RhoGAP: GTPase-activator protein (GAP) for Rho-like GTPases; GAPs towards Rho/Rac/Cdc42-like small GTPases. Small GTPases (G proteins) cluster into distinct families, and all act as molecular switches, active in their GTP-bound form but inactive when bound to GDP. The Rho family of small G proteins, which includes Cdc42Hs, activates effectors involved in a wide variety of developmental processes, including regulation of cytoskeleton formation, cell proliferation and the JNK signaling pathway. G proteins 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. The RhoGAPs are one of the major classes of regulators of Rho G proteins.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45555251  374 MDGTEPTYLAPGKIK--VSEAYHLDEAGFMFIRRCIQVLEIRGLEDEGIYRKSGVGTKISKLLALGLNQKESDDVFVDDK 451
Cdd:cd04374    1 MDGKEPVYHSPGRLQseVEGEAQLDDIGFKFVRKCIEAVETRGINEQGLYRVVGVNSKVQKLLSLGLDPKTSTPGDVDLD 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45555251  452 YRDlMESNTIASALKMYLRNLNEPLMTYQYHSDFIEAAKQETLNQRVNEVHKLVYKLPQPNFQMLDMVICHLTDVSRKYE 531
Cdd:cd04374   81 NSE-WEIKTITSALKTYLRNLPEPLMTYELHNDFINAAKSENLESRVNAIHSLVHKLPEKNREMLELLIKHLTNVSDHSK 159

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|....
gi 45555251  532 KNKMSVFNLGVVFGPTLLRPREESVAAILDIKFNNIVINILIDN 575
Cdd:cd04374  160 KNLMTVSNLGVVFGPTLLRPQEETVAAIMDIKFQNIVVEILIEN 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 45555251  273 TKRGYLFLMEKKPFKATWTKYYCTFKKQKREFTMLQFNQMnhnfTRPEARDDEKLTLFSCQRRASE-FEKRFCFDLTFKE 351
Cdd:cd01249    1 TKEGYLYLQEKKPLGSTWTKHYCTYRKESKMFTMIPYNQQ----SSGKLGTTEVVTLKSCVRRKTDsIDRRFCFDIEVVD 76

                         90       100       110
                 ....*....|....*....|....*....|
gi 45555251  352 KPGvVYTFQALSEKDHRYWISAMDGTEPTY 381
Cdd:cd01249   77 RPT-VLTLQALSEEDRKLWLEAMDGKEPIY 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 45555251  374 MDGTEPTYLAPGKIK--VSEAYHLDEAGFMFIRRCIQVLEIRGLEDEGIYRKSGVGTKISKLLALGLNQKESDDVFVDDK 451
Cdd:cd04374    1 MDGKEPVYHSPGRLQseVEGEAQLDDIGFKFVRKCIEAVETRGINEQGLYRVVGVNSKVQKLLSLGLDPKTSTPGDVDLD 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45555251  452 YRDlMESNTIASALKMYLRNLNEPLMTYQYHSDFIEAAKQETLNQRVNEVHKLVYKLPQPNFQMLDMVICHLTDVSRKYE 531
Cdd:cd04374   81 NSE-WEIKTITSALKTYLRNLPEPLMTYELHNDFINAAKSENLESRVNAIHSLVHKLPEKNREMLELLIKHLTNVSDHSK 159

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|....
gi 45555251  532 KNKMSVFNLGVVFGPTLLRPREESVAAILDIKFNNIVINILIDN 575
Cdd:cd04374  160 KNLMTVSNLGVVFGPTLLRPQEETVAAIMDIKFQNIVVEILIEN 203

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 45555251     14 LEFEECIVDSPDFRENLNRHEKELDHTSHQIKRIIKEVKDLMSAAKILSTRMKQLAILLNDFNFECIGTAQTDdenvicE 93
Cdd:pfam16746    1 LEFEECLKDSPQFRSLLEEHEAELDELEKKLKKLLKLCKRMIEAGKEYSAAQRLFANSLLDFKFEFIGDEETD------E 74

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45555251     94 SLKRFGAIIGNIEDEREKMLTLADKHIIESLEDFRKKQIGGVKENKKKFDKKTEKFCQSQERFLNMSTKKPENTIQEADA 173
Cdd:pfam16746   75 SLKKFSQLLQEMENFHTILLDQAQRTIIKPLENFRKEDLKEVKELKKKFDKASEKLDAALEKNAQLSKKKKPSELEEADN 154

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45555251    174 SLGMHEREYIQESLSYVLRIQEVQERIKFEFVEILLAFISGWLVFYHTAHEQAEDHRDYLQDLRHKVQKTRenfEEAREK 253
Cdd:pfam16746  155 ELAATRKCFHHASLDYVLQINELQERKKFEILEPLLSFMHAQFTFFHQGYELFKDLEPFMKDLQAQLQQTR---EDTREE 231

                   ....
gi 45555251    254 VTEL 257
Cdd:pfam16746  232 KEEL 235

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 45555251  273 TKRGYLFLMEKKPFKATWTKYYCTFKKQKREFTMLQFNQMnhnfTRPEARDDEKLTLFSCQRRASE-FEKRFCFDLTFKE 351
Cdd:cd01249    1 TKEGYLYLQEKKPLGSTWTKHYCTYRKESKMFTMIPYNQQ----SSGKLGTTEVVTLKSCVRRKTDsIDRRFCFDIEVVD 76

                         90       100       110
                 ....*....|....*....|....*....|
gi 45555251  352 KPGvVYTFQALSEKDHRYWISAMDGTEPTY 381
Cdd:cd01249   77 RPT-VLTLQALSEEDRKLWLEAMDGKEPIY 105

Src Homology 3 domain of GTPase Regulator Associated with Focal adhesion kinase and similar proteins; This subfamily is composed of Rho GTPase activating proteins (GAPs) with similarity to GRAF. Members contain an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, a Rho GAP domain, and a C-terminal SH3 domain. Although vertebrates harbor four Rho GAPs in the GRAF subfamily including GRAF, GRAF2, GRAF3, and Oligophrenin-1 (OPHN1), only three are included in this model. OPHN1 contains the BAR, PH and GAP domains, but not the C-terminal SH3 domain. GRAF and GRAF2 show GAP activity towards RhoA and Cdc42. GRAF influences Rho-mediated cytoskeletal rearrangements and binds focal adhesion kinase. GRAF2 regulates caspase-activated p21-activated protein kinase-2. The SH3 domain of GRAF and GRAF2 binds PKNbeta, a target of the small GTPase Rho. SH3 domains bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs; they play a role in the regulation of enzymes by intramolecular interactions, changing the subcellular localization of signal pathway components and mediate multiprotein complex assemblies.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....
gi 45555251  958 RVRTLYACMGESEGELSFEPNQIITNVRYSHEPGWLQGTLNGKTGLIPENYVEH 1011
Cdd:cd11882    1 RARALYACKAEDESELSFEPGQIITNVQPSDEPGWLEGTLNGRTGLIPENYVEF 54

Variant SH3 domain;

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|..
gi 45555251    969 SEGELSFEPNQIITNVRySHEPGWLQGTLNGKTGLIPENYVE 1010
Cdd:pfam14604    9 DDDELSLQRGDVITVIE-ESEDGWWEGINTGRTGLVPANYVE 49

PH domain; PH stands for pleckstrin homology.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45555251    273 TKRGYLfLMEKKPFKATWTKYYCTFKKQkrEFTMLQFNQMNHNFTRPEARDdekLTLFSCQRRA--SEFEKRFCFDLTFK 350
Cdd:pfam00169    2 VKEGWL-LKKGGGKKKSWKKRYFVLFDG--SLLYYKDDKSGKSKEPKGSIS---LSGCEVVEVVasDSPKRKFCFELRTG 75

                           90       100
                   ....*....|....*....|....*
gi 45555251    351 EKPGV-VYTFQALSEKDHRYWISAM 374
Cdd:pfam00169   76 ERTGKrTYLLQAESEEERKDWIKAI 100

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 45555251  374 MDGTEPTYLAPGKIK--VSEAYHLDEAGFMFIRRCIQVLEIRGLEDEGIYRKSGVGTKISKLLALGLNQKESDDVFVDDK 451
Cdd:cd04374    1 MDGKEPVYHSPGRLQseVEGEAQLDDIGFKFVRKCIEAVETRGINEQGLYRVVGVNSKVQKLLSLGLDPKTSTPGDVDLD 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45555251  452 YRDlMESNTIASALKMYLRNLNEPLMTYQYHSDFIEAAKQETLNQRVNEVHKLVYKLPQPNFQMLDMVICHLTDVSRKYE 531
Cdd:cd04374   81 NSE-WEIKTITSALKTYLRNLPEPLMTYELHNDFINAAKSENLESRVNAIHSLVHKLPEKNREMLELLIKHLTNVSDHSK 159

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|....
gi 45555251  532 KNKMSVFNLGVVFGPTLLRPREESVAAILDIKFNNIVINILIDN 575
Cdd:cd04374  160 KNLMTVSNLGVVFGPTLLRPQEETVAAIMDIKFQNIVVEILIEN 203

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 45555251     14 LEFEECIVDSPDFRENLNRHEKELDHTSHQIKRIIKEVKDLMSAAKILSTRMKQLAILLNDFNFECIGTAQTDdenvicE 93
Cdd:pfam16746    1 LEFEECLKDSPQFRSLLEEHEAELDELEKKLKKLLKLCKRMIEAGKEYSAAQRLFANSLLDFKFEFIGDEETD------E 74

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45555251     94 SLKRFGAIIGNIEDEREKMLTLADKHIIESLEDFRKKQIGGVKENKKKFDKKTEKFCQSQERFLNMSTKKPENTIQEADA 173
Cdd:pfam16746   75 SLKKFSQLLQEMENFHTILLDQAQRTIIKPLENFRKEDLKEVKELKKKFDKASEKLDAALEKNAQLSKKKKPSELEEADN 154

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45555251    174 SLGMHEREYIQESLSYVLRIQEVQERIKFEFVEILLAFISGWLVFYHTAHEQAEDHRDYLQDLRHKVQKTRenfEEAREK 253
Cdd:pfam16746  155 ELAATRKCFHHASLDYVLQINELQERKKFEILEPLLSFMHAQFTFFHQGYELFKDLEPFMKDLQAQLQQTR---EDTREE 231

                   ....
gi 45555251    254 VTEL 257
Cdd:pfam16746  232 KEEL 235

The Bin/Amphiphysin/Rvs (BAR) domain of GTPase Regulator Associated with Focal adhesion 2; 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 2 (GRAF2), also called Rho GTPase activating protein 10 (ARHGAP10) or PS-GAP, is a GAP with activity towards Cdc42 and RhoA which regulates caspase-activated p21-activated protein kinase-2 (PAK-2p34). GRAF2 interacts with PAK-2p34, leading to its stabilization and decrease of cell death. It is highly expressed in skeletal muscle and also interacts with PKNbeta, which is a target of Rho. GRAF2 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 the related protein 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 45555251   27 RENLNRHEKELDHTSHQIKRIIKEVKDLMSAAKILSTRMKQLAILLNDFNFECIGTAQTDDENVICESLKRFGAIIGNIE 106
Cdd:cd07635    1 RERIRAHEAELERTNRFIKELLKDGKNLIAATKSLSAAQRKFAHSLRDFKFEFIGDAETDDERCIDASLQEFSNFLKNLE 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45555251  107 DEREKMLTLADKHIIESLEDFRKKQIGGVKENKKKFDKKTEKFCQSQERFLNMSTKKPENTIQEADASLGMHEREYIQES 186
Cdd:cd07635   81 EQREIMALNVTETLIKPLERFRKEQLGAVKEEKKKFDKETEKNYSLLEKHLNLSAKKKEPQLQEADVQVEQNRQHFYELS 160

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|....*.
gi 45555251  187 LSYVLRIQEVQERIKFEFVEILLAFISGWLVFYHTAHEQAEDHRDY 232
Cdd:cd07635  161 LEYVCKLQEIQERKKFECVEPMLSFFQGVFTFYHQGYELAKDFNHY 206

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 45555251     401 MFIRRCIQVLEIRGLEDEGIYRKSGVGTKISKLLALgLNQKESDDVFVDDkyrdlMESNTIASALKMYLRNLNEPLMTYQ 480
Cdd:smart00324    5 IIVEKCIEYLEKRGLDTEGIYRVSGSKSRVKELRDA-FDSGPDPDLDLSE-----YDVHDVAGLLKLFLRELPEPLITYE 78

                            90       100       110       120       130       140       150       160
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45555251     481 YHSDFIEAAKQETLNQRVNEVHKLVYKLPQPNFQMLDMVICHLTDVSRKYEKNKMSVFNLGVVFGPTLLRPREESVAAIL 560
Cdd:smart00324   79 LYEEFIEAAKLEDETERLRALRELLSLLPPANRATLRYLLAHLNRVAEHSEENKMTARNLAIVFGPTLLRPPDGEVASLK 158

                           170
                    ....*....|....*.
gi 45555251     561 DIKFNNIVINILIDNY 576
Cdd:smart00324  159 DIRHQNTVIEFLIENA 174

RhoGAP: GTPase-activator protein (GAP) for Rho-like GTPases; GAPs towards Rho/Rac/Cdc42-like small GTPases. Small GTPases (G proteins) cluster into distinct families, and all act as molecular switches, active in their GTP-bound form but inactive when bound to GDP. The Rho family of small G proteins, which includes Cdc42Hs, activates effectors involved in a wide variety of developmental processes, including regulation of cytoskeleton formation, cell proliferation and the JNK signaling pathway. G proteins 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. The RhoGAPs are one of the major classes of regulators of Rho G proteins.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45555251  401 MFIRRCIQVLEIRGLEDEGIYRKSGVGTKISKLLALGlnqkESDDVFVDDKYRDLmesNTIASALKMYLRNLNEPLMTYQ 480
Cdd:cd00159    2 LIIEKCIEYLEKNGLNTEGIFRVSGSASKIEELKKKF----DRGEDIDDLEDYDV---HDVASLLKLYLRELPEPLIPFE 74

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45555251  481 YHSDFIEAAKQETLNQRVNEVHKLVYKLPQPNFQMLDMVICHLTDVSRKYEKNKMSVFNLGVVFGPTLLRPREESVAAIL 560
Cdd:cd00159   75 LYDEFIELAKIEDEEERIEALKELLKSLPPENRDLLKYLLKLLHKISQNSEVNKMTASNLAIVFAPTLLRPPDSDDELLE 154

                        170
                 ....*....|....*
gi 45555251  561 DIKFNNIVINILIDN 575
Cdd:cd00159  155 DIKKLNEIVEFLIEN 169

RhoGAP_fRGD1: RhoGAP (GTPase-activator protein [GAP] for Rho-like small GTPases) domain of fungal RGD1-like proteins. Yeast Rgd1 is a GAP protein for Rho3 and Rho4 and plays a role in low-pH response. 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 45555251  401 MFIRRCIQVLEIRGLEDEGIYRKSGVGTKISKLLALglNQKESDDVFVDDKYRDLMESNTIASALKMYLRNLNEPLMTYQ 480
Cdd:cd04398   18 NIVYQCIQAIENFGLNLEGIYRLSGNVSRVNKLKEL--FDKDPLNVLLISPEDYESDIHSVASLLKLFFRELPEPLLTKA 95

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45555251  481 YHSDFIEAAKQETLNQRVNEVHKLVYKLPQPNFQMLDMVICHLTDVSRKYEKNKMSVFNLGVVFGPTLLRPREESVAail 560
Cdd:cd04398   96 LSREFIEAAKIEDESRRRDALHGLINDLPDANYATLRALMFHLARIKEHESVNRMSVNNLAIIWGPTLMNAAPDNAA--- 172

                        170       180
                 ....*....|....*....|
gi 45555251  561 DIKFNNIVINILIDNYERIF 580
Cdd:cd04398  173 DMSFQSRVIETLLDNAYQIF 192

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 45555251  401 MFIRRCIQVLEIRGLEDEGIYRKSGVGTKISKL-LALGLNQKESDdvFVDDKYRDLmesNTIASALKMYLRNLNEPLMTY 479
Cdd:cd04372   18 MVVDMCIREIEARGLQSEGLYRVSGFAEEIEDVkMAFDRDGEKAD--ISATVYPDI---NVITGALKLYFRDLPIPVITY 92

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45555251  480 QYHSDFIEAAKQETLNQRVNEVHKLVYKLPQPNFQMLDMVICHLTDVSRKYEKNKMSVFNLGVVFGPTLLRPREESVAAI 559
Cdd:cd04372   93 DTYPKFIDAAKISNPDERLEAVHEALMLLPPAHYETLRYLMEHLKRVTLHEKDNKMNAENLGIVFGPTLMRPPEDSALTT 172

                        170       180
                 ....*....|....*....|..
gi 45555251  560 L-DIKFNNIVINILIDNYERIF 580
Cdd:cd04372  173 LnDMRYQILIVQLLITNEDVLF 194

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 45555251  401 MFIRRCIQVLEIRGLEDEGIYRKSGVGTKISKLLALgLNQKESDDVFVDDKYRDLmesNTIASALKMYLRNLNEPLMTYQ 480
Cdd:cd04395   20 LIVEVCCNIVEARGLETVGIYRVPGNNAAISALQEE-LNRGGFDIDLQDPRWRDV---NVVSSLLKSFFRKLPEPLFTNE 95

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45555251  481 YHSDFIEAAKQETLNQRVNEVHKLVYKLPQPNFQMLDMVICHLTDVSRKYEKNKMSVFNLGVVFGPTLLRPREESVA-AI 559
Cdd:cd04395   96 LYPDFIEANRIEDPVERLKELRRLIHSLPDHHYETLKHLIRHLKTVADNSEVNKMEPRNLAIVFGPTLVRTSDDNMEtMV 175

                        170       180
                 ....*....|....*....|.
gi 45555251  560 LDIKFNNIVINILIDNYERIF 580
Cdd:cd04395  176 THMPDQCKIVETLIQHYDWFF 196

RhoGAP_GMIP_PARG1: RhoGAP (GTPase-activator protein [GAP] for Rho-like small GTPases) domain of GMIP (Gem interacting protein) and PARG1 (PTPL1-associated RhoGAP1). 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. PARG1 interacts with Rap2, also a member of the Ras small GTPase superfamily whose exact function is unknown, and shows strong preference for Rho. 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 45555251  396 DEAGFMfIRRCIQVLEIRGLEDEGIYRKSGVGTKISKLLALGLNQKEsddvFVDdkyrdLME--SNTIASALKMYLRNLN 473
Cdd:cd04378   14 DEVPFI-IKKCTSEIENRALGVQGIYRVSGSKARVEKLCQAFENGKD----LVE-----LSElsPHDISSVLKLFLRQLP 83

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45555251  474 EPLMTYQYHSDFIEAAKQ--------------ETLNQRVNEVHKLVYKLPQPNFQMLDMVICHLTDVSRKYEKNKMSVFN 539
Cdd:cd04378   84 EPLILFRLYNDFIALAKEiqrdteedkapntpIEVNRIIRKLKDLLRQLPASNYNTLQHLIAHLYRVAEQFEENKMSPNN 163

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|
gi 45555251  540 LGVVFGPTLLRPR----EESVAAILDIKFNNIVINILIDN 575
Cdd:cd04378  164 LGIVFGPTLIRPRpgdaDVSLSSLVDYGYQARLVEFLITN 203

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 45555251  403 IRRCIQVLEIRGLEDEGIYRKSGVGTKISKL-LALGLNQKEsddvfVDDKYRDlMESNTIASALKMYLRNLNEPLMTYQY 481
Cdd:cd04387   20 VRQCVEEVERRGMEEVGIYRISGVATDIQALkAAFDTNNKD-----VSVMLSE-MDVNAIAGTLKLYFRELPEPLFTDEL 93

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 45555251  482 HSDFIEAAKQETLNQRVNEVHKLVYKLPQPNFQMLDMVICHLTDVSRKYEKNKMSVFNLGVVFGPTLLRPREESV 556
Cdd:cd04387   94 YPNFAEGIALSDPVAKESCMLNLLLSLPDPNLVTFLFLLHHLKRVAEREEVNKMSLHNLATVFGPTLLRPSEKES 168

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 45555251  401 MFIRRCIQVLEIRGLEDEGIYRKSGVGTKISKLlalglnQKEsddvFVDDKYRDLMES----NTIASALKMYLRNLNEPL 476
Cdd:cd04373   17 IFLEKCVEFIEATGLETEGIYRVSGNKTHLDSL------QKQ----FDQDHNLDLVSKdftvNAVAGALKSFFSELPDPL 86

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 45555251  477 MTYQYHSDFIEAAKQETLNQRVNEVHKLVYKLPQPNFQMLDMVICHLTDVSRKYEKNKMSVFNLGVVFGPTLLRPREESV 556
Cdd:cd04373   87 IPYSMHLELVEAAKINDREQRLHALKELLKKFPPENFDVFKYVITHLNKVSQNSKVNLMTSENLSICFWPTLMRPDFTSM 166

                        170
                 ....*....|....*....
gi 45555251  557 AAILDIKFNNIVINILIDN 575
Cdd:cd04373  167 EALSATRIYQTIIETFIQQ 185

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 45555251  403 IRRCIQVLEIRGLEDEGIYRKSGVGTKIsKLLALGLnQKESDDVFVDDkyrdlMESNTIASALKMYLRNLNEPLMTYQYH 482
Cdd:cd04377   19 LEKLLEHIEMHGLYTEGIYRKSGSANKI-KELRQGL-DTDPDSVNLED-----YPIHVITSVLKQWLRELPEPLMTFELY 91

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 45555251  483 SDFIEAAKQETLNQRVNEVHKLVYKLPQPNFQMLDMVICHLTDVSRKYEKNKMSVFNLGVVFGPTLLR 550
Cdd:cd04377   92 ENFLRAMELEEKQERVRALYSVLEQLPRANLNTLERLIFHLVRVALQEEVNRMSANALAIVFAPCILR 159