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 530361574 383 QFQLSIENLNQPVLLFGRPQGDGEIRITTLDKHTKQERHIFLFDLAVIVCKR-KGDNYEMKEIIDLQQYKIANNPT--TD 459
Cdd:cd01223    1 SIQDLIENLNESLADYGRLQIDGELKIKSHEDQKKKDRYAFLFDKVLLICKSlRGDQYEYKEIINLSEYRIEDDPSrrTL 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*..
gi 530361574 460 KENKKWSYGFYLIHTQGQNGLEFYCKTKDLKKKWLEQFEMALSNIRP 506
Cdd:cd01223   81 KRDKRWSYQFLLVHKQGKTAYTLYAKTEELKKKWMEAIEMALSNIEP 127

protein kinase C conserved region 1 (C1 domain) found in VAV3 protein; VAV3 is ubiquitously expressed and functions as a phosphorylation-dependent guanine nucleotide exchange factor (GEF) for RhoA, RhoG, and Rac1. Its function has been implicated 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 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. 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 530361574 506 PDYADSNFHDFKMHTFTRVTSCKVCQMLLRGTFYQGYLCFKCGARAHKECLGRVDNCGR 564
Cdd:cd20869    1 PDNATSNSHDFKMHTFERVTSCKVCQMLLRGTFYQGYLCSKCGAGAHKECLGRLDSCGR 59

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 530361574 383 QFQLSIENLNQPVLLFGRPQGDGEIRITTLDKHTKQERHIFLFDLAVIVCKR-KGDNYEMKEIIDLQQYKIANNPT--TD 459
Cdd:cd01223    1 SIQDLIENLNESLADYGRLQIDGELKIKSHEDQKKKDRYAFLFDKVLLICKSlRGDQYEYKEIINLSEYRIEDDPSrrTL 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*..
gi 530361574 460 KENKKWSYGFYLIHTQGQNGLEFYCKTKDLKKKWLEQFEMALSNIRP 506
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 530361574   196 CLAEIKQTEEKYTETLESIEKYFMAPLKR---FLTAAEFDSVFINIPELVKLHRNLMQEIHDSIVNKND--QNLYQVFIN 270
Cdd:smart00325   1 VLKELLQTERNYVRDLKLLVEVFLKPLKKelkLLSPNELETLFGNIEEIYEFHRDFLDELEERIEEWDDsvERIGDVFLK 80

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530361574   271 YKERLVIYGQYCSGVESAISSLDYiSKTKEDVKLKLEECSKRANNGKFTLRDLLVVPMQRVLKYHLLLQELVKHTT-DPT 349
Cdd:smart00325  81 LEEFFKIYSEYCSNHPDALELLKK-LKKNPRFQKFLKEIESSPQCRRLTLESLLLKPVQRLTKYPLLLKELLKHTPeDHE 159

                          170       180
                   ....*....|....*....|.
gi 530361574   350 EKANLKLALDAMKDLAQYVNE 370
Cdd:smart00325 160 DREDLKKALKAIKELANQVNE 180

protein kinase C conserved region 1 (C1 domain) found in VAV3 protein; VAV3 is ubiquitously expressed and functions as a phosphorylation-dependent guanine nucleotide exchange factor (GEF) for RhoA, RhoG, and Rac1. Its function has been implicated 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 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. 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 530361574 506 PDYADSNFHDFKMHTFTRVTSCKVCQMLLRGTFYQGYLCFKCGARAHKECLGRVDNCGR 564
Cdd:cd20869    1 PDNATSNSHDFKMHTFERVTSCKVCQMLLRGTFYQGYLCSKCGAGAHKECLGRLDSCGR 59

Calponin homology domain; Actin binding domains present in duplicate at the N-termini of spectrin-like proteins (including dystrophin, alpha-actinin). These domains cross-link actin filaments into bundles and networks. A calponin homology domain is predicted in yeasst Cdc24p.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530361574    30 VFDLAQTLRDGVLLCQLLNNLRAHSINlkEINLRPQMSQFLCLKNIRTFLTACCETFGmrKSELFEAFDLFDVR-DFGKV 108
Cdd:smart00033  19 VTNFSSDLKDGVALCALLNSLSPGLVD--KKKVAASLSRFKKIENINLALSFAEKLGG--KVVLFEPEDLVEGPkLILGV 94

                   ....*..
gi 530361574   109 IETLSRL 115
Cdd:smart00033  95 IWTLISL 101

Protein kinase C conserved region 1 (C1) domains (Cysteine-rich domains); Some bind phorbol esters and diacylglycerol. Some bind RasGTP. Zinc-binding domains.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|
gi 530361574   514 HDFKMHTFTRVTSCKVCQMLLRGTFYQGYLCFKCGARAHKECLGRV-DNC 562
Cdd:smart00109   1 HKHVFRTFTKPTFCCVCRKSIWGSFKQGLRCSECKVKCHKKCADKVpKAC 50

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530361574  407 IRITTLDKHTKQERHIFLFDLAVIVCKRKGDN--YEMKEIIDLQQYKIANNPTTDKENKKWSYGFYLIHTQGQNGLEFYC 484
Cdd:pfam00169   8 LKKGGGKKKSWKKRYFVLFDGSLLYYKDDKSGksKEPKGSISLSGCEVVEVVASDSPKRKFCFELRTGERTGKRTYLLQA 87

                          90
                  ....*....|....*...
gi 530361574  485 KTKDLKKKWLEQFEMALS 502
Cdd:pfam00169  88 ESEEERKDWIKAIQSAIR 105

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 530361574   2 EPWKQCAQWLIHCKVLPTNHRVTWDSAQVFDLAQTLRDGVLLCQLLNNLRAHSINLKEINLRPQMSQFLCLKNIRTFLTA 81
Cdd:cd21262    1 ELWRQCAHWLIQCRVLPPNHRVTWDSAQVCDLAQALRDGVLLCQLLNNLLPHAVNLREINLRPQMSQFLCLKNIRTFLST 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|
gi 530361574  82 CCETFGMRKSELFEAFDLFDVRDFGKVIETLSRLSRTPIA 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 530361574 383 QFQLSIENLNQPVLLFGRPQGDGEIRITTLDKHTKQERHIFLFDLAVIVCKR-KGDNYEMKEIIDLQQYKIANNPT--TD 459
Cdd:cd01223    1 SIQDLIENLNESLADYGRLQIDGELKIKSHEDQKKKDRYAFLFDKVLLICKSlRGDQYEYKEIINLSEYRIEDDPSrrTL 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*..
gi 530361574 460 KENKKWSYGFYLIHTQGQNGLEFYCKTKDLKKKWLEQFEMALSNIRP 506
Cdd:cd01223   81 KRDKRWSYQFLLVHKQGKTAYTLYAKTEELKKKWMEAIEMALSNIEP 127

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 530361574 193 RSCCLAEIKQTEEKYTETLESIEKYFMAPLKRF---LTAAEFDSVFINIPELVKLHRNLMQEIHDSIVNKND--QNLYQV 267
Cdd:cd00160    1 RQEVIKELLQTERNYVRDLKLLVEVFLKPLDKEllpLSPEEVELLFGNIEEIYEFHRIFLKSLEERVEEWDKsgPRIGDV 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530361574 268 FINYKERLVIYGQYCSGVESAISSLdyisKTKEDVKLKLEECSKRANN--GKFTLRDLLVVPMQRVLKYHLLLQELVKHT 345
Cdd:cd00160   81 FLKLAPFFKIYSEYCSNHPDALELL----KKLKKFNKFFQEFLEKAESecGRLKLESLLLKPVQRLTKYPLLLKELLKHT 156

                        170       180
                 ....*....|....*....|....*
gi 530361574 346 TD-PTEKANLKLALDAMKDLAQYVN 369
Cdd:cd00160  157 PDgHEDREDLKKALEAIKEVASQVN 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 530361574  196 CLAEIKQTEEKYTETLESIEKYFMAPLKRFL--TAAEFDSVFINIPELVKLHRNLMQEiHDSIVNKNDQNLYQVFINYKE 273
Cdd:pfam00621   1 VIKELLQTERSYVRDLEILVEVFLPPNSKPLseSEEEIKTIFSNIEEIYELHRQLLLE-ELLKEWISIQRIGDIFLKFAP 79

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530361574  274 RLVIYGQYCSGVESAISSLDYISKTKEDVKLKLEECSKRANNGKFTLRDLLVVPMQRVLKYHLLLQELVKHTT-DPTEKA 352
Cdd:pfam00621  80 GFKVYSTYCSNYPKALKLLKKLLKKNPKFRAFLEELEANPECRGLDLNSFLIKPVQRIPRYPLLLKELLKHTPpDHPDYE 159

                         170
                  ....*....|....*..
gi 530361574  353 NLKLALDAMKDLAQYVN 369
Cdd:pfam00621 160 DLKKALEAIKEVAKQIN 176

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530361574   18 PTNHRVTWDSAQVFDLAQTLRDGVLLCQLLNNLRAHSINLKEINLRPQMSQFLCLKNIRTFLTACCETFGMRKSELfEAF 97
Cdd:pfam11971   1 PLSQRSLPLSPPVEDLLRDLSDGCALAALIHFYCPQLIDLEDICLKESMSLADSLYNIQLLQEFCQRHLGNRCCHL-TLE 79

                  ....*.
gi 530361574   98 DLFDVR 103
Cdd:pfam11971  80 DLLYAR 85

protein kinase C conserved region 1 (C1 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 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 530361574 512 NFHDFKMHTFTRVTSCKVCQMLLRGTFYQGYLCFKCGARAHKECLGRVDNCG 563
Cdd:cd20810    1 TGHSFELTTFKEPTTCSVCKKLLKGLFFQGYKCSVCGAAVHKECIAKVKRCG 52

Calponin homology (CH) domain; The CH domain is found in both cytoskeletal proteins and signal transduction proteins. The CH domain is involved in actin binding in some members of the family. However in calponins there is evidence that the CH domain is not involved in its actin binding activity. Most member proteins have from two to four copies of the CH domain, however some proteins such as calponin have only a single copy.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530361574    1 MEPWKQCAQWLIHCKVLPTNHRvtwdsaQVFDLAQTLRDGVLLCQLLNNLRAHSINLKEINLRPqmsqFLCLKNIRTFLT 80
Cdd:pfam00307   1 LELEKELLRWINSHLAEYGPGV------RVTNFTTDLRDGLALCALLNKLAPGLVDKKKLNKSE----FDKLENINLALD 70

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 530361574   81 ACCETFGMRKSELfEAFDLFDVRDFgKVIETLSRLSRT 118
Cdd:pfam00307  71 VAEKKLGVPKVLI-EPEDLVEGDNK-SVLTYLASLFRR 106

calponin homology (CH) domain found in alpha-Pak Interactive eXchange factor; Alpha-Pak Interactive eXchange factor (alpha-PIX), also called PAK-interacting exchange factor alpha, Rho guanine nucleotide exchange factor 6 (ARHGEF6), Rac/Cdc42 guanine nucleotide exchange factor 6, or Cool (Cloned out of Library)-2, activates small GTPases by exchanging bound GDP for free GTP. It acts as a GEF for both Cdc42 and Rac1, and is localized in dendritic spines where it regulates spine morphogenesis. It controls dendritic length and spine density in the hippocampus. Mutations in the ARHGEF6 gene cause X-linked intellectual disability in humans. Alpha-PIX contains a single copy of the CH domain at its N-terminus. CH domains are actin filament (F-actin) binding motifs.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530361574   1 MEPWKQCAQWLIHCKVLPTNHRVTWDSAQVfdLAQTLRDGVLLCQLLNNLRAHSINlkEINLRPQmSQFLCLKNIRTFLT 80
Cdd:cd21265    1 MNPEEQTVTWLISLGVLNSPKKTISDPEEF--LKSSLKDGVVLCKLIERLLPGSVE--KYCLEPK-TEADCIGNIKEFLK 75

                         90       100       110
                 ....*....|....*....|....*....|....*..
gi 530361574  81 ACCETfgmrKSELFEAFDLFDVRDFGKVIETLSRLSR 117
Cdd:cd21265   76 GCAAL----KVETFEPDDLYTGENFSKVLSTLLAVNK 108

calponin homology (CH) domain found in Drosophila melanogaster muscle-specific protein 20 (dMP20) and similar domains; This subfamily contains Drosophila melanogaster muscle-specific protein 20 (dMP20), Echinococcus granulosus myophilin, Dictyostelium discoideum Rac guanine nucleotide exchange factor B (also called Trix), and similar proteins. dMP20 is present only in the synchronous muscles of D. melanogaster. It may be involved in the system linking the nerve impulse with the contraction or the relaxation process. Trix is involved in the regulation of the late steps of the endocytic pathway. dMP20 contains a single copy of the CH domain, while Trix (triple CH-domain array exchange factor) contains three, two type 3 CH domains which are included in this model, and one type 1 CH domain that is not included in this subfamily, but is part of the superfamily. CH domains are actin filament (F-actin) binding motifs.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530361574  32 DLAQTLRDGVLLCQLLNNLRAHSInlKEINlrPQMSQFLCLKNIRTFLTACcETFGMRKSELFEAFDLFDVRDFGKVIET 111
Cdd:cd21207   27 DYEDVLKDGVILCKLINILKPGSV--KKIN--TSKMAFKLMENIENFLTAC-KGYGVPKTDLFQTVDLYEKKNIPQVTNC 101

                 ....*.
gi 530361574 112 LSRLSR 117
Cdd:cd21207  102 LFALGR 107

calponin homology (CH) domain found in beta-Pak Interactive eXchange factor; Beta-Pak Interactive eXchange factor (beta-PIX), also called PAK-interacting exchange factor beta, Rho guanine nucleotide exchange factor 7 (ARHGEF7), p85, or Cool (Cloned out of Library)-1, activates small GTPases by exchanging bound GDP for free GTP. It acts as a GEF for both Cdc42 and Rac1, and plays important roles in regulating neuroendocrine exocytosis, focal adhesion maturation, cell migration, synaptic vesicle localization, and insulin secretion. Beta-PIX contains a single copy of the CH domain at its N-terminus. CH domains are actin filament (F-actin) binding motifs.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530361574   5 KQCAQWLIHCKVLPTNHRVTWDSAQVfdLAQTLRDGVLLCQLLNNLRAHSINlkEINLRPQmSQFLCLKNIRTFLTACce 84
Cdd:cd21266    3 EQTVTWLITLGVLESPKKTISDPEGF--LQASLKDGVVLCRLLERLLPGSID--KVYPEPR-TESECLSNIREFLRGC-- 75

                         90       100       110
                 ....*....|....*....|....*....|...
gi 530361574  85 tfGMRKSELFEAFDLFDVRDFGKVIETLSRLSR 117
Cdd:cd21266   76 --GALRLETFDANDLYQGQNFNKVLSSLVALNK 106

calponin homology (CH) domain found in the Pak Interactive eXchange factor family; Pak Interactive eXchange factor (PIX) proteins are Rho guanine nucleotide exchange factors (GEFs), which activate small GTPases by exchanging bound GDP for free GTP. They act as GEFs for both Cdc42 and Rac1, and have been implicated in cell motility, adhesion, neurite outgrowth, and cell polarity. Vertebrates contain two proteins from the PIX family, alpha-PIX and beta-PIX. Alpha-PIX, also called Rho guanine nucleotide exchange factor 6 (ARHGEF6), is localized in dendritic spines where it regulates spine morphogenesis. It controls dendritic length and spine density in the hippocampus. Mutations in the ARHGEF6 gene cause X-linked intellectual disability in humans. Beta-PIX, also called Rho guanine nucleotide exchange factor 7 (ARHGEF7), plays important roles in regulating neuroendocrine exocytosis, focal adhesion maturation, cell migration, synaptic vesicle localization, and insulin secretion. Both alpha-PIX and beta-PIX contain a single copy of the CH domain at the N-terminus. CH domains are actin filament (F-actin) binding motifs.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530361574   5 KQCAQWLIHCKVLPTNHRVTWDSAQVFdLAQTLRDGVLLCQLLNNLRAHSINlkEINLRPQmSQFLCLKNIRTFLTAcCE 84
Cdd:cd21202    3 EQIVTWLISLGLLESPKKETIEDPERF-LSESLKNGVVLCRLVNRLKPGTVE--KIYDEPT-TEEECLYNFESFLKA-CQ 77

                         90       100       110
                 ....*....|....*....|....*....|...
gi 530361574  85 TFGMRKSELFEAFDLFDVRDFGKVIETLSRLSR 117
Cdd:cd21202   78 ELGILAEEIFDPNDLYSGGNFQKVLSTLERLEK 110

calponin homology (CH) domain found in LIM domain only protein 7 and similar proteins; This family includes LIM domain only protein 7 (LMO-7) and LIM and calponin homology domains-containing protein 1 (LIMCH1), and similar proteins. LMO-7, also called F-box only protein 20, or LOMP, is a transcription regulator for expression of many Emery-Dreifuss muscular dystrophy (EDMD)-relevant genes. It binds to alpha-actinin and AF6/afadin at adherens junctions for epithelial cell-cell adhesion. LIMCH1 acts as an actin stress fiber-associated protein that activates the non-muscle myosin IIa complex by promoting the phosphorylation of its regulatory subunit MRLC/MYL9. It positively regulates actin stress fiber assembly and stabilizes focal adhesions, and therefore negatively regulates cell spreading and cell migration. Members of this family contain a single copy of the CH domain at the N-terminus. CH domains are actin filament (F-actin) binding motifs.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 530361574  37 LRDGVLLCQLLNNLRAHSInlKEINLRPqmSQFLCLKNIRTFLTAcCETFGMRKSELFEAFDLFDVrdFGKVIETLSR 114
Cdd:cd21208   26 LEDGILLCELINAIKPGSI--KKINRLP--TPIAGLDNLNLFLKA-CEDLGLKDSQLFDPTDLQDL--SNRRIATHVR 96

second protein kinase C conserved region 1 (C1 domain) found in protein kinase D2 (PKD2) and similar proteins; PKD2, also called PRKD2, HSPC187, or serine/threonine-protein kinase D2 (nPKC-D2), is a serine/threonine-protein kinase that converts transient diacylglycerol (DAG) signals into prolonged physiological effects downstream of PKC, and is involved in the regulation of cell proliferation via MAPK1/3 (ERK1/2) signaling, oxidative stress-induced NF-kappa-B activation, inhibition of HDAC7 transcriptional repression, signaling downstream of T-cell antigen receptor (TCR) and cytokine production, and plays a role in Golgi membrane trafficking, angiogenesis, secretory granule release and cell adhesion. PKD2 contains N-terminal tandem cysteine-rich zinc binding C1 (PKC conserved region 1), central PH (Pleckstrin Homology), and C-terminal catalytic kinase domains. This model corresponds to the second 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
                 ....*....|....*....|....*....|....*....|....*...
gi 530361574 514 HDFKMHTFTRVTSCKVCQMLLRGTFYQGYLCFKCGARAHKECLGRVDN 561
Cdd:cd20843   12 HTFVIHSYTRPTVCQFCKKLLKGLFRQGLQCKDCKFNCHKRCATRVPN 59

calponin homology (CH) domain found in the leucine-rich repeat and calponin homology domain-containing protein family; The leucine-rich repeat and calponin homology domain-containing protein (LRCH) family includes LRCH1-4. LRCH1, also called calponin homology domain-containing protein 1, or neuronal protein 81 (NP81), acts as a negative regulator of GTPase Cdc42 by sequestering Cdc42-guanine exchange factor DOCK8. LRCH2 may play a role in the organization of the cytoskeleton. LRCH3 is part of the DISP complex and may regulate the association of septins with actin and thereby regulate the actin cytoskeleton. LRCH4, also called leucine-rich repeat neuronal protein 4, or leucine-rich neuronal protein, acts as a novel Toll-like receptor (TLR) accessory protein that regulates the innate immune response. Members of this family contain a single copy of the CH domain at the C-terminus. CH domains are actin filament (F-actin) binding motifs.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530361574  32 DLAQTLRDGVLLCQLLNNLRAHSINlkEINLR----PQMSQFLCLKNIRTFLTAcCETFGMRKSELFEAFDLFDVRDFGK 107
Cdd:cd21205   21 DLGEALMDGVVLCHLANHVRPRSVP--SIHVPspavPKLSMAKCRRNVENFLEA-CRKLGVPEERLCSPGDILEEKGLVR 97

                 ....*...
gi 530361574 108 VIETLSRL 115
Cdd:cd21205   98 VAVTVQAL 105

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530361574  407 IRITTLDKHTKQERHIFLFDLAVIVCKRKGDN--YEMKEIIDLQQYKIANNPTTDKENKKWSYGFYLIHTQGQNGLEFYC 484
Cdd:pfam00169   8 LKKGGGKKKSWKKRYFVLFDGSLLYYKDDKSGksKEPKGSISLSGCEVVEVVASDSPKRKFCFELRTGERTGKRTYLLQA 87

                          90
                  ....*....|....*...
gi 530361574  485 KTKDLKKKWLEQFEMALS 502
Cdd:pfam00169  88 ESEEERKDWIKAIQSAIR 105

calponin homology (CH) domain found in the growth arrest-specific protein 2 family; The growth arrest-specific protein 2 (GAS-2) family includes GAS-2, and GAS-2 like proteins, GAS2L1-3. GAS-2 may play a role in apoptosis by acting as a cell death substrate for caspases. GAS2L1 (also called GAS2-related protein on chromosome 22 or growth arrest-specific protein 2-like 1) and GAS2L2 (also called GAS2-related protein on chromosome 17 or growth arrest-specific protein 2-like 2) may be involved in the cross-linking of microtubules and microfilaments. GAS2L3, also called GAS2-like protein 3, is a cytoskeletal linker protein that may promote and stabilize the formation of the actin and microtubule network. Members of this family contain a single copy of the CH domain at the N-terminal region. CH domains are actin filament (F-actin) binding motifs.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530361574   7 CAQWLihCKVLPTNhrVTWDsaqvfDLAQTLRDGVLLCQLLN--------NLRAHSINLKEINLRPQMSQ------FLCL 72
Cdd:cd21204   11 LAEWL--NDLLGDD--LTPD-----NFLDELRNGVVLCQLAQkiqeaaekAREAGKKNGPPPSYKLKCNEnakpgsFFAR 81

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*
gi 530361574  73 KNIRTFLTACcETFGMRKSELFEAFDLFDVRDFGKVIETLSRLSR 117
Cdd:cd21204   82 DNVANFLRWC-RKLGVDEVLLFESEDLVLHKNPRQVLLCLLELAR 125

calponin homology (CH) domain found in calponin-2; Calponin-2 (CNN2), also called neutral calponin, or smooth muscle calponin H2, is an actin cytoskeleton-associated regulatory protein that inhibits the activity of myosin-ATPase and cytoskeleton dynamics. It contains a single copy of the CH domain. CH domains are actin filament (F-actin) binding motifs.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530361574  32 DLAQTLRDGVLLCQLLNNLRAHSInlKEINLRPQmsQFLCLKNIRTFLTACCeTFGMRKSELFEAFDLFDVRDFGKVIET 111
Cdd:cd21283   23 DFQKGLKDGVILCELMNKLQPGSV--PKINRSMQ--NWHQLENLSNFIKAMV-SYGMKPVDLFEANDLFESGNMTQVQVS 97

                 ....*
gi 530361574 112 LSRLS 116
Cdd:cd21283   98 LLALA 102

calponin homology (CH) domain found in the calponin family; Calponin is an actin filament-associated regulatory protein expressed in smooth muscle and many types of non-muscle cells. There are three calponin isoforms, calponin-1, -2, -3. All of them are actin-binding proteins with functions in inhibiting actin-activated myosin ATPase and stabilizing the actin cytoskeleton. Calponin-1 is specifically expressed in smooth muscle cells and plays a role in fine-tuning smooth muscle contractility. Calponin-2 is expressed in both smooth muscle and non-muscle cells and regulates multiple actin cytoskeleton-based functions. Calponin-3 is expressed in the brain and participates in actin cytoskeleton-based activities in embryonic development and myogenesis. Members of this family contain a single copy of the CH domain. CH domains are actin filament (F-actin) binding motifs.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530361574  32 DLAQTLRDGVLLCQLLNNLRAHSInlKEINlrPQMSQFLCLKNIRTFLTAcCETFGMRKSELFEAFDLFDVRDFGKVIET 111
Cdd:cd21211   23 NFQKGLKDGIILCELINKLQPGSV--KKIN--ESMQNWHQLENIGNFIKA-IVSYGMKPHDIFEANDLFENGNMTQVQVT 97

                 ....*
gi 530361574 112 LSRLS 116
Cdd:cd21211   98 LLALA 102

calponin homology (CH) domain found in calponin-3; Calponin-3 (CNN3), also called acidic isoform calponin, is an F-actin-binding protein that is expressed in the brain and has been shown to control dendritic spine morphology, density, and plasticity by regulating actin cytoskeletal reorganization and dynamics. It contains a single copy of the CH domain. CH domains are actin filament (F-actin) binding motifs.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530361574  35 QTLRDGVLLCQLLNNLRAHSInlKEINLRPQmsQFLCLKNIRTFLTAcCETFGMRKSELFEAFDLFDVRDFGKVIETLSR 114
Cdd:cd21284   28 KGLKDGVILCELINKLQPGSI--RKINESKL--NWHQLENIGNFIKA-IQAYGMKPHDIFEANDLFENGNMTQVQTTLLA 102

                 ..
gi 530361574 115 LS 116
Cdd:cd21284  103 LA 104

protein kinase C conserved region 1 (C1 domain) found in uncharacterized Rho guanine nucleotide exchange factor (ARHGEF)-like proteins; The family includes a group of uncharacterized proteins that show high sequence similarity to vertebrate Rho guanine nucleotide exchange factors ARHGEF11 and ARHGEF12, which may play a role in the regulation of RhoA GTPase by guanine nucleotide-binding alpha-12 (GNA12) and alpha-13 (GNA13). Unlike typical ARHGEF11 and ARHGEF12, members of this family contain a C1 domain. 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
                 ....*....|....*....|....*....|....*....|...
gi 530361574 514 HDFKMHTFTRVTSCKVCQMLLRGTFYQGYLCFKCGARAHKECL 556
Cdd:cd20832    2 HQFVLQHYYQVTFCNHCSGLLWGIGYQGYQCSDCEFNIHKQCI 44

second protein kinase C conserved region 1 (C1 domain) found in novel protein kinase C (nPKC) epsilon, eta, and similar proteins; PKCs are classified into three groups (classical, atypical, and novel) depending on their mode of activation and the structural characteristics of their regulatory domain. nPKCs are calcium-independent, but require DAG (1,2-diacylglycerol) and phosphatidylserine (PS) for activity. PKC-epsilon has been shown to behave as an oncoprotein. Its overexpression contributes to neoplastic transformation depending on the cell type. It contributes to oncogenesis by inducing disordered cell growth and inhibiting cell death. It also plays a role in tumor invasion and metastasis. PKC-epsilon has also been found to confer cardioprotection against ischemia and reperfusion-mediated damage. Other cellular functions include the regulation of gene expression, cell adhesion, and cell motility. PKC-eta is predominantly expressed in squamous epithelia, where it plays a crucial role in the signaling of cell-type specific differentiation. It is also expressed in pro-B cells and early-stage thymocytes, and acts as a key regulator in early B-cell development. PKC-eta increases glioblastoma multiforme (GBM) proliferation and resistance to radiation, and is being developed as a therapeutic target for the management of GBM. Members of this family contain two copies of C1 domain. This model corresponds to the second one. 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 530361574 514 HDFKMHTFTRVTSCKVCQMLLRGTFYQGYLCFKCGARAHKECLGRV-DNCG 563
Cdd:cd20838    3 HRFSVHNYKRPTFCDHCGSLLYGLYKQGLQCKVCKMNVHKRCQKNVaNNCG 53

protein kinase C conserved region 1 (C1 domain) found in the SH3 and cysteine-rich domain-containing protein (Stac) family; Stac proteins are putative adaptor proteins that are important for neuronal function. There are three mammalian members (Stac1, Stac2 and Stac3) of this family. Stac1 and Stac3 contain two SH3 domains while Stac2 contains a single SH3 domain at the C-terminus. Stac1 and Stac2 have been found to be expressed differently in mature dorsal root ganglia (DRG) neurons. Stac1 is mainly expressed in peptidergic neurons while Stac2 is found in a subset of nonpeptidergic and all trkB+ neurons. Stac proteins contain a cysteine-rich C1 domain and one or two SH3 domains at the C-terminus. 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
                 ....*....|....*....|....*....|....*....|....*....
gi 530361574 514 HDFKMHTFTRVTSCKVCQMLLRGTFYQGYLCFKCGARAHKECLGRVDNC 562
Cdd:cd20817    1 HSFQEHTFKKPTFCDVCKELLVGLSKQGLRCKNCKMNVHHKCQEGVPDC 49

Collybistin/APC-stimulated guanine nucleotide exchange factor pleckstrin homology (PH) domain; Collybistin (also called PEM2) is homologous to the Dbl proteins ASEF (also called ARHGEF4/RhoGEF4) and SPATA13 (Spermatogenesis-associated protein 13; also called ASEF2). It activates CDC42 specifically and not any other Rho-family GTPases. Collybistin consists of an SH3 domain, followed by a RhoGEF/DH and PH domain. In Dbl proteins, the DH and PH domains catalyze the exchange of GDP for GTP in Rho GTPases, allowing them to signal to downstream effectors. It induces submembrane clustering of the receptor-associated peripheral membrane protein gephyrin, which is thought to form a scaffold underneath the postsynaptic membrane linking receptors to the cytoskeleton. It also acts as a tumor suppressor that links adenomatous polyposis coli (APC) protein, a negative regulator of the Wnt signaling pathway and promotes the phosphorylation and degradation of beta-catenin, to Cdc42. Autoinhibition of collybistin is accomplished by the binding of its SH3 domain with both the RhoGEF and PH domains to block access of Cdc42 to the GTPase-binding site. Inactivation promotes cancer progression. 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 530361574 408 RITTLDKHTKQERHIFLFDLAVIVCKR---KGDNYEMKEIIDLQQYKIANNPttDKENKKWSYGFY---LIHTQGQNGLE 481
Cdd:cd01224   34 ELTKISAGRAQERTFFLFDHQLVYCKKdllRRKNYIYKGRIDTDNMEIEDLP--DGKDDESGVTVKnawKIYNASKNKWY 111

                         90
                 ....*....|....*..
gi 530361574 482 -FYCKTKDLKKKWLEQF 497
Cdd:cd01224  112 vLCAKSAEEKQRWLEAF 128