH3 domains. This model characterizes the first SH3 domain of Tks 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.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|...
gi 1622884774 1144 KYTVVADHEKGGPDALVVRSGDVVELVQQGDEGLWYVRdpTTGKEGWVPASSL 1196
Cdd:cd12015      1 QYVVVADYKKQQPNEISLRAGDVVDVIEKNENGWWFVS--LEDEQGWVPATYL 51

Second Src homology 3 domain of Tyrosine kinase substrate with five SH3 domains; Tks5, also called SH3 and PX domain-containing protein 2A (SH3PXD2A) or Five SH (FISH), is a scaffolding protein and Src substrate that is localized in podosomes, which are electron-dense structures found in Src-transformed fibroblasts, osteoclasts, macrophages, and some invasive cancer cells. It binds and regulates some members of the ADAMs family of transmembrane metalloproteases, which function as sheddases and mediators of cell and matrix interactions. It is required for podosome formation, degradation of the extracellular matrix, and cancer cell invasion. Tks5 contains an N-terminal Phox homology (PX) domain and five SH3 domains. This model characterizes the second SH3 domain of Tks5. 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.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|...
gi 1622884774 1144 KYTVVADHEKGGPDALVVRSGDVVELVQQGDEGLWYVRdpTTGKEGWVPASSL 1196
Cdd:cd12077      2 KYVTVQPYTSQGKDEIGFEKGVTVEVIQKNLEGWWYIR--YLGKEGWAPASYL 52

First or N-terminal Src homology 3 domain of the p47phox subunit of NADPH oxidase, also called Neutrophil Cytosolic Factor 1; p47phox, or NCF1, is a cytosolic subunit of the phagocytic NADPH oxidase complex (also called Nox2 or gp91phox), which plays a key role in the ability of phagocytes to defend against bacterial infections. NADPH oxidase catalyzes the transfer of electrons from NADPH to oxygen during phagocytosis forming superoxide and reactive oxygen species. p47phox is required for activation of NADH oxidase and plays a role in translocation. It contains an N-terminal Phox homology (PX) domain, tandem SH3 domains (N-SH3 and C-SH3), a polybasic/autoinhibitory region, and a C-terminal proline-rich region (PRR). This model characterizes the first SH3 domain (or N-SH3) of p47phox. In its inactive state, the tandem SH3 domains interact intramolecularly with the autoinhibitory region; upon activation, the tandem SH3 domains are exposed through a conformational change, resulting in their binding to the PRR of p22phox and the activation of NADPH oxidase. 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.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1622884774 1145 YTVVADHEKGGPDALVVRSGDVVELVQQGDEGLWYVRDPTtgKEGWVPASSL 1196
Cdd:cd12021      2 YRAIADYEKSSKSEMALKTGDVVEVVEKSENGWWFCQLKA--KRGWVPASYL 51

First 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 first 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.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*.
gi 1622884774 1144 KYTVVADHEKGGPDALVVRSGDVVELVQQGDEGLWYVRdpTTGKEGWVPASSLSVQ 1199
Cdd:cd12075      2 QYVVVANYQKQESSEISLYVGQVVDIIEKNESGWWFVS--TADEQGWVPATCLEAQ 55

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.

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                    ....*....|....*....|....*....|....*....|....*....|....
gi 1622884774  1141 VPGKYTVVADHEKGGPDALVVRSGDVVELVQQGDEGLWYVRDPtTGKEGWVPAS 1194
Cdd:smart00326    1 EGPQVRALYDYTAQDPDELSFKKGDIITVLEKSDDGWWKGRLG-RGKEGLFPSN 53

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.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1622884774 1144 KYTVVADHEKGGPDALVVRSGDVVELVQQGDEGLWYVRDpTTGKEGWVPAS 1194
Cdd:cd00174      1 YARALYDYEAQDDDELSFKKGDIITVLEKDDDGWWEGEL-NGGREGLFPAN 50

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.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1622884774 1145 YTVVADHEKGGPDALVVRSGDVVELVQQGDEGLWYVRDPTTGKEGWVPASSL 1196
Cdd:cd11858      2 YKALYDFAGSVANELSLKKDDIVYIVQKEDNGWWLAKKLDESKEGWVPAAYL 53

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 1622884774  821 EDLQEALSSILGILKAVND-------SMHL----IAITGYDG-NLGDLGKLLMQGSFSVwtdhkRGHTKvkelarfkpmQ 888
Cdd:cd13243      2 SVVEEALDTMTQVAWHINDmkrkhehAVRVqeiqSLLDGWEGpELTTYGDLVLEGTFRM-----AGAKN----------E 66

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622884774  889 RHLFLHEKAVLFCKKREENGegyekapsYSYKQSLNMAAVGITENVKGDAKKFEIW-YNAREEVYIVQAPTPEIKAAWVN 967
Cdd:cd13243     67 RLLFLFDKMLLITKKREDGI--------LQYKTHIMCSNLMLSESIPKEPLSFQVLpFDNPKLQYTLQAKNQEQKRLWTQ 138

                   ....*.
gi 1622884774  968 EIRKVL 973
Cdd:cd13243    139 EIKRLI 144

Vav pleckstrin homology (PH) domain; Vav acts as a guanosine nucleotide exchange factor (GEF) for Rho/Rac proteins. They control processes including T cell activation, phagocytosis, and migration of cells. The Vav subgroup of Dbl GEFs consists of three family members (Vav1, Vav2, and Vav3) in mammals. Vav1 is preferentially expressed in the hematopoietic system, while Vav2 and Vav3 are described by broader expression patterns. Mammalian Vav proteins consist of a calponin homology (CH) domain, an acidic region, a catalytic Dbl homology (DH) domain, a PH domain, a zinc finger cysteine rich domain (C1/CRD), and an SH2 domain, flanked by two SH3 domains. In invertebrates such as Drosophila and C. elegans, Vav is missing the N-terminal SH3 domain. The DH domain is involved in RhoGTPase recognition and selectivity and stimulates the reorganization of the switch regions for GDP/GTP exchange. The PH domain is implicated in directing membrane localization, allosteric regulation of guanine nucleotide exchange activity, and as a phospholipid- dependent regulator of GEF activity. Vavs bind RhoGTPases including Rac1, RhoA, RhoG, and Cdc42, while other members of the GEF family are specific for a single RhoGTPase. This promiscuity is thought to be a result of its CRD. 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.polarized. PH domains also have diverse functions. They are often 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.

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                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622884774  874 GHTKVKELARFKPMQRHLFLHEKAVLFCKKREENgegyekapSYSYKQSLNMAAVGITEN----VKGDAKKFE-IWYNAR 948
Cdd:cd01223     23 GELKIKSHEDQKKKDRYAFLFDKVLLICKSLRGD--------QYEYKEIINLSEYRIEDDpsrrTLKRDKRWSyQFLLVH 94

                           90       100
                   ....*....|....*....|....*...
gi 1622884774  949 EE---VYIVQAPTPEIKAAWVNEIRKVL 973
Cdd:cd01223     95 KQgktAYTLYAKTEELKKKWMEAIEMAL 122

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.