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 924182086 339 MDGKEPIYHTPITKQ----EEMELNEVGFKFVRKCINFIETKGIKTEGLYRTVGSNIQVQKLLYAFFDPK--CPGDVDFH 412
Cdd:cd04374    1 MDGKEPVYHSPGRLQseveGEAQLDDIGFKFVRKCIEAVETRGINEQGLYRVVGVNSKVQKLLSLGLDPKtsTPGDVDLD 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 924182086 413 NSDWDIKTITSSLKFYLRNLSEPVMTYKLHKELVSAAKSDNLDYRLGAIHSLVYKLPEKNREMLELLIKHLVNVCEHSKE 492
Cdd:cd04374   81 NSEWEIKTITSALKTYLRNLPEPLMTYELHNDFINAAKSENLESRVNAIHSLVHKLPEKNREMLELLIKHLTNVSDHSKK 160

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|...
gi 924182086 493 NLMTPSNMGVIFGPTLMRAQEDTVAAMMNIKFQNIVVEILIEH 535
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 924182086 243 TIEGYLYTQEKWALGISWAKYYCRYEKETRMLTMIPMEQKPGAK-QGPVDLTLKYCVRRKTESIDKRFCFDIETNERPGT 321
Cdd:cd01249    1 TKEGYLYLQEKKPLGSTWTKHYCTYRKESKMFTMIPYNQQSSGKlGTTEVVTLKSCVRRKTDSIDRRFCFDIEVVDRPTV 80

                         90       100
                 ....*....|....*....|....*
gi 924182086 322 ITLQAPSEANRRLWMEAMDGKEPIY 346
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 924182086 339 MDGKEPIYHTPITKQ----EEMELNEVGFKFVRKCINFIETKGIKTEGLYRTVGSNIQVQKLLYAFFDPK--CPGDVDFH 412
Cdd:cd04374    1 MDGKEPVYHSPGRLQseveGEAQLDDIGFKFVRKCIEAVETRGINEQGLYRVVGVNSKVQKLLSLGLDPKtsTPGDVDLD 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 924182086 413 NSDWDIKTITSSLKFYLRNLSEPVMTYKLHKELVSAAKSDNLDYRLGAIHSLVYKLPEKNREMLELLIKHLVNVCEHSKE 492
Cdd:cd04374   81 NSEWEIKTITSALKTYLRNLPEPLMTYELHNDFINAAKSENLESRVNAIHSLVHKLPEKNREMLELLIKHLTNVSDHSKK 160

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|...
gi 924182086 493 NLMTPSNMGVIFGPTLMRAQEDTVAAMMNIKFQNIVVEILIEH 535
Cdd:cd04374  161 NLMTVSNLGVVFGPTLLRPQEETVAAIMDIKFQNIVVEILIEN 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 924182086    6 LEFSDCYLDSPDFRQRLKYYEEELERTNKFIKDVIKDGSALISAMRNYSSAVQKFSQTLQSFQFDFIGDTLTDdeiniaE 85
Cdd:pfam16746   1 LEFEECLKDSPQFRSLLEEHEAELDELEKKLKKLLKLCKRMIEAGKEYSAAQRLFANSLLDFKFEFIGDEETD------E 74

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 924182086   86 SFKEFAELLNEVENERMMM------------------------ERKKKFEKDGERFYSLLDRHLHLSSKKKESQLLEADL 141
Cdd:pfam16746  75 SLKKFSQLLQEMENFHTILldqaqrtiikplenfrkedlkevkELKKKFDKASEKLDAALEKNAQLSKKKKPSELEEADN 154

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 924182086  142 QVDKERHNFFESSLDYVYQIQEVQESKKFNIVEPVLAFLHSLFISNSLTVELTQDFLPYKQQLQLSLQNTRNhfsSTREE 221
Cdd:pfam16746 155 ELAATRKCFHHASLDYVLQINELQERKKFEILEPLLSFMHAQFTFFHQGYELFKDLEPFMKDLQAQLQQTRE---DTREE 231

                  ....
gi 924182086  222 MEEL 225
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 924182086 243 TIEGYLYTQEKWALGISWAKYYCRYEKETRMLTMIPMEQKPGAK-QGPVDLTLKYCVRRKTESIDKRFCFDIETNERPGT 321
Cdd:cd01249    1 TKEGYLYLQEKKPLGSTWTKHYCTYRKESKMFTMIPYNQQSSGKlGTTEVVTLKSCVRRKTDSIDRRFCFDIEVVDRPTV 80

                         90       100
                 ....*....|....*....|....*
gi 924182086 322 ITLQAPSEANRRLWMEAMDGKEPIY 346
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 924182086   242 PTIEGYLYTQEKWALGiSWAKYYCRYeKETRMLTMIPMEQKPGAK-QGPVDLTLKYCVRR-KTESIDKRFCFDIETNERp 319
Cdd:smart00233   1 VIKEGWLYKKSGGGKK-SWKKRYFVL-FNSTLLYYKSKKDKKSYKpKGSIDLSGCTVREApDPDSSKKPHCFEIKTSDR- 77

                           90       100
                   ....*....|....*....|
gi 924182086   320 GTITLQAPSEANRRLWMEAM 339
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 924182086 339 MDGKEPIYHTPITKQ----EEMELNEVGFKFVRKCINFIETKGIKTEGLYRTVGSNIQVQKLLYAFFDPK--CPGDVDFH 412
Cdd:cd04374    1 MDGKEPVYHSPGRLQseveGEAQLDDIGFKFVRKCIEAVETRGINEQGLYRVVGVNSKVQKLLSLGLDPKtsTPGDVDLD 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 924182086 413 NSDWDIKTITSSLKFYLRNLSEPVMTYKLHKELVSAAKSDNLDYRLGAIHSLVYKLPEKNREMLELLIKHLVNVCEHSKE 492
Cdd:cd04374   81 NSEWEIKTITSALKTYLRNLPEPLMTYELHNDFINAAKSENLESRVNAIHSLVHKLPEKNREMLELLIKHLTNVSDHSKK 160

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|...
gi 924182086 493 NLMTPSNMGVIFGPTLMRAQEDTVAAMMNIKFQNIVVEILIEH 535
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 924182086  19 RQRLKYYEEELERTNKFIKDVIKDGSALISAMRNYSSAVQKFSQTLQSFQFDFIGDTLTDDEINIAESFKEFAELLNEVE 98
Cdd:cd07602    1 RENLHEHEAELERTNKAIKELIKECKNLISATKNLSKAQRSFAQTLQNFKFECIGETQTDDEIEIAESLKEFGRLIETVE 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 924182086  99 NERMMM------------------------ERKKKFEKDGERFYSLLDRHLHLSSKKKESQLLEADLQVDKERHNFFESS 154
Cdd:cd07602   81 DERDRMlenaeeqlieplekfrkeqiggakEEKKKFDKETEKFCSSLEKHLNLSTKKKENQLQEADAQLDMERRNFHQAS 160

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|....*..
gi 924182086 155 LDYVYQIQEVQESKKFNIVEPVLAFLHSLFISNSLTVELTQDFLPYK 201
Cdd:cd07602  161 LEYVFKLQEVQERKKFEFVETLLSFMYGWLTFYHQGHEVAKDFKPYL 207

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 924182086  19 RQRLKYYEEELERTNKFIKDVIKDGSALISAMRNYSSAVQKFSQTLQSFQFDFIGDTLTDDEINIAESFKEFAELLNEVE 98
Cdd:cd07634    1 RERLQCHEIELERTNKFIKELIKDGSLLIGALRNLSMAVQKFSQSLQDFQFECIGDAETDDEISIAQSLKEFARLLIAVE 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 924182086  99 NERMMM------------------------ERKKKFEKDGERFYSLLDRHLHLSSKKKESQLLEADLQVDKERHNFFESS 154
Cdd:cd07634   81 EERRRLiqnandvliaplekfrkeqigaakDGKKKFDKESEKYYSILEKHLNLSAKKKESHLQRADTQIDREHQNFYEAS 160

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|....*..
gi 924182086 155 LDYVYQIQEVQESKKFNIVEPVLAFLHSLFISNSLTVELTQDFLPYK 201
Cdd:cd07634  161 LEYVFKIQEVQEKKKFEFVEPLLAFLQGLFTFYHEGYELAQEFAPYK 207

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 924182086  19 RQRLKYYEEELERTNKFIKDVIKDGSALISAMRNYSSAVQKFSQTLQSFQFDFIGDTLTDDEINIAESFKEFAELLNEVE 98
Cdd:cd07635    1 RERIRAHEAELERTNRFIKELLKDGKNLIAATKSLSAAQRKFAHSLRDFKFEFIGDAETDDERCIDASLQEFSNFLKNLE 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 924182086  99 NERMMM------------------------ERKKKFEKDGERFYSLLDRHLHLSSKKKESQLLEADLQVDKERHNFFESS 154
Cdd:cd07635   81 EQREIMalnvtetlikplerfrkeqlgavkEEKKKFDKETEKNYSLLEKHLNLSAKKKEPQLQEADVQVEQNRQHFYELS 160

                        170       180       190       200
                 ....*....|....*....|....*....|....*....|....*..
gi 924182086 155 LDYVYQIQEVQESKKFNIVEPVLAFLHSLFISNSLTVELTQDFLPYK 201
Cdd:cd07635  161 LEYVCKLQEIQERKKFECVEPMLSFFQGVFTFYHQGYELAKDFNHYK 207

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 924182086 243 TIEGYLYTQEKWALGISWAKYYCRYEKETRMLTMIPMEQKPGAK-QGPVDLTLKYCVRRKTESIDKRFCFDIETNERPGT 321
Cdd:cd01249    1 TKEGYLYLQEKKPLGSTWTKHYCTYRKESKMFTMIPYNQQSSGKlGTTEVVTLKSCVRRKTDSIDRRFCFDIEVVDRPTV 80

                         90       100
                 ....*....|....*....|....*
gi 924182086 322 ITLQAPSEANRRLWMEAMDGKEPIY 346
Cdd:cd01249   81 LTLQALSEEDRKLWLEAMDGKEPIY 105

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 924182086  364 KFVRKCINFIETKGIKTEGLYRTVGSNIQVQKLLYAFfdpKCPGDVDFHNSDWDIKTITSSLKFYLRNLSEPVMTYKLHK 443
Cdd:pfam00620   2 LIVRKCVEYLEKRGLDTEGIFRVSGSASRIKELREAF---DRGPDVDLDLEEEDVHVVASLLKLFLRELPEPLLTFELYE 78

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 924182086  444 ELVSAAKSDNLDYRLGAIHSLVYKLPEKNREMLELLIKHLVNVCEHSKENLMTPSNMGVIFGPTLMR 510
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 924182086 366 VRKCINFIETKGIKTEGLYRTVGSNIQVQKLLYAFfdpkcpgDVDFHNSDW------DIKTITSSLKFYLRNLSEPVMTY 439
Cdd:cd04372   20 VDMCIREIEARGLQSEGLYRVSGFAEEIEDVKMAF-------DRDGEKADIsatvypDINVITGALKLYFRDLPIPVITY 92

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 924182086 440 KLHKELVSAAKSDNLDYRLGAIHSLVYKLPEKNREMLELLIKHLVNVCEHSKENLMTPSNMGVIFGPTLMRA-QEDTVAA 518
Cdd:cd04372   93 DTYPKFIDAAKISNPDERLEAVHEALMLLPPAHYETLRYLMEHLKRVTLHEKDNKMNAENLGIVFGPTLMRPpEDSALTT 172

                        170
                 ....*....|....*..
gi 924182086 519 MMNIKFQNIVVEILIEH 535
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 924182086 366 VRKCINFIETKGIKTEGLYRTVGSNIQVQKLLYAFfdPKCPGDVDFHNSDWDIKTITSSLKFYLRNLSEPVMTYKLHKEL 445
Cdd:cd04385   19 VDKCIDFITQHGLMSEGIYRKNGKNSSVKKLLEAF--RKDARSVQLREGEYTVHDVADVLKRFLRDLPDPLLTSELHAEW 96

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 924182086 446 VSAAKSDNLDYRLGAIHSLVYKLPEKNREMLELLIKHLVNVCEHSKENLMTPSNMGVIFGPTLMRAQEDTVA-AMMNIKf 524
Cdd:cd04385   97 IEAAELENKDERIARYKELIRRLPPINRATLKVLIGHLYRVQKHSDENQMSVHNLALVFGPTLFQTDEHSVGqTSHEVK- 175

                        170
                 ....*....|..
gi 924182086 525 qniVVEILIEHF 536
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 924182086 365 FVRKCINFIETKGIKTEGLYRTVGSNIQVQKLLYAFfdPKCPGDVDFHNSDW-DIKTITSSLKFYLRNLSEPVMTYKLHK 443
Cdd:cd04395   21 IVEVCCNIVEARGLETVGIYRVPGNNAAISALQEEL--NRGGFDIDLQDPRWrDVNVVSSLLKSFFRKLPEPLFTNELYP 98

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 924182086 444 ELVSAAKSDNLDYRLGAIHSLVYKLPEKNREMLELLIKHLVNVCEHSKENLMTPSNMGVIFGPTLMRAQEDTVAAMM-NI 522
Cdd:cd04395   99 DFIEANRIEDPVERLKELRRLIHSLPDHHYETLKHLIRHLKTVADNSEVNKMEPRNLAIVFGPTLVRTSDDNMETMVtHM 178

                        170
                 ....*....|...
gi 924182086 523 KFQNIVVEILIEH 535
Cdd:cd04395  179 PDQCKIVETLIQH 191

RhoGAP_nadrin: RhoGAP (GTPase-activator protein [GAP] for Rho-like small GTPases) domain of Nadrin-like proteins. Nadrin, also named Rich-1, has been shown to be involved in the regulation of Ca2+-dependent exocytosis in neurons and recently has been implicated in tight junction maintenance in mammalian epithelium. 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 924182086 366 VRKCINFIETKGIKTEGLYRTVGSNIQVQKLLYAF----FDPKCPgdvDFHNsdwDIKTITSSLKFYLRNLSEPVMTYKL 441
Cdd:cd04386   24 IEACVMCLLETGMNEEGLFRVGGGASKLKRLKAALdagtFSLPLD---EFYS---DPHAVASALKSYLRELPDPLLTYNL 97

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 924182086 442 HKELVSAAKSDNLDYRLGAIHSLVYKLPEKNREMLELLIKHLVNVCEHSKENLMTPSNMGVIFGPTLMRAQEDTVAAMMN 521
Cdd:cd04386   98 YEDWVQAANKPDEDERLQAIWRILNKLPRENRDNLRYLIKFLSKLAQKSDENKMSPSNIAIVLAPNLLWAKNEGSLAEMA 177

                        170       180
                 ....*....|....*....|....
gi 924182086 522 IKFQ---NIVVEILIEHFGKIYLG 542
Cdd:cd04386  178 AGTSvhvVAIVELIISHADWFFPG 201

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 924182086 365 FVRKCINFIETKGIKTEGLYRTVGSNIQVQKLLYAFFDPkcpGDVDFHNSDWDIKTITSSLKFYLRNLSEPVMTYKLHKE 444
Cdd:cd04373   18 FLEKCVEFIEATGLETEGIYRVSGNKTHLDSLQKQFDQD---HNLDLVSKDFTVNAVAGALKSFFSELPDPLIPYSMHLE 94

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 924182086 445 LVSAAKSDNLDYRLGAIHSLVYKLPEKNREMLELLIKHLVNVCEHSKENLMTPSNMGVIFGPTLMRAQEDTVAAMMNIKF 524
Cdd:cd04373   95 LVEAAKINDREQRLHALKELLKKFPPENFDVFKYVITHLNKVSQNSKVNLMTSENLSICFWPTLMRPDFTSMEALSATRI 174

                 ....*....
gi 924182086 525 QNIVVEILI 533
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 924182086 366 VRKCINFIETKGIKTEGLYRTVGSNIQVQKLLYAFfdPKCPGDVDFhnSDWDIKTITSSLKFYLRNLSEPVMTYKLHKEL 445
Cdd:cd04377   19 LEKLLEHIEMHGLYTEGIYRKSGSANKIKELRQGL--DTDPDSVNL--EDYPIHVITSVLKQWLRELPEPLMTFELYENF 94

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 924182086 446 VSAAKSDNLDYRLGAIHSLVYKLPEKNREMLELLIKHLVNVCEHSKENLMTPSNMGVIFGPTLMRAQE--DTVAAMMNIK 523
Cdd:cd04377   95 LRAMELEEKQERVRALYSVLEQLPRANLNTLERLIFHLVRVALQEEVNRMSANALAIVFAPCILRCPDtaDPLQSLQDVS 174

                        170
                 ....*....|.
gi 924182086 524 FQNIVVEILIE 534
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 924182086 360 EVGFkFVRKCINFIETKGIKTEGLYRTVGSNIQVQKLLYAFFDPKCPGDVdfhnSDWDIKTITSSLKFYLRNLSEPVMTY 439
Cdd:cd04408   15 EVPF-VVVRCTAEIENRALGVQGIYRISGSKARVEKLCQAFENGRDLVDL----SGHSPHDITSVLKHFLKELPEPVLPF 89

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 924182086 440 KLHKELVSAAKS---------DNLDYRLGAIHS---LVYKLPEKNREMLELLIKHLVNVCEHSKENLMTPSNMGVIFGPT 507
Cdd:cd04408   90 QLYDDFIALAKElqrdsekaaESPSIVENIIRSlkeLLGRLPVSNYNTLRHLMAHLYRVAERFEDNKMSPNNLGIVFGPT 169

                        170       180       190
                 ....*....|....*....|....*....|.
gi 924182086 508 LMR---AQEDTVAAMMNIKFQNIVVEILIEH 535
Cdd:cd04408  170 LLRplvGGDVSMICLLDTGYQAQLVEFLISN 200