RhoGAP_Graf: GTPase-activator protein (GAP) domain for Rho-like GTPases found in GRAF (GTPase regulator associated with focal adhesion kinase); Graf is a multi-domain protein, containing SH3 and PH domains, that binds focal adhesion kinase and influences cytoskeletal changes mediated by Rho proteins. Graf exhibits GAP activity toward RhoA and Cdc42, but only weakly activates Rac1. Small GTPases cluster into distinct families, and all act as molecular switches, active in their GTP-bound form but inactive when GDP-bound. The Rho family of GTPases activates effectors involved in a wide variety of developmental processes, including regulation of cytoskeleton formation, cell proliferation and the JNK signaling pathway. GTPases generally have a low intrinsic GTPase hydrolytic activity but there are family-specific groups of GAPs that enhance the rate of GTP hydrolysis by several orders of magnitude.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907206495 285 MDGKEPIYHTPITKQ----EEMELNEVGFKFVRKCINFIETKGIKTEGLYRTVGSNIQVQKLLYAFFDPK--CPGDVDFH 358
Cdd:cd04374     1 MDGKEPVYHSPGRLQseveGEAQLDDIGFKFVRKCIEAVETRGINEQGLYRVVGVNSKVQKLLSLGLDPKtsTPGDVDLD 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907206495 359 NSDWDIKTITSSLKFYLRNLSEPVMTYKLHKELVSAAKSDNLDYRLGAIHSLVYKLPEKNREMLELLIKHLVNVCEHSKE 438
Cdd:cd04374    81 NSEWEIKTITSALKTYLRNLPEPLMTYELHNDFINAAKSENLESRVNAIHSLVHKLPEKNREMLELLIKHLTNVSDHSKK 160

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|...
gi 1907206495 439 NLMTPSNMGVIFGPTLMRAQEDTVAAMMNIKFQNIVVEILIEH 481
Cdd:cd04374   161 NLMTVSNLGVVFGPTLLRPQEETVAAIMDIKFQNIVVEILIEN 203

GTPase Regulator Associated with Focal adhesion and related proteins Pleckstrin homology (PH) domain; This hierarchy contains GRAF family members: OPHN1/oligophrenin1, GRAF1 (also called ARHGAP26/Rho GTPase activating protein 26), GRAF2 (also called ARHGAP10/ARHGAP42), AK057372, and LOC129897, all of which are members of the APPL family. OPHN1 is a RhoGAP involved in X-linked mental retardation, epilepsy, rostral ventricular enlargement, and cerebellar hypoplasia. Affected individuals have morphological abnormalities of their brain with enlargement of the cerebral ventricles and cerebellar hypoplasia. OPHN1 negatively regulates RhoA, Cdc42, and Rac1 in neuronal and non-neuronal cells. GRAF1 sculpts the endocytic membranes of the CLIC/GEEC (clathrin-independent carriers/GPI-enriched early endosomal compartments) endocytic pathway. It strongly interacts with dynamin and inhibition of dynamin abolishes CLIC/GEEC endocytosis. GRAF2, GRAF3 and oligophrenin are likely to play similar roles during clathrin-independent endocytic events. GRAF1 mutations are linked to leukaemia. All members are composed of a N-terminal BAR-PH domain, followed by a RhoGAP domain, a proline rich region, and a C-terminal SH3 domain. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907206495 189 TIEGYLYTQEKWALGISWAKYYCRYEKETRMLTMIPMEQKPGAK-QGPVDLTLKYCVRRKTESIDKRFCFDIETNERPGT 267
Cdd:cd01249     1 TKEGYLYLQEKKPLGSTWTKHYCTYRKESKMFTMIPYNQQSSGKlGTTEVVTLKSCVRRKTDSIDRRFCFDIEVVDRPTV 80

                          90       100
                  ....*....|....*....|....*
gi 1907206495 268 ITLQAPSEANRRLWMEAMDGKEPIY 292
Cdd:cd01249    81 LTLQALSEEDRKLWLEAMDGKEPIY 105

RhoGAP_Graf: GTPase-activator protein (GAP) domain for Rho-like GTPases found in GRAF (GTPase regulator associated with focal adhesion kinase); Graf is a multi-domain protein, containing SH3 and PH domains, that binds focal adhesion kinase and influences cytoskeletal changes mediated by Rho proteins. Graf exhibits GAP activity toward RhoA and Cdc42, but only weakly activates Rac1. Small GTPases cluster into distinct families, and all act as molecular switches, active in their GTP-bound form but inactive when GDP-bound. The Rho family of GTPases activates effectors involved in a wide variety of developmental processes, including regulation of cytoskeleton formation, cell proliferation and the JNK signaling pathway. GTPases generally have a low intrinsic GTPase hydrolytic activity but there are family-specific groups of GAPs that enhance the rate of GTP hydrolysis by several orders of magnitude.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907206495 285 MDGKEPIYHTPITKQ----EEMELNEVGFKFVRKCINFIETKGIKTEGLYRTVGSNIQVQKLLYAFFDPK--CPGDVDFH 358
Cdd:cd04374     1 MDGKEPVYHSPGRLQseveGEAQLDDIGFKFVRKCIEAVETRGINEQGLYRVVGVNSKVQKLLSLGLDPKtsTPGDVDLD 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907206495 359 NSDWDIKTITSSLKFYLRNLSEPVMTYKLHKELVSAAKSDNLDYRLGAIHSLVYKLPEKNREMLELLIKHLVNVCEHSKE 438
Cdd:cd04374    81 NSEWEIKTITSALKTYLRNLPEPLMTYELHNDFINAAKSENLESRVNAIHSLVHKLPEKNREMLELLIKHLTNVSDHSKK 160

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|...
gi 1907206495 439 NLMTPSNMGVIFGPTLMRAQEDTVAAMMNIKFQNIVVEILIEH 481
Cdd:cd04374   161 NLMTVSNLGVVFGPTLLRPQEETVAAIMDIKFQNIVVEILIEN 203

GTPase-activator protein for Rho-like GTPases; GTPase activator proteins towards Rho/Rac/Cdc42-like small GTPases. etter domain limits and outliers.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907206495  310 KFVRKCINFIETKGIKTEGLYRTVGSNIQVQKLLYAFfdpKCPGDVDFHNSDWDIKTITSSLKFYLRNLSEPVMTYKLHK 389
Cdd:smart00324   5 IIVEKCIEYLEKRGLDTEGIYRVSGSKSRVKELRDAF---DSGPDPDLDLSEYDVHDVAGLLKLFLRELPEPLITYELYE 81

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907206495  390 ELVSAAKSDNLDYRLGAIHSLVYKLPEKNREMLELLIKHLVNVCEHSKENLMTPSNMGVIFGPTLMRAQEDTVAAMMNIK 469
Cdd:smart00324  82 EFIEAAKLEDETERLRALRELLSLLPPANRATLRYLLAHLNRVAEHSEENKMTARNLAIVFGPTLLRPPDGEVASLKDIR 161

                          170
                   ....*....|..
gi 1907206495  470 FQNIVVEILIEH 481
Cdd:smart00324 162 HQNTVIEFLIEN 173

GTPase Regulator Associated with Focal adhesion and related proteins Pleckstrin homology (PH) domain; This hierarchy contains GRAF family members: OPHN1/oligophrenin1, GRAF1 (also called ARHGAP26/Rho GTPase activating protein 26), GRAF2 (also called ARHGAP10/ARHGAP42), AK057372, and LOC129897, all of which are members of the APPL family. OPHN1 is a RhoGAP involved in X-linked mental retardation, epilepsy, rostral ventricular enlargement, and cerebellar hypoplasia. Affected individuals have morphological abnormalities of their brain with enlargement of the cerebral ventricles and cerebellar hypoplasia. OPHN1 negatively regulates RhoA, Cdc42, and Rac1 in neuronal and non-neuronal cells. GRAF1 sculpts the endocytic membranes of the CLIC/GEEC (clathrin-independent carriers/GPI-enriched early endosomal compartments) endocytic pathway. It strongly interacts with dynamin and inhibition of dynamin abolishes CLIC/GEEC endocytosis. GRAF2, GRAF3 and oligophrenin are likely to play similar roles during clathrin-independent endocytic events. GRAF1 mutations are linked to leukaemia. All members are composed of a N-terminal BAR-PH domain, followed by a RhoGAP domain, a proline rich region, and a C-terminal SH3 domain. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907206495 189 TIEGYLYTQEKWALGISWAKYYCRYEKETRMLTMIPMEQKPGAK-QGPVDLTLKYCVRRKTESIDKRFCFDIETNERPGT 267
Cdd:cd01249     1 TKEGYLYLQEKKPLGSTWTKHYCTYRKESKMFTMIPYNQQSSGKlGTTEVVTLKSCVRRKTDSIDRRFCFDIEVVDRPTV 80

                          90       100
                  ....*....|....*....|....*
gi 1907206495 268 ITLQAPSEANRRLWMEAMDGKEPIY 292
Cdd:cd01249    81 LTLQALSEEDRKLWLEAMDGKEPIY 105

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 1907206495  188 PTIEGYLYTQEKWALGiSWAKYYCRYeKETRMLTMIPMEQKPGAK-QGPVDLTLKYCVRR-KTESIDKRFCFDIETNERp 265
Cdd:smart00233   1 VIKEGWLYKKSGGGKK-SWKKRYFVL-FNSTLLYYKSKKDKKSYKpKGSIDLSGCTVREApDPDSSKKPHCFEIKTSDR- 77

                           90       100
                   ....*....|....*....|
gi 1907206495  266 GTITLQAPSEANRRLWMEAM 285
Cdd:smart00233  78 KTLLLQAESEEEREKWVEAL 97

RhoGAP_Graf: GTPase-activator protein (GAP) domain for Rho-like GTPases found in GRAF (GTPase regulator associated with focal adhesion kinase); Graf is a multi-domain protein, containing SH3 and PH domains, that binds focal adhesion kinase and influences cytoskeletal changes mediated by Rho proteins. Graf exhibits GAP activity toward RhoA and Cdc42, but only weakly activates Rac1. Small GTPases cluster into distinct families, and all act as molecular switches, active in their GTP-bound form but inactive when GDP-bound. The Rho family of GTPases activates effectors involved in a wide variety of developmental processes, including regulation of cytoskeleton formation, cell proliferation and the JNK signaling pathway. GTPases generally have a low intrinsic GTPase hydrolytic activity but there are family-specific groups of GAPs that enhance the rate of GTP hydrolysis by several orders of magnitude.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907206495 285 MDGKEPIYHTPITKQ----EEMELNEVGFKFVRKCINFIETKGIKTEGLYRTVGSNIQVQKLLYAFFDPK--CPGDVDFH 358
Cdd:cd04374     1 MDGKEPVYHSPGRLQseveGEAQLDDIGFKFVRKCIEAVETRGINEQGLYRVVGVNSKVQKLLSLGLDPKtsTPGDVDLD 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907206495 359 NSDWDIKTITSSLKFYLRNLSEPVMTYKLHKELVSAAKSDNLDYRLGAIHSLVYKLPEKNREMLELLIKHLVNVCEHSKE 438
Cdd:cd04374    81 NSEWEIKTITSALKTYLRNLPEPLMTYELHNDFINAAKSENLESRVNAIHSLVHKLPEKNREMLELLIKHLTNVSDHSKK 160

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|...
gi 1907206495 439 NLMTPSNMGVIFGPTLMRAQEDTVAAMMNIKFQNIVVEILIEH 481
Cdd:cd04374   161 NLMTVSNLGVVFGPTLLRPQEETVAAIMDIKFQNIVVEILIEN 203

The Bin/Amphiphysin/Rvs (BAR) domain of Oligophrenin1-like Rho GTPase Activating Proteins; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions. This subfamily is composed of Rho and Rac GTPase activating proteins (GAPs) with similarity to oligophrenin1 (OPHN1). Members contain an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, and a Rho GAP domain. Some members contain a C-terminal SH3 domain. Vertebrates harbor at least three Rho GAPs in this subfamily including OPHN1, GTPase Regulator Associated with Focal adhesion kinase (GRAF), GRAF2, and an uncharacterized protein called GAP10-like. OPHN1, GRAF and GRAF2 show GAP activity towards RhoA and Cdc42. In addition, OPHN1 is active towards Rac. BAR domains form dimers that bind to membranes, induce membrane bending and curvature, and may also be involved in protein-protein interactions. The BAR domains of OPHN1 and GRAF directly interact with their Rho GAP domains and inhibit their activity. The autoinhibited proteins are able to bind membranes and tubulate liposomes, showing that the membrane-tubulation and GAP-inhibitory functions of the BAR domains can occur simultaneously.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907206495   3 NCLAESFKEFAELLNEVENERMMMVQNASDLLIKPLETFRKEQIGFTKERKKKFEKDGERFYSLLDRHLHLSSKKKESQL 82
Cdd:cd07602    63 IEIAESLKEFGRLIETVEDERDRMLENAEEQLIEPLEKFRKEQIGGAKEEKKKFDKETEKFCSSLEKHLNLSTKKKENQL 142

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1907206495  83 LEADLQVDKERHNFFESSLDYVYQIQEVQESKKFNIVEPVLAFLHSLFISNSLTVELTQDFLPYK 147
Cdd:cd07602   143 QEADAQLDMERRNFHQASLEYVFKLQEVQERKKFEFVETLLSFMYGWLTFYHQGHEVAKDFKPYL 207

BAR domain of APPL family; BAR_12 is the BAR coiled-coil domain at the N-terminus of APPL or adaptor protein containing PH domain, PTB domain, and leucine zipper motif proteins in higher eukaryotes. This BAR domain contains four helices whereas the other classical BAR domains contain only three helices. The first three helices form an antiparallel coiled-coil, while the fourth helix, is unique to APPL1. BAR domains take part in many varied biological processes such as fission of synaptic vesicles, endocytosis, regulation of the actin cytoskeleton, transcriptional repression, cell-cell fusion, apoptosis, secretory vesicle fusion, and tissue differentiation.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907206495   7 ESFKEFAELLNEVENERMMMVQNASDLLIKPLETFRKEQIGFTKERKKKFEKDGERFYSLLDRHLHLSSKKKESQLLEAD 86
Cdd:pfam16746  74 ESLKKFSQLLQEMENFHTILLDQAQRTIIKPLENFRKEDLKEVKELKKKFDKASEKLDAALEKNAQLSKKKKPSELEEAD 153

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907206495  87 LQVDKERHNFFESSLDYVYQIQEVQESKKFNIVEPVLAFLHSLFISNSLTVELTQDFLPYKQQLQLSLQNTRNhfsSTRE 166
Cdd:pfam16746 154 NELAATRKCFHHASLDYVLQINELQERKKFEILEPLLSFMHAQFTFFHQGYELFKDLEPFMKDLQAQLQQTRE---DTRE 230

                  ....*
gi 1907206495 167 EMEEL 171
Cdd:pfam16746 231 EKEEL 235

The Bin/Amphiphysin/Rvs (BAR) domain of Rho GTPase activating protein 10-like; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions. This group is composed of uncharacterized proteins called Rho GTPase activating protein (GAP) 10-like. GAP10-like may be a GAP with activity towards RhoA and Cdc42. Similar to GRAF and GRAF2, it contains an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, a Rho GAP domain, and a C-terminal SH3 domain. BAR domains form dimers that bind to membranes, induce membrane bending and curvature, and may also be involved in protein-protein interactions. The BAR domains of the related proteins GRAF and OPHN1, directly interact with their Rho GAP domains and inhibit theiractivity. The autoinhibited proteins are capable of binding membranes and tubulating liposomes, showing that the membrane-tubulation and GAP-inhibitory functions of the BAR domain can occur simultaneously.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907206495   5 LAESFKEFAELLNEVENERMMMVQNASDLLIKPLETFRKEQIGFTKERKKKFEKDGERFYSLLDRHLHLSSKKKESQLLE 84
Cdd:cd07634    65 IAQSLKEFARLLIAVEEERRRLIQNANDVLIAPLEKFRKEQIGAAKDGKKKFDKESEKYYSILEKHLNLSAKKKESHLQR 144

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1907206495  85 ADLQVDKERHNFFESSLDYVYQIQEVQESKKFNIVEPVLAFLHSLFISNSLTVELTQDFLPYK 147
Cdd:cd07634   145 ADTQIDREHQNFYEASLEYVFKIQEVQEKKKFEFVEPLLAFLQGLFTFYHEGYELAQEFAPYK 207

The Bin/Amphiphysin/Rvs (BAR) domain of GTPase Regulator Associated with Focal adhesion kinase; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions. GTPase Regulator Associated with Focal adhesion kinase (GRAF), also called Rho GTPase activating protein 26 (ARHGAP26), is a GAP with activity towards RhoA and Cdc42 and is only weakly active towards Rac1. It influences Rho-mediated cytoskeletal rearrangements and binds focal adhesion kinase (FAK), which is a critical component of integrin signaling. GRAF contains an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, a Rho GAP domain, and a C-terminal SH3 domain. BAR domains form dimers that bind to membranes, induce membrane bending and curvature, and may also be involved in protein-protein interactions. The BAR domain of GRAF directly interacts with its Rho GAP domain and inhibits its activity. Autoinhibited GRAF is capable of binding membranes and tubulating liposomes, showing that the membrane-tubulation and GAP-inhibitory functions of the BAR domain can occur simultaneously.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907206495   4 CLAESFKEFAELLNEVENERMMMVQNASDLLIKPLETFRKEQIGFTKERKKKFEKDGERFYSLLDRHLHLSSKKKESQLL 83
Cdd:cd07636    64 CIARSLQEFAAVLRNLEDERTRMIENASEVLITPLEKFRKEQIGAAKEAKKKYDKETEKYCAVLEKHLNLSSKKKESQLH 143

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1907206495  84 EADLQVDKERHNFFESSLDYVYQIQEVQESKKFNIVEPVLAFLHSLFISNSLTVELTQDFLPYK 147
Cdd:cd07636   144 EADSQVDLVRQHFYEVSLEYVFKVQEVQERKMFEFVEPLLAFLQGLFTFYHHGYELAKDFSDFK 207

RhoGAP domain; GTPase activator proteins towards Rho/Rac/Cdc42-like small GTPases.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907206495 310 KFVRKCINFIETKGIKTEGLYRTVGSNIQVQKLLYAFfdpKCPGDVDFHNSDWDIKTITSSLKFYLRNLSEPVMTYKLHK 389
Cdd:pfam00620   2 LIVRKCVEYLEKRGLDTEGIFRVSGSASRIKELREAF---DRGPDVDLDLEEEDVHVVASLLKLFLRELPEPLLTFELYE 78

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1907206495 390 ELVSAAKSDNLDYRLGAIHSLVYKLPEKNREMLELLIKHLVNVCEHSKENLMTPSNMGVIFGPTLMR 456
Cdd:pfam00620  79 EFIEAAKLPDEEERLEALRELLRKLPPANRDTLRYLLAHLNRVAQNSDVNKMNAHNLAIVFGPTLLR 145

RhoGAP_chimaerin: RhoGAP (GTPase-activator protein [GAP] for Rho-like small GTPases) domain of chimaerins. Chimaerins are a family of phorbolester- and diacylglycerol-responsive GAPs specific for the Rho-like GTPase Rac. Chimaerins exist in two alternative splice forms that each contain a C-terminal GAP domain, and a central C1 domain which binds phorbol esters, inducing a conformational change that activates the protein; one splice form is lacking the N-terminal Src homology-2 (SH2) domain. Small GTPases cluster into distinct families, and all act as molecular switches, active in their GTP-bound form but inactive when GDP-bound. The Rho family of GTPases activates effectors involved in a wide variety of developmental processes, including regulation of cytoskeleton formation, cell proliferation and the JNK signaling pathway. GTPases generally have a low intrinsic GTPase hydrolytic activity but there are family-specific groups of GAPs that enhance the rate of GTP hydrolysis by several orders of magnitude.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907206495 312 VRKCINFIETKGIKTEGLYRTVGSNIQVQKLLYAFfdpkcpgDVDFHNSDW------DIKTITSSLKFYLRNLSEPVMTY 385
Cdd:cd04372    20 VDMCIREIEARGLQSEGLYRVSGFAEEIEDVKMAF-------DRDGEKADIsatvypDINVITGALKLYFRDLPIPVITY 92

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907206495 386 KLHKELVSAAKSDNLDYRLGAIHSLVYKLPEKNREMLELLIKHLVNVCEHSKENLMTPSNMGVIFGPTLMRA-QEDTVAA 464
Cdd:cd04372    93 DTYPKFIDAAKISNPDERLEAVHEALMLLPPAHYETLRYLMEHLKRVTLHEKDNKMNAENLGIVFGPTLMRPpEDSALTT 172

                         170
                  ....*....|....*..
gi 1907206495 465 MMNIKFQNIVVEILIEH 481
Cdd:cd04372   173 LNDMRYQILIVQLLITN 189

RhoGAP_ARAP: RhoGAP (GTPase-activator protein [GAP] for Rho-like small GTPases) domain present in ARAPs. ARAPs (also known as centaurin deltas) contain, besides the RhoGAP domain, an Arf GAP, ankyrin repeat ras-associating, and PH domains. Since their ArfGAP activity is PIP3-dependent, ARAPs are considered integration points for phosphoinositide, Arf and Rho signaling. Small GTPases cluster into distinct families, and all act as molecular switches, active in their GTP-bound form but inactive when GDP-bound. The Rho family of GTPases activates effectors involved in a wide variety of developmental processes, including regulation of cytoskeleton formation, cell proliferation and the JNK signaling pathway. GTPases generally have a low intrinsic GTPase hydrolytic activity but there are family-specific groups of GAPs that enhance the rate of GTP hydrolysis by several orders of magnitude.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907206495 312 VRKCINFIETKGIKTEGLYRTVGSNIQVQKLLYAFfdPKCPGDVDFHNSDWDIKTITSSLKFYLRNLSEPVMTYKLHKEL 391
Cdd:cd04385    19 VDKCIDFITQHGLMSEGIYRKNGKNSSVKKLLEAF--RKDARSVQLREGEYTVHDVADVLKRFLRDLPDPLLTSELHAEW 96

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907206495 392 VSAAKSDNLDYRLGAIHSLVYKLPEKNREMLELLIKHLVNVCEHSKENLMTPSNMGVIFGPTLMRAQEDTVA-AMMNIKf 470
Cdd:cd04385    97 IEAAELENKDERIARYKELIRRLPPINRATLKVLIGHLYRVQKHSDENQMSVHNLALVFGPTLFQTDEHSVGqTSHEVK- 175

                         170
                  ....*....|..
gi 1907206495 471 qniVVEILIEHF 482
Cdd:cd04385   176 ---VIEDLIDNY 184

RhoGAP_ARHGAP21: RhoGAP (GTPase-activator protein [GAP] for Rho-like small GTPases) domain of ArhGAP21-like proteins. ArhGAP21 is a multi-domain protein, containing RhoGAP, PH and PDZ domains, and is believed to play a role in the organization of the cell-cell junction complex. It has been shown to function as a GAP of Cdc42 and RhoA, and to interact with alpha-catenin and Arf6. Small GTPases cluster into distinct families, and all act as molecular switches, active in their GTP-bound form but inactive when GDP-bound. The Rho family of GTPases activates effectors involved in a wide variety of developmental processes, including regulation of cytoskeleton formation, cell proliferation and the JNK signaling pathway. GTPases generally have a low intrinsic GTPase hydrolytic activity but there are family-specific groups of GAPs that enhance the rate of GTP hydrolysis by several orders of magnitude.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907206495 311 FVRKCINFIETKGIKTEGLYRTVGSNIQVQKLLYAFfdPKCPGDVDFHNSDW-DIKTITSSLKFYLRNLSEPVMTYKLHK 389
Cdd:cd04395    21 IVEVCCNIVEARGLETVGIYRVPGNNAAISALQEEL--NRGGFDIDLQDPRWrDVNVVSSLLKSFFRKLPEPLFTNELYP 98

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907206495 390 ELVSAAKSDNLDYRLGAIHSLVYKLPEKNREMLELLIKHLVNVCEHSKENLMTPSNMGVIFGPTLMRAQEDTVAAMM-NI 468
Cdd:cd04395    99 DFIEANRIEDPVERLKELRRLIHSLPDHHYETLKHLIRHLKTVADNSEVNKMEPRNLAIVFGPTLVRTSDDNMETMVtHM 178

                         170
                  ....*....|...
gi 1907206495 469 KFQNIVVEILIEH 481
Cdd:cd04395   179 PDQCKIVETLIQH 191

RhoGAP-p50rhoGAP: RhoGAP (GTPase-activator protein [GAP] for Rho-like small GTPases) domain of p50RhoGAP-like proteins; p50RhoGAP, also known as RhoGAP-1, contains a C-terminal RhoGAP domain and an N-terminal Sec14 domain which binds phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3). It is ubiquitously expressed and preferentially active on Cdc42. This subgroup also contains closely related ARHGAP8. Small GTPases cluster into distinct families, and all act as molecular switches, active in their GTP-bound form but inactive when GDP-bound. The Rho family of GTPases activates effectors involved in a wide variety of developmental processes, including regulation of cytoskeleton formation, cell proliferation and the JNK signaling pathway. GTPases generally have a low intrinsic GTPase hydrolytic activity but there are family-specific groups of GAPs that enhance the rate of GTP hydrolysis by several orders of magnitude.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907206495 312 VRKCINFIETKGIKTEGLYRTVGsNIQVQKLLYAFFDPKCPgdVDFHNSDwDIKTITSSLKFYLRNLSEPVMTYKLHKEL 391
Cdd:cd04404    27 VRETVEYLQAHALTTEGIFRRSA-NTQVVKEVQQKYNMGEP--VDFDQYE-DVHLPAVILKTFLRELPEPLLTFDLYDDI 102

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907206495 392 VSAAKSDNLDyRLGAIHSLVYKLPEKNREMLELLIKHLVNVCEHSKENLMTPSNMGVIFGPTLMRA--QEDTVAAMMNIk 469
Cdd:cd04404   103 VGFLNVDKEE-RVERVKQLLQTLPEENYQVLKYLIKFLVQVSAHSDQNKMTNSNLAVVFGPNLLWAkdASMSLSAINPI- 180

                         170
                  ....*....|....*..
gi 1907206495 470 fqNIVVEILIEHFGKIY 486
Cdd:cd04404   181 --NTFTKFLLDHQDEIF 195

RhoGAP_p190: RhoGAP (GTPase-activator protein [GAP] for Rho-like small GTPases) domain of p190-like proteins. p190, also named RhoGAP5, plays a role in neuritogenesis and axon branch stability. p190 shows a preference for Rho, over Rac and Cdc42, and consists of an N-terminal GTPase domain and a C-terminal GAP domain. The central portion of p190 contains important regulatory phosphorylation sites. Small GTPases cluster into distinct families, and all act as molecular switches, active in their GTP-bound form but inactive when GDP-bound. The Rho family of GTPases activates effectors involved in a wide variety of developmental processes, including regulation of cytoskeleton formation, cell proliferation and the JNK signaling pathway. GTPases generally have a low intrinsic GTPase hydrolytic activity but there are family-specific groups of GAPs that enhance the rate of GTP hydrolysis by several orders of magnitude.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907206495 311 FVRKCINFIETKGIKTEGLYRTVGSNIQVQKLLYAFFDPkcpGDVDFHNSDWDIKTITSSLKFYLRNLSEPVMTYKLHKE 390
Cdd:cd04373    18 FLEKCVEFIEATGLETEGIYRVSGNKTHLDSLQKQFDQD---HNLDLVSKDFTVNAVAGALKSFFSELPDPLIPYSMHLE 94

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907206495 391 LVSAAKSDNLDYRLGAIHSLVYKLPEKNREMLELLIKHLVNVCEHSKENLMTPSNMGVIFGPTLMRAQEDTVAAMMNIKF 470
Cdd:cd04373    95 LVEAAKINDREQRLHALKELLKKFPPENFDVFKYVITHLNKVSQNSKVNLMTSENLSICFWPTLMRPDFTSMEALSATRI 174

                  ....*....
gi 1907206495 471 QNIVVEILI 479
Cdd:cd04373   175 YQTIIETFI 183

RhoGAP_myosin_IX: RhoGAP (GTPase-activator protein [GAP] for Rho-like small GTPases) domain present in class IX myosins. Class IX myosins contain a characteristic head domain, a neck domain, a tail domain which contains a C6H2-zinc binding motif and a RhoGAP domain. Class IX myosins are single-headed, processive myosins that are partly cytoplasmic, and partly associated with membranes and the actin cytoskeleton. Class IX myosins are implicated in the regulation of neuronal morphogenesis and function of sensory systems, like the inner ear. There are two major isoforms, myosin IXA and IXB with several splice variants, which are both expressed in developing neurons. Small GTPases cluster into distinct families, and all act as molecular switches, active in their GTP-bound form but inactive when GDP-bound. The Rho family of GTPases activates effectors involved in a wide variety of developmental processes, including regulation of cytoskeleton formation, cell proliferation and the JNK signaling pathway. GTPases generally have a low intrinsic GTPase hydrolytic activity but there are family-specific groups of GAPs that enhance the rate of GTP hydrolysis by several orders of magnitude.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907206495 312 VRKCINFIETKGIKTEGLYRTVGSNIQVQKLLYAFfdPKCPGDVDFhnSDWDIKTITSSLKFYLRNLSEPVMTYKLHKEL 391
Cdd:cd04377    19 LEKLLEHIEMHGLYTEGIYRKSGSANKIKELRQGL--DTDPDSVNL--EDYPIHVITSVLKQWLRELPEPLMTFELYENF 94

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907206495 392 VSAAKSDNLDYRLGAIHSLVYKLPEKNREMLELLIKHLVNVCEHSKENLMTPSNMGVIFGPTLMRAQE--DTVAAMMNIK 469
Cdd:cd04377    95 LRAMELEEKQERVRALYSVLEQLPRANLNTLERLIFHLVRVALQEEVNRMSANALAIVFAPCILRCPDtaDPLQSLQDVS 174

                         170
                  ....*....|.
gi 1907206495 470 FQNIVVEILIE 480
Cdd:cd04377   175 KTTTCVETLIK 185

RhoGAP_GMIP: RhoGAP (GTPase-activator protein [GAP] for Rho-like small GTPases) domain of GMIP (Gem interacting protein). GMIP plays important roles in neurite growth and axonal guidance, and interacts with Gem, a member of the RGK subfamily of the Ras small GTPase superfamily, through the N-terminal half of the protein. GMIP contains a C-terminal RhoGAP domain. GMIP inhibits RhoA function, but is inactive towards Rac1 and Cdc41. Small GTPases cluster into distinct families, and all act as molecular switches, active in their GTP-bound form but inactive when GDP-bound. The Rho family of GTPases activates effectors involved in a wide variety of developmental processes, including regulation of cytoskeleton formation, cell proliferation and the JNK signaling pathway. GTPases generally have a low intrinsic GTPase hydrolytic activity but there are family-specific groups of GAPs that enhance the rate of GTP hydrolysis by several orders of magnitude.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907206495 306 EVGFkFVRKCINFIETKGIKTEGLYRTVGSNIQVQKLLYAFFDPKCPGDVdfhnSDWDIKTITSSLKFYLRNLSEPVMTY 385
Cdd:cd04408    15 EVPF-VVVRCTAEIENRALGVQGIYRISGSKARVEKLCQAFENGRDLVDL----SGHSPHDITSVLKHFLKELPEPVLPF 89

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907206495 386 KLHKELVSAAKS---------DNLDYRLGAIHS---LVYKLPEKNREMLELLIKHLVNVCEHSKENLMTPSNMGVIFGPT 453
Cdd:cd04408    90 QLYDDFIALAKElqrdsekaaESPSIVENIIRSlkeLLGRLPVSNYNTLRHLMAHLYRVAERFEDNKMSPNNLGIVFGPT 169

                         170       180       190
                  ....*....|....*....|....*....|.
gi 1907206495 454 LMR---AQEDTVAAMMNIKFQNIVVEILIEH 481
Cdd:cd04408   170 LLRplvGGDVSMICLLDTGYQAQLVEFLISN 200

RhoGAP_Bcr: RhoGAP (GTPase-activator protein [GAP] for Rho-like small GTPases) domain of Bcr (breakpoint cluster region protein)-like proteins. Bcr is a multidomain protein with a variety of enzymatic functions. It contains a RhoGAP and a Rho GEF domain, a Ser/Thr kinase domain, an N-terminal oligomerization domain, and a C-terminal PDZ binding domain, in addition to PH and C2 domains. Bcr is a negative regulator of: i) RacGTPase, via the Rho GAP domain, ii) the Ras-Raf-MEK-ERK pathway, via phosphorylation of the Ras binding protein AF-6, and iii) the Wnt signaling pathway through binding beta-catenin. Bcr can form a complex with beta-catenin and Tcf1. The Wnt signaling pathway is involved in cell proliferation, differentiation, and cell renewal. Bcr was discovered as a fusion partner of Abl. The Bcr-Abl fusion is characteristic for a large majority of chronic myelogenous leukemias (CML). Small GTPases cluster into distinct families, and all act as molecular switches, active in their GTP-bound form but inactive when GDP-bound. The Rho family of GTPases activates effectors involved in a wide variety of developmental processes, including regulation of cytoskeleton formation, cell proliferation and the JNK signaling pathway. GTPases generally have a low intrinsic GTPase hydrolytic activity but there are family-specific groups of GAPs that enhance the rate of GTP hydrolysis by several orders of magnitude.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907206495 296 ITKQEEMELNEVgfkfVRKCINFIETKGIKTEGLYRTVGSNIQVQKLLYAFfdPKCPGDVDFHNSDWDIKTITSSLKFYL 375
Cdd:cd04387     8 VTKRERSKVPYI----VRQCVEEVERRGMEEVGIYRISGVATDIQALKAAF--DTNNKDVSVMLSEMDVNAIAGTLKLYF 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907206495 376 RNLSEPVMTYKLHKELVSAAKSDNLDYRLGAIHSLVYKLPEKNREMLELLIKHLVNVCEHSKENLMTPSNMGVIFGPTLM 455
Cdd:cd04387    82 RELPEPLFTDELYPNFAEGIALSDPVAKESCMLNLLLSLPDPNLVTFLFLLHHLKRVAEREEVNKMSLHNLATVFGPTLL 161

                         170       180
                  ....*....|....*....|....*
gi 1907206495 456 RAQEDTVAAMMNIKFQNIVVEILIE 480
Cdd:cd04387   162 RPSEKESKIPTNTMTDSWSLEVMSQ 186

RhoGAP_ARHGAP22_24_25: GTPase-activator protein (GAP) domain for Rho-like GTPases found in ARHGAP22, 24 and 25-like proteins; longer isoforms of these proteins contain an additional N-terminal pleckstrin homology (PH) domain. ARHGAP25 (KIA0053) has been identified as a GAP for Rac1 and Cdc42. Short isoforms (without the PH domain) of ARHGAP24, called RC-GAP72 and p73RhoGAP, and of ARHGAP22, called p68RacGAP, has been shown to be involved in angiogenesis and endothelial cell capillary formation. Small GTPases cluster into distinct families, and all act as molecular switches, active in their GTP-bound form but inactive when GDP-bound. The Rho family of GTPases activates effectors involved in a wide variety of developmental processes, including regulation of cytoskeleton formation, cell proliferation and the JNK signaling pathway. GTPases generally have a low intrinsic GTPase hydrolytic activity but there are family-specific groups of GAPs that enhance the rate of GTP hydrolysis by several orders of magnitude.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1907206495 312 VRKCINFIETKGIKTEGLYRTVGSNIQVQKLLYAFfdpKCpGDVDFHNSDWDIKTITSSLKFYLRNLSEPVMTYKLHKEL 391
Cdd:cd04390    26 VEQCVDFIREHGLKEEGLFRLPGQANLVKQLQDAF---DA-GERPSFDSDTDVHTVASLLKLYLRELPEPVIPWAQYEDF 101