calponin homology (CH) domain found in VAV1 protein; VAV1 is expressed predominantly in the hematopoietic system and it plays an important role in the development and activation of B and T cells. It is activated by tyrosine phosphorylation to function as a guanine nucleotide exchange factor (GEF) for Rho GTPases following cell surface receptor activation, triggering various effects such as cytoskeletal reorganization, transcription regulation, cell cycle progression, and calcium mobilization. It also serves as a scaffold protein and has been shown to interact with Ku70, Socs1, Janus kinase 2, SIAH2, S100B, Abl gene, ZAP-70, SLP76, and Syk, among others. VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. This model corresponds to the CH domain, an actin-binding domain which is present as a single copy in VAV1 protein.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1753053953   2 ELWRQCTHWLIQCRVLPPSHRVTWDGAQVCELAQALRDGVLLCQLLNNLLPHAINLREVNLRPQMSQFLCLKNIRTFLST 81
Cdd:cd21262     1 ELWRQCAHWLIQCRVLPPNHRVTWDSAQVCDLAQALRDGVLLCQLLNNLLPHAVNLREINLRPQMSQFLCLKNIRTFLST 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 1753053953  82 CCEKFGLKRSELFEAFDLFDVQDFGKVIYTLSALSWTPIA 121
Cdd:cd21262    81 CCEKFGLRKSELFEAFDLFDVRDFGKVIDTLSILSWTPIA 120

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1753053953 353 NFQLSIENLDQSLAHYGRPKIDGELKITSVERRSKMDRYAFLLDKALLICKR-RGDSYDLKDFVNLHSFQVRDDSSG--D 429
Cdd:cd01223     1 SIQDLIENLNESLADYGRLQIDGELKIKSHEDQKKKDRYAFLFDKVLLICKSlRGDQYEYKEIINLSEYRIEDDPSRrtL 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 1753053953 430 RDNKKWSHMFLLIEDQGAQGYELFFKTRELKKKWMEQFEMAISNIYP 476
Cdd:cd01223    81 KRDKRWSYQFLLVHKQGKTAYTLYAKTEELKKKWMEAIEMALSNIEP 127

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 1753053953  187 HFLKPLQR---FLKPQDIEIIFINIEDLLRVHTHFLKEMKEALGT--PGAANLYQVFIKYKERFLVYGRYCSQVESASKH 261
Cdd:smart00325  22 VFLKPLKKelkLLSPNELETLFGNIEEIYEFHRDFLDELEERIEEwdDSVERIGDVFLKLEEFFKIYSEYCSNHPDALEL 101

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1753053953  262 LDRvAAAREDVQMKLEECSQRANNGRFTLRDLLMVPMQRVLKYHLLLQELVKHTQEAM-EKENLRLALDAMRDLAQCVNE 340
Cdd:smart00325 102 LKK-LKKNPRFQKFLKEIESSPQCRRLTLESLLLKPVQRLTKYPLLLKELLKHTPEDHeDREDLKKALKAIKELANQVNE 180

C-terminal (or second) Src homology 3 domain of VAV1 protein; VAV1 is expressed predominantly in the hematopoietic system and it plays an important role in the development and activation of B and T cells. It is activated by tyrosine phosphorylation to function as a guanine nucleotide exchange factor (GEF) for Rho GTPases following cell surface receptor activation, triggering various effects such as cytoskeletal reorganization, transcription regulation, cell cycle progression, and calcium mobilization. It also serves as a scaffold protein and has been shown to interact with Ku70, Socs1, Janus kinase 2, SIAH2, S100B, Abl gene, ZAP-70, SLP76, and Syk, among others. VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. The C-terminal SH3 domain of Vav1 interacts with a wide variety of proteins including cytoskeletal regulators (zyxin), RNA-binding proteins (Sam68), transcriptional regulators, viral proteins, and dynamin 2. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1753053953 754 TAKARYDFCARDRSELSLKEGDIIKILNKKGQQGWWRGEIYGRVGWFPANYVEE 807
Cdd:cd11976     1 TAKARYDFCARDRSELSLKEGDIIKILNKKGQQGWWRGEIYGRVGWFPANYVEE 54

calponin homology (CH) domain found in VAV1 protein; VAV1 is expressed predominantly in the hematopoietic system and it plays an important role in the development and activation of B and T cells. It is activated by tyrosine phosphorylation to function as a guanine nucleotide exchange factor (GEF) for Rho GTPases following cell surface receptor activation, triggering various effects such as cytoskeletal reorganization, transcription regulation, cell cycle progression, and calcium mobilization. It also serves as a scaffold protein and has been shown to interact with Ku70, Socs1, Janus kinase 2, SIAH2, S100B, Abl gene, ZAP-70, SLP76, and Syk, among others. VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. This model corresponds to the CH domain, an actin-binding domain which is present as a single copy in VAV1 protein.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1753053953   2 ELWRQCTHWLIQCRVLPPSHRVTWDGAQVCELAQALRDGVLLCQLLNNLLPHAINLREVNLRPQMSQFLCLKNIRTFLST 81
Cdd:cd21262     1 ELWRQCAHWLIQCRVLPPNHRVTWDSAQVCDLAQALRDGVLLCQLLNNLLPHAVNLREINLRPQMSQFLCLKNIRTFLST 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 1753053953  82 CCEKFGLKRSELFEAFDLFDVQDFGKVIYTLSALSWTPIA 121
Cdd:cd21262    81 CCEKFGLRKSELFEAFDLFDVRDFGKVIDTLSILSWTPIA 120

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1753053953 353 NFQLSIENLDQSLAHYGRPKIDGELKITSVERRSKMDRYAFLLDKALLICKR-RGDSYDLKDFVNLHSFQVRDDSSG--D 429
Cdd:cd01223     1 SIQDLIENLNESLADYGRLQIDGELKIKSHEDQKKKDRYAFLFDKVLLICKSlRGDQYEYKEIINLSEYRIEDDPSRrtL 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 1753053953 430 RDNKKWSHMFLLIEDQGAQGYELFFKTRELKKKWMEQFEMAISNIYP 476
Cdd:cd01223    81 KRDKRWSYQFLLVHKQGKTAYTLYAKTEELKKKWMEAIEMALSNIEP 127

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 1753053953  187 HFLKPLQR---FLKPQDIEIIFINIEDLLRVHTHFLKEMKEALGT--PGAANLYQVFIKYKERFLVYGRYCSQVESASKH 261
Cdd:smart00325  22 VFLKPLKKelkLLSPNELETLFGNIEEIYEFHRDFLDELEERIEEwdDSVERIGDVFLKLEEFFKIYSEYCSNHPDALEL 101

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1753053953  262 LDRvAAAREDVQMKLEECSQRANNGRFTLRDLLMVPMQRVLKYHLLLQELVKHTQEAM-EKENLRLALDAMRDLAQCVNE 340
Cdd:smart00325 102 LKK-LKKNPRFQKFLKEIESSPQCRRLTLESLLLKPVQRLTKYPLLLKELLKHTPEDHeDREDLKKALKAIKELANQVNE 180

protein kinase C conserved region 1 (C1 domain) found in VAV1 protein; VAV1 is expressed predominantly in the hematopoietic system and plays an important role in the development and activation of B and T cells. It is activated by tyrosine phosphorylation to function as a guanine nucleotide exchange factor (GEF) for Rho GTPases following cell surface receptor activation, triggering various effects such as cytoskeletal reorganization, transcription regulation, cell cycle progression, and calcium mobilization. It also serves as a scaffold protein and has been shown to interact with Ku70, Socs1, Janus kinase 2, SIAH2, S100B, Abl gene, ZAP-70, SLP76, and Syk, among others. VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. This model corresponds to the C1 domain. The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1753053953 478 NATANGHDFQMFSFEETTSCKACQMLLRGTFYQGYRCHRCRASAHKECLGRVPPCGR 534
Cdd:cd20867     1 NATANGHDFQMFSFEETTSCKACQMLLRGTFYQGYRCHRCRAPAHKECLGRVPPCGR 57

C-terminal (or second) Src homology 3 domain of VAV1 protein; VAV1 is expressed predominantly in the hematopoietic system and it plays an important role in the development and activation of B and T cells. It is activated by tyrosine phosphorylation to function as a guanine nucleotide exchange factor (GEF) for Rho GTPases following cell surface receptor activation, triggering various effects such as cytoskeletal reorganization, transcription regulation, cell cycle progression, and calcium mobilization. It also serves as a scaffold protein and has been shown to interact with Ku70, Socs1, Janus kinase 2, SIAH2, S100B, Abl gene, ZAP-70, SLP76, and Syk, among others. VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. The C-terminal SH3 domain of Vav1 interacts with a wide variety of proteins including cytoskeletal regulators (zyxin), RNA-binding proteins (Sam68), transcriptional regulators, viral proteins, and dynamin 2. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1753053953 754 TAKARYDFCARDRSELSLKEGDIIKILNKKGQQGWWRGEIYGRVGWFPANYVEE 807
Cdd:cd11976     1 TAKARYDFCARDRSELSLKEGDIIKILNKKGQQGWWRGEIYGRVGWFPANYVEE 54

SH2 domain;

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1753053953 639 WYAGPMERAGAESILANR-SDGTFLVRQRVKDAAEFAISIKYNVEVKHIKIM-TAEGLYRITEKKAFRGLTELVEFY 713
Cdd:pfam00017   1 WYHGKISRQEAERLLLNGkPDGTFLVRESESTPGGYTLSVRDDGKVKHYKIQsTDNGGYYISGGVKFSSLAELVEHY 77

CAMSAP CH domain; This domain is the N-terminal CH domain from the CAMSAP proteins.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1753053953  18 PPSHRVTWDGAQVCELAQALRDGVLLCQLLNNLLPHAINLREVNLRPQMSQFLCLKNIRTFLSTCCEKFGLKRSELfEAF 97
Cdd:pfam11971   1 PLSQRSLPLSPPVEDLLRDLSDGCALAALIHFYCPQLIDLEDICLKESMSLADSLYNIQLLQEFCQRHLGNRCCHL-TLE 79

                  ....*
gi 1753053953  98 DLFDV 102
Cdd:pfam11971  80 DLLYA 84

Phorbol esters/diacylglycerol binding domain (C1 domain); This domain is also known as the Protein kinase C conserved region 1 (C1) domain.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|...
gi 1753053953 484 HDFQMFSFEETTSCKACQMLLRGTFYQGYRCHRCRASAHKECLGRVPP-CGRH 535
Cdd:pfam00130   1 HHFVHRNFKQPTFCDHCGEFLWGLGKQGLKCSWCKLNVHKRCHEKVPPeCGCD 53

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 1753053953  371 PKIDGEL-KITSVERRSKMDRYAFLLDKALLICKRRGD--SYDLKDFVNLHSFQVRDdsSGDRDNKKWSHMFLLIEDQGA 447
Cdd:smart00233   1 VIKEGWLyKKSGGGKKSWKKRYFVLFNSTLLYYKSKKDkkSYKPKGSIDLSGCTVRE--APDPDSSKKPHCFEIKTSDRK 78

                           90       100
                   ....*....|....*....|....*
gi 1753053953  448 QgYELFFKTRELKKKWMEQFEMAIS 472
Cdd:smart00233  79 T-LLLQAESEEEREKWVEALRKAIA 102

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.

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|
gi 1753053953  585 LRLNPGDIVELTKaEAEQNWWEGRNtSTNEIGWFPCNRVK 624
Cdd:smart00326  19 LSFKKGDIITVLE-KSDDGWWKGRL-GRGKEGLFPSNYVE 56

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
                  ....*....|....*....|....*....|....*.
gi 1753053953 585 LRLNPGDIVELTKAEaEQNWWEGRNTsTNEIGWFPC 620
Cdd:pfam00018  14 LSFKKGDIIIVLEKS-EDGWWKGRNK-GGKEGLIPS 47

calponin homology (CH) domain found in VAV1 protein; VAV1 is expressed predominantly in the hematopoietic system and it plays an important role in the development and activation of B and T cells. It is activated by tyrosine phosphorylation to function as a guanine nucleotide exchange factor (GEF) for Rho GTPases following cell surface receptor activation, triggering various effects such as cytoskeletal reorganization, transcription regulation, cell cycle progression, and calcium mobilization. It also serves as a scaffold protein and has been shown to interact with Ku70, Socs1, Janus kinase 2, SIAH2, S100B, Abl gene, ZAP-70, SLP76, and Syk, among others. VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. This model corresponds to the CH domain, an actin-binding domain which is present as a single copy in VAV1 protein.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1753053953   2 ELWRQCTHWLIQCRVLPPSHRVTWDGAQVCELAQALRDGVLLCQLLNNLLPHAINLREVNLRPQMSQFLCLKNIRTFLST 81
Cdd:cd21262     1 ELWRQCAHWLIQCRVLPPNHRVTWDSAQVCDLAQALRDGVLLCQLLNNLLPHAVNLREINLRPQMSQFLCLKNIRTFLST 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 1753053953  82 CCEKFGLKRSELFEAFDLFDVQDFGKVIYTLSALSWTPIA 121
Cdd:cd21262    81 CCEKFGLRKSELFEAFDLFDVRDFGKVIDTLSILSWTPIA 120

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1753053953 353 NFQLSIENLDQSLAHYGRPKIDGELKITSVERRSKMDRYAFLLDKALLICKR-RGDSYDLKDFVNLHSFQVRDDSSG--D 429
Cdd:cd01223     1 SIQDLIENLNESLADYGRLQIDGELKIKSHEDQKKKDRYAFLFDKVLLICKSlRGDQYEYKEIINLSEYRIEDDPSRrtL 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 1753053953 430 RDNKKWSHMFLLIEDQGAQGYELFFKTRELKKKWMEQFEMAISNIYP 476
Cdd:cd01223    81 KRDKRWSYQFLLVHKQGKTAYTLYAKTEELKKKWMEAIEMALSNIEP 127

calponin homology (CH) domain found in VAV proteins; VAV proteins function both as cytoplasmic guanine nucleotide exchange factors (GEFs) for Rho GTPases and as scaffold proteins, and they play important roles in cell signaling by coupling cell surface receptors to various effector functions. They play key roles in processes that require cytoskeletal reorganization including immune synapse formation, phagocytosis, cell spreading, and platelet aggregation, among others. Vertebrates have three VAV proteins (VAV1, VAV2, and VAV3). VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. This model corresponds to the CH domain, an actin-binding domain which is present as a single copy in VAV proteins.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1753053953   2 ELWRQCTHWLIQCRVLPPSHRVTWDGAQVCELAQALRDGVLLCQLLNNLLPHAINLREVNLRPQMSQFLCLKNIRTFLST 81
Cdd:cd21201     1 ELWRQCADWLIRCGVLPPDHRATQPNATVFDLAQALRDGVLLCQLLNRLSPGSVDDREINLRPQMSQFLCLKNIRTFLQA 80

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 1753053953  82 CCEKFGLKRSELFEAFDLFDVQDFGKVIYTLSALSWT 118
Cdd:cd21201    81 CRTVFGLRSADLFEPEDLYDVTNFGKVIRTLSKLSHT 117

First Src homology 3 domain of VAV1 protein; VAV1 is expressed predominantly in the hematopoietic system and it plays an important role in the development and activation of B and T cells. It is activated by tyrosine phosphorylation to function as a guanine nucleotide exchange factor (GEF) for Rho GTPases following cell surface receptor activation, triggering various effects such as cytoskeletal reorganization, transcription regulation, cell cycle progression, and calcium mobilization. It also serves as a scaffold protein and has been shown to interact with Ku70, Socs1, Janus kinase 2, SIAH2, S100B, Abl gene, ZAP-70, SLP76, and Syk, among others. VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. The first SH3 domain of Vav1 has been shown to bind the adaptor protein Grb2. 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        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1753053953 564 KMEVFQEYYGLPPPPGAIGPFLRLNPGDIVELTKAEAEQNWWEGRNTSTNEIGWFPCNRVKPY 626
Cdd:cd11979     1 KMEVFQEYYGIPPPPGAFGPFLRLNPGDIVELTKAEAEQNWWEGRNTSTNEIGWFPCNRVKPY 63

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1753053953 633 DLSVHLWYAGPMERAGAESILANRSDGTFLVRQRVKDAAEFAISIKYNVEVKHIKIMTAEGLYRITEKKAFRGLTELVEF 712
Cdd:cd10407     1 DYSCQPWYAGAMERLQAETELINRVNSTYLVRHRTKESGEYAISIKYNNEVKHIKILTRDGFFHIAENRKFKSLMELVEY 80

                          90       100
                  ....*....|....*....|...
gi 1753053953 713 YQQNSLKDCFKSLDTTLQFPFKE 735
Cdd:cd10407    81 YKHHSLKEGFRSLDTTLQFPYKE 103

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 1753053953 187 HFLKPLQRFLK---PQDIEIIFINIEDLLRVHTHFLKEMKEALGTPGAA--NLYQVFIKYKERFLVYGRYCSQVESASKH 261
Cdd:cd00160    25 VFLKPLDKELLplsPEEVELLFGNIEEIYEFHRIFLKSLEERVEEWDKSgpRIGDVFLKLAPFFKIYSEYCSNHPDALEL 104

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1753053953 262 LDrvaaAREDVQMKLEECSQRANN--GRFTLRDLLMVPMQRVLKYHLLLQELVKHTQEAM-EKENLRLALDAMRDLAQCV 338
Cdd:cd00160   105 LK----KLKKFNKFFQEFLEKAESecGRLKLESLLLKPVQRLTKYPLLLKELLKHTPDGHeDREDLKKALEAIKEVASQV 180

                  .
gi 1753053953 339 N 339
Cdd:cd00160   181 N 181

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 1753053953 187 HFLKPLQRFLK--PQDIEIIFINIEDLLRVHTHFLKEMKEALGtPGAANLYQVFIKYKERFLVYGRYCSQVESASKHLDR 264
Cdd:pfam00621  22 VFLPPNSKPLSesEEEIKTIFSNIEEIYELHRQLLLEELLKEW-ISIQRIGDIFLKFAPGFKVYSTYCSNYPKALKLLKK 100

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1753053953 265 VAAAREDVQMKLEECSQRANNGRFTLRDLLMVPMQRVLKYHLLLQELVKHTQEA-MEKENLRLALDAMRDLAQCVN 339
Cdd:pfam00621 101 LLKKNPKFRAFLEELEANPECRGLDLNSFLIKPVQRIPRYPLLLKELLKHTPPDhPDYEDLKKALEAIKEVAKQIN 176

C-terminal (or second) Src homology 3 domain of VAV1 protein; VAV1 is expressed predominantly in the hematopoietic system and it plays an important role in the development and activation of B and T cells. It is activated by tyrosine phosphorylation to function as a guanine nucleotide exchange factor (GEF) for Rho GTPases following cell surface receptor activation, triggering various effects such as cytoskeletal reorganization, transcription regulation, cell cycle progression, and calcium mobilization. It also serves as a scaffold protein and has been shown to interact with Ku70, Socs1, Janus kinase 2, SIAH2, S100B, Abl gene, ZAP-70, SLP76, and Syk, among others. VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. The C-terminal SH3 domain of Vav1 interacts with a wide variety of proteins including cytoskeletal regulators (zyxin), RNA-binding proteins (Sam68), transcriptional regulators, viral proteins, and dynamin 2. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1753053953 754 TAKARYDFCARDRSELSLKEGDIIKILNKKGQQGWWRGEIYGRVGWFPANYVEE 807
Cdd:cd11976     1 TAKARYDFCARDRSELSLKEGDIIKILNKKGQQGWWRGEIYGRVGWFPANYVEE 54

C-terminal (or second) Src homology 3 domain of VAV proteins; VAV proteins function both as cytoplasmic guanine nucleotide exchange factors (GEFs) for Rho GTPases and scaffold proteins and they play important roles in cell signaling by coupling cell surface receptors to various effector functions. They play key roles in processes that require cytoskeletal reorganization including immune synapse formation, phagocytosis, cell spreading, and platelet aggregation, among others. Vertebrates have three VAV proteins (VAV1, VAV2, and VAV3). VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. The SH3 domain of VAV is involved in the localization of proteins to specific sites within the cell, by interacting with proline-rich sequences within target proteins. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1753053953 754 TAKARYDFCARDRSELSLKEGDIIKILNKKGQQGWWRGEIYGRVGWFPANYVEE 807
Cdd:cd11830     1 TAKARYDFCARDMRELSLKEGDVVKIYNKKGQQGWWRGEINGRIGWFPSTYVEE 54

protein kinase C conserved region 1 (C1 domain) found in VAV2 protein; VAV2 is widely expressed and functions as a guanine nucleotide exchange factor (GEF) for RhoA, RhoB and RhoG and also activates Rac1 and Cdc42. It is implicated in many cellular and physiological functions including blood pressure control, eye development, neurite outgrowth and branching, EGFR endocytosis and degradation, and cell cluster morphology, among others. It has been reported to associate with Nek3. VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. This model corresponds to the C1 domain. The C1 domain is a cysteine-rich zinc binding domain that does not bind DNA nor possess structural similarity to conventional zinc finger domains; it contains two separate Zn(2+)-binding sites.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1753053953 479 ATANGHDFQMFSFEETTSCKACQMLLRGTFYQGYRCHRCRASAHKECLGRVPPC 532
Cdd:cd20868     1 ATANHHNFQMYTFDKTTNCKACKMLLRGTFYQGYYCSKCGAGAHKECLEVIPPC 54

C-terminal (or second) Src homology 3 domain of VAV3 protein; VAV3 is ubiquitously expressed and functions as a phosphorylation-dependent guanine nucleotide exchange factor (GEF) for RhoA, RhoG, and Rac1. It has been implicated to function in the hematopoietic, bone, cerebellar, and cardiovascular systems. VAV3 is essential in axon guidance in neurons that control blood pressure and respiration. It is overexpressed in prostate cancer cells and it plays a role in regulating androgen receptor transcriptional activity. VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. The SH3 domain of VAV is involved in the localization of proteins to specific sites within the cell, by interacting with proline-rich sequences within target proteins. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1753053953 753 GTAKARYDFCARDRSELSLKEGDIIKILNKKGQQGWWRGEIYGRVGWFPANYVEED 808
Cdd:cd11978     1 GIAIARYDFCARDMRELSLLKGDVVKIYTKMSTNGWWRGEVNGRVGWFPSTYVEED 56

C-terminal (or second) Src homology 3 domain of VAV2 protein; VAV2 is widely expressed and functions as a guanine nucleotide exchange factor (GEF) for RhoA, RhoB and RhoG and also activates Rac1 and Cdc42. It is implicated in many cellular and physiological functions including blood pressure control, eye development, neurite outgrowth and branching, EGFR endocytosis and degradation, and cell cluster morphology, among others. It has been reported to associate with Nek3. VAV proteins contain several domains that enable their function: N-terminal calponin homology (CH), acidic, RhoGEF (also called Dbl-homologous or DH), Pleckstrin Homology (PH), C1 (zinc finger), SH2, and two SH3 domains. The SH3 domain of VAV is involved in the localization of proteins to specific sites within the cell, by interacting with proline-rich sequences within target proteins. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1753053953 753 GTAKARYDFCARDRSELSLKEGDIIKILNK-KGQQGWWRGEIYGRVGWFPANYVEED 808
Cdd:cd11977     1 GTAVARYNFAARDMRELSLREGDVVRIYSRiGGDQGWWKGETNGRIGWFPSTYVEEE 57

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.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*
gi 1753053953  753 GTAKARYDFCARDRSELSLKEGDIIKILNKKGqQGWWRGEI-YGRVGWFPANYVE 806
Cdd:smart00326   3 PQVRALYDYTAQDPDELSFKKGDIITVLEKSD-DGWWKGRLgRGKEGLFPSNYVE 56

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

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1753053953 756 KARYDFCARDRSELSLKEGDIIKIlNKKGQQGWWRGEIYGRVGWFPANYVEE 807
Cdd:cd11823     3 KALYSYTANREDELSLQPGDIIEV-HEKQDDGWWLGELNGKKGIFPATYVEE 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 1753053953 754 TAKARYDFCARDRSELSLKEGDIIKILNKKGqQGWWRGEIY-GRVGWFPANY 804
Cdd:cd00174     1 YARALYDYEAQDDDELSFKKGDIITVLEKDD-DGWWEGELNgGREGLFPANY 51

CAMSAP CH domain; This domain is the N-terminal CH domain from the CAMSAP proteins.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1753053953  18 PPSHRVTWDGAQVCELAQALRDGVLLCQLLNNLLPHAINLREVNLRPQMSQFLCLKNIRTFLSTCCEKFGLKRSELfEAF 97
Cdd:pfam11971   1 PLSQRSLPLSPPVEDLLRDLSDGCALAALIHFYCPQLIDLEDICLKESMSLADSLYNIQLLQEFCQRHLGNRCCHL-TLE 79

                  ....*
gi 1753053953  98 DLFDV 102
Cdd:pfam11971  80 DLLYA 84

Src Homology 3 domain of fungal peroxisomal membrane protein Pex13p; Pex13p, located in the peroxisomal membrane, contains two transmembrane regions and a C-terminal SH3 domain. It binds to the peroxisomal targeting type I (PTS1) receptor Pex5p and the docking factor Pex14p through its SH3 domain. It is essential for both PTS1 and PTS2 protein import pathways into the peroxisomal matrix. Pex13p binds Pex14p, which contains a PxxP motif, in a classical fashion to the proline-rich ligand binding site of its SH3 domain. It binds the WxxxF/Y motif of Pex5p in a novel site that does not compete with Pex14p binding. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 1753053953 755 AKARYDFCARDRS-ELSLKEGDIIKILNKKGQQG----WWRGEIY-GRVGWFPANYVEE 807
Cdd:cd11771     2 CRALYDFTPENPEmELSLKKGDIVAVLSKTDPLGrdseWWKGRTRdGRIGWFPSNYVEV 60

First Src homology 3 domain (or SH3A) of Intersectin; Intersectins (ITSNs) are adaptor proteins that function in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. They are essential for initiating clathrin-coated pit formation. They bind to many proteins through their multidomain structure and facilitate the assembly of multimeric complexes. Vertebrates contain two ITSN proteins, ITSN1 and ITSN2, which exist in alternatively spliced short and long isoforms. The short isoforms contain two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoforms, in addition, contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. ITSN1 and ITSN2 are both widely expressed, with variations depending on tissue type and stage of development. The first SH3 domain (or SH3A) of ITSN1 has been shown to bind many proteins including Sos1, dynamin1/2, CIN85, c-Cbl, PI3K-C2, SHIP2, N-WASP, and CdGAP, among others. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1753053953 756 KARYDFCARDRSELSLKEGDIIKI-LNKKGQQGWWRGEIYGRVGWFPANYVE 806
Cdd:cd11836     3 RALYAFEARNPDEISFQPGDIIQVdESQVAEPGWLAGELKGKTGWFPANYVE 54

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

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1753053953 754 TAKARYDFCARDRSELSLKEGDIIKILNKKGQqGWWRGEIYGRVGWFPANYVEE 807
Cdd:cd11766     1 PAVVKFNYEAQREDELSLRKGDRVLVLEKSSD-GWWRGECNGQVGWFPSNYVTE 53

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

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1753053953 754 TAKARYDFCARDRSELSLKEGDIIKILnKKGQQGWWRGEIYGRVGWFPANYVEE 807
Cdd:cd11827     1 QCKALYAYDAQDTDELSFNEGDIIEIL-KEDPSGWWTGRLRGKEGLFPGNYVEK 53

C-terminal Src homology 3 domain of GRB2-related adaptor protein; GRAP is a GRB-2 like adaptor protein that is highly expressed in lymphoid tissues. It acts as a negative regulator of T cell receptor (TCR)-induced lymphocyte proliferation by downregulating the signaling to the Ras/ERK pathway. It has been identified as a regulator of TGFbeta signaling in diabetic kidney tubules and may have a role in the pathogenesis of the disease. GRAP contains an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. The C-terminal SH3 domains (SH3c) of the related proteins, GRB2 and GRAP2, have been shown to bind to classical PxxP motif ligands, as well as to non-classical motifs. GRB2 SH3c binds Gab2 (Grb2-associated binder 2) through epitopes containing RxxK motifs, while the SH3c of GRAP2 binds to the phosphatase-like protein HD-PTP via a RxxxxK motif. SH3 domains are protein interaction domains that typically bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1753053953 755 AKARYDFCARDRSELSLKEGDIIKILNKKgQQGWWRGEIYGRVGWFPANYV 805
Cdd:cd11951     2 VQAQYDFSAEDPSQLSFRRGDIIEVLDCP-DPNWWRGRISGRVGFFPRNYV 51

Src homology 3 domain of Ysc84p and similar fungal proteins; This family is composed of the Saccharomyces cerevisiae proteins, Ysc84p (also called LAS17-binding protein 4, Lsb4p) and Lsb3p, and similar fungal proteins. They contain an N-terminal SYLF domain (also called DUF500) and a C-terminal SH3 domain. Ysc84p localizes to actin patches and plays an important in actin polymerization during endocytosis. The N-terminal domain of both Ysc84p and Lsb3p can bind and bundle actin filaments. A study of the yeast SH3 domain interactome predicts that the SH3 domains of Lsb3p and Lsb4p may function as molecular hubs for the assembly of endocytic complexes. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1753053953 754 TAKARYDFCARDRSELSLKEGDIIKILNKKGQQG-WWRGEIYGRVGWFPANYVEE 807
Cdd:cd11842     1 KAVALYDFAGEQPGDLAFQKGDIITILKKSDSQNdWWTGRIGGREGIFPANYVEL 55

Third Src Homology 3 domain (SH3C) of CD2-associated protein and similar proteins; This subfamily is composed of the third SH3 domain (SH3C) of CD2AP, CIN85 (Cbl-interacting protein of 85 kDa), and similar domains. CD2AP and CIN85 are adaptor proteins that bind to protein partners and assemble complexes that have been implicated in T cell activation, kidney function, and apoptosis of neuronal cells. They also associate with endocytic proteins, actin cytoskeleton components, and other adaptor proteins involved in receptor tyrosine kinase (RTK) signaling. CD2AP and the main isoform of CIN85 contain three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP and CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. SH3C of both proteins have been shown to bind to ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1753053953 754 TAKARYDFCARDRSELSLKEGDIIKILNKK-GQQGWWRGEIYGRVGWFPANYVEE 807
Cdd:cd11875     1 KARVLFDYEAENEDELTLREGDIVTILSKDcEDKGWWKGELNGKRGVFPDNFVEP 55