The Bin/Amphiphysin/Rvs (BAR) domain of Oligophrenin-1; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions. Oligophrenin-1 (OPHN1) is a GTPase activating protein (GAP) with activity towards RhoA, Rac, and Cdc42, that is expressed in developing spinal cord and in adult brain areas with high plasticity. It plays a role in regulating the actin cystoskeleton as well as morphology changes in axons and dendrites, and may also function in modulating neuronal connectivity. Mutations in the OPHN1 gene causes X-linked mental retardation associated with cerebellar hypoplasia, lateral ventricle enlargement and epilepsy. OPHN1 contains an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, and a Rho GAP domain. BAR domains form dimers that bind to membranes, induce membrane bending and curvature, and may also be involved in protein-protein interactions.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024496457  19 RERLKCYEQELERTNKFIKDVIKDGNALIAAIRSYSSAVQKFSQTLQSFQFDFIGDTLTDDEINIAESFKEFAELLQEVE 98
Cdd:cd07633     1 RERLKCYEQELERTNKFIKDVIKDGNALISAIKEYSSAVQKFSQTLQSFQFDFIGDTLTDDEINIAESFKEFAELLQEVE 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024496457  99 LERSMMVQNASDLLIKPLENFRKEQIGFTKERKKKFEKDGEKFYSMLDRHLHLSSKKKESQLQEADLQVDKERHNFFESS 178
Cdd:cd07633    81 EERMMMVQNASDLLIKPLENFRKEQIGFTKERKKKFEKDSEKFYSLLDRHVNLSSKKKESQLQEADLQVDKERQNFYESS 160

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|....*..
gi 2024496457 179 LEYVYQIQEVQESKKFSIVEPVLAFLHSLFTYNNLTVELTQDFLPYK 225
Cdd:cd07633   161 LEYVYQIQEVQESKKFDVVEPVLAFLHSLFTSNNLTVELTQDFLPYK 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 2024496457 267 TIEGYLYTQEKWALGISWVKYYCQYEKEAKTLRMTPMDQKPGAKQGT-LDLTLKSCVRRKTDSIDKRFCFDIETNERSGT 345
Cdd:cd01249     1 TKEGYLYLQEKKPLGSTWTKHYCTYRKESKMFTMIPYNQQSSGKLGTtEVVTLKSCVRRKTDSIDRRFCFDIEVVDRPTV 80

                          90       100
                  ....*....|....*....|....*
gi 2024496457 346 ITLQALSEANRRLWMEAMDGKEPIY 370
Cdd:cd01249    81 LTLQALSEEDRKLWLEAMDGKEPIY 105

The Bin/Amphiphysin/Rvs (BAR) domain of Oligophrenin-1; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions. Oligophrenin-1 (OPHN1) is a GTPase activating protein (GAP) with activity towards RhoA, Rac, and Cdc42, that is expressed in developing spinal cord and in adult brain areas with high plasticity. It plays a role in regulating the actin cystoskeleton as well as morphology changes in axons and dendrites, and may also function in modulating neuronal connectivity. Mutations in the OPHN1 gene causes X-linked mental retardation associated with cerebellar hypoplasia, lateral ventricle enlargement and epilepsy. OPHN1 contains an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, and a Rho GAP domain. BAR domains form dimers that bind to membranes, induce membrane bending and curvature, and may also be involved in protein-protein interactions.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024496457  19 RERLKCYEQELERTNKFIKDVIKDGNALIAAIRSYSSAVQKFSQTLQSFQFDFIGDTLTDDEINIAESFKEFAELLQEVE 98
Cdd:cd07633     1 RERLKCYEQELERTNKFIKDVIKDGNALISAIKEYSSAVQKFSQTLQSFQFDFIGDTLTDDEINIAESFKEFAELLQEVE 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024496457  99 LERSMMVQNASDLLIKPLENFRKEQIGFTKERKKKFEKDGEKFYSMLDRHLHLSSKKKESQLQEADLQVDKERHNFFESS 178
Cdd:cd07633    81 EERMMMVQNASDLLIKPLENFRKEQIGFTKERKKKFEKDSEKFYSLLDRHVNLSSKKKESQLQEADLQVDKERQNFYESS 160

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|....*..
gi 2024496457 179 LEYVYQIQEVQESKKFSIVEPVLAFLHSLFTYNNLTVELTQDFLPYK 225
Cdd:cd07633   161 LEYVYQIQEVQESKKFDVVEPVLAFLHSLFTSNNLTVELTQDFLPYK 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 2024496457   6 LEFSDCYLDSPDFRERLKCYEQELERTNKFIKDVIKDGNALIAAIRSYSSAVQKFSQTLQSFQFDFIGDTLTDdeiniaE 85
Cdd:pfam16746   1 LEFEECLKDSPQFRSLLEEHEAELDELEKKLKKLLKLCKRMIEAGKEYSAAQRLFANSLLDFKFEFIGDEETD------E 74

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024496457  86 SFKEFAELLQEVELERSMMVQNASDLLIKPLENFRKEQIGFTKERKKKFEKDGEKFYSMLDRHLHLSSKKKESQLQEADL 165
Cdd:pfam16746  75 SLKKFSQLLQEMENFHTILLDQAQRTIIKPLENFRKEDLKEVKELKKKFDKASEKLDAALEKNAQLSKKKKPSELEEADN 154

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024496457 166 QVDKERHNFFESSLEYVYQIQEVQESKKFSIVEPVLAFLHSLFTYNNLTVELTQDFLPYKQQLQLSLQNTRNhfsSTREE 245
Cdd:pfam16746 155 ELAATRKCFHHASLDYVLQINELQERKKFEILEPLLSFMHAQFTFFHQGYELFKDLEPFMKDLQAQLQQTRE---DTREE 231

                  ....
gi 2024496457 246 LEDL 249
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 2024496457 267 TIEGYLYTQEKWALGISWVKYYCQYEKEAKTLRMTPMDQKPGAKQGT-LDLTLKSCVRRKTDSIDKRFCFDIETNERSGT 345
Cdd:cd01249     1 TKEGYLYLQEKKPLGSTWTKHYCTYRKESKMFTMIPYNQQSSGKLGTtEVVTLKSCVRRKTDSIDRRFCFDIEVVDRPTV 80

                          90       100
                  ....*....|....*....|....*
gi 2024496457 346 ITLQALSEANRRLWMEAMDGKEPIY 370
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 2024496457  266 PTIEGYLYTQEKWALGiSWVKYYCQYekeaKTLRMTPMDQKPGAK----QGTLDLTLKSCVRR-KTDSIDKRFCFDIETN 340
Cdd:smart00233   1 VIKEGWLYKKSGGGKK-SWKKRYFVL----FNSTLLYYKSKKDKKsykpKGSIDLSGCTVREApDPDSSKKPHCFEIKTS 75

                           90       100
                   ....*....|....*....|...
gi 2024496457  341 ERSgTITLQALSEANRRLWMEAM 363
Cdd:smart00233  76 DRK-TLLLQAESEEEREKWVEAL 97

The Bin/Amphiphysin/Rvs (BAR) domain of Oligophrenin-1; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions. Oligophrenin-1 (OPHN1) is a GTPase activating protein (GAP) with activity towards RhoA, Rac, and Cdc42, that is expressed in developing spinal cord and in adult brain areas with high plasticity. It plays a role in regulating the actin cystoskeleton as well as morphology changes in axons and dendrites, and may also function in modulating neuronal connectivity. Mutations in the OPHN1 gene causes X-linked mental retardation associated with cerebellar hypoplasia, lateral ventricle enlargement and epilepsy. OPHN1 contains an N-terminal BAR domain, followed by a Pleckstrin homology (PH) domain, and a Rho GAP domain. BAR domains form dimers that bind to membranes, induce membrane bending and curvature, and may also be involved in protein-protein interactions.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024496457  19 RERLKCYEQELERTNKFIKDVIKDGNALIAAIRSYSSAVQKFSQTLQSFQFDFIGDTLTDDEINIAESFKEFAELLQEVE 98
Cdd:cd07633     1 RERLKCYEQELERTNKFIKDVIKDGNALISAIKEYSSAVQKFSQTLQSFQFDFIGDTLTDDEINIAESFKEFAELLQEVE 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024496457  99 LERSMMVQNASDLLIKPLENFRKEQIGFTKERKKKFEKDGEKFYSMLDRHLHLSSKKKESQLQEADLQVDKERHNFFESS 178
Cdd:cd07633    81 EERMMMVQNASDLLIKPLENFRKEQIGFTKERKKKFEKDSEKFYSLLDRHVNLSSKKKESQLQEADLQVDKERQNFYESS 160

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|....*..
gi 2024496457 179 LEYVYQIQEVQESKKFSIVEPVLAFLHSLFTYNNLTVELTQDFLPYK 225
Cdd:cd07633   161 LEYVYQIQEVQESKKFDVVEPVLAFLHSLFTSNNLTVELTQDFLPYK 207

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 2024496457  19 RERLKCYEQELERTNKFIKDVIKDGNALIAAIRSYSSAVQKFSQTLQSFQFDFIGDTLTDDEINIAESFKEFAELLQEVE 98
Cdd:cd07602     1 RENLHEHEAELERTNKAIKELIKECKNLISATKNLSKAQRSFAQTLQNFKFECIGETQTDDEIEIAESLKEFGRLIETVE 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024496457  99 LERSMMVQNASDLLIKPLENFRKEQIGFTKERKKKFEKDGEKFYSMLDRHLHLSSKKKESQLQEADLQVDKERHNFFESS 178
Cdd:cd07602    81 DERDRMLENAEEQLIEPLEKFRKEQIGGAKEEKKKFDKETEKFCSSLEKHLNLSTKKKENQLQEADAQLDMERRNFHQAS 160

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|....*..
gi 2024496457 179 LEYVYQIQEVQESKKFSIVEPVLAFLHSLFTYNNLTVELTQDFLPYK 225
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 2024496457  19 RERLKCYEQELERTNKFIKDVIKDGNALIAAIRSYSSAVQKFSQTLQSFQFDFIGDTLTDDEINIAESFKEFAELLQEVE 98
Cdd:cd07634     1 RERLQCHEIELERTNKFIKELIKDGSLLIGALRNLSMAVQKFSQSLQDFQFECIGDAETDDEISIAQSLKEFARLLIAVE 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024496457  99 LERSMMVQNASDLLIKPLENFRKEQIGFTKERKKKFEKDGEKFYSMLDRHLHLSSKKKESQLQEADLQVDKERHNFFESS 178
Cdd:cd07634    81 EERRRLIQNANDVLIAPLEKFRKEQIGAAKDGKKKFDKESEKYYSILEKHLNLSAKKKESHLQRADTQIDREHQNFYEAS 160

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|....*..
gi 2024496457 179 LEYVYQIQEVQESKKFSIVEPVLAFLHSLFTYNNLTVELTQDFLPYK 225
Cdd:cd07634   161 LEYVFKIQEVQEKKKFEFVEPLLAFLQGLFTFYHEGYELAQEFAPYK 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 2024496457  19 RERLKCYEQELERTNKFIKDVIKDGNALIAAIRSYSSAVQKFSQTLQSFQFDFIGDTLTDDEINIAESFKEFAELLQEVE 98
Cdd:cd07636     1 RERLKSHEAELDKTNKFIKELIKDGKSLIAALKNLSSAKRKFADSLNEFKFQCIGDAETDDEICIARSLQEFAAVLRNLE 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024496457  99 LERSMMVQNASDLLIKPLENFRKEQIGFTKERKKKFEKDGEKFYSMLDRHLHLSSKKKESQLQEADLQVDKERHNFFESS 178
Cdd:cd07636    81 DERTRMIENASEVLITPLEKFRKEQIGAAKEAKKKYDKETEKYCAVLEKHLNLSSKKKESQLHEADSQVDLVRQHFYEVS 160

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|....*..
gi 2024496457 179 LEYVYQIQEVQESKKFSIVEPVLAFLHSLFTYNNLTVELTQDFLPYK 225
Cdd:cd07636   161 LEYVFKVQEVQERKMFEFVEPLLAFLQGLFTFYHHGYELAKDFSDFK 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 2024496457 267 TIEGYLYTQEKWALGISWVKYYCQYEKEAKTLRMTPMDQKPGAKQGT-LDLTLKSCVRRKTDSIDKRFCFDIETNERSGT 345
Cdd:cd01249     1 TKEGYLYLQEKKPLGSTWTKHYCTYRKESKMFTMIPYNQQSSGKLGTtEVVTLKSCVRRKTDSIDRRFCFDIEVVDRPTV 80

                          90       100
                  ....*....|....*....|....*
gi 2024496457 346 ITLQALSEANRRLWMEAMDGKEPIY 370
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 2024496457 388 KFVRKCINAVETKGISTEGVYRTVGSNIQVQKLLNAFfdpKCPGDVDLQSSEWDIKTITSSLKFYLRNLSEPVMTYKLHK 467
Cdd:pfam00620   2 LIVRKCVEYLEKRGLDTEGIFRVSGSASRIKELREAF---DRGPDVDLDLEEEDVHVVASLLKLFLRELPEPLLTFELYE 78

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 2024496457 468 ELVLAAKSENLDYRLGAIHALVYKLPDKNREMLELLIRHLVNVCEHSRENLMSPSNMGVIFGPTLMR 534
Cdd:pfam00620  79 EFIEAAKLPDEEERLEALRELLRKLPPANRDTLRYLLAHLNRVAQNSDVNKMNAHNLAIVFGPTLLR 145

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 2024496457 388 KFVRKCINAVETKGISTEGVYRTVGSNIQVQKLLNAFfdPKCPGDVD-LQSSEW--DIKTITSSLKFYLRNLSEPVMTYK 464
Cdd:cd04398    18 NIVYQCIQAIENFGLNLEGIYRLSGNVSRVNKLKELF--DKDPLNVLlISPEDYesDIHSVASLLKLFFRELPEPLLTKA 95

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024496457 465 LHKELVLAAKSENLDYRLGAIHALVYKLPDKNREMLELLIRHLVNVCEHSRENLMSPSNMGVIFGPTLMRAQEDTVAAMm 544
Cdd:cd04398    96 LSREFIEAAKIEDESRRRDALHGLINDLPDANYATLRALMFHLARIKEHESVNRMSVNNLAIIWGPTLMNAAPDNAADM- 174

                         170       180
                  ....*....|....*....|
gi 2024496457 545 niKFQNIVVEILIEHFGKIY 564
Cdd:cd04398   175 --SFQSRVIETLLDNAYQIF 192

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 2024496457 389 FVRKCINAVETKGISTEGVYRTVGSN---IQVQKLLNaffdpKCPGDVDLQSSEW-DIKTITSSLKFYLRNLSEPVMTYK 464
Cdd:cd04395    21 IVEVCCNIVEARGLETVGIYRVPGNNaaiSALQEELN-----RGGFDIDLQDPRWrDVNVVSSLLKSFFRKLPEPLFTNE 95

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024496457 465 LHKELVLAAKSENLDYRLGAIHALVYKLPDKNREMLELLIRHLVNVCEHSRENLMSPSNMGVIFGPTLMRAQEDTVAAMM 544
Cdd:cd04395    96 LYPDFIEANRIEDPVERLKELRRLIHSLPDHHYETLKHLIRHLKTVADNSEVNKMEPRNLAIVFGPTLVRTSDDNMETMV 175

                         170
                  ....*....|....*.
gi 2024496457 545 -NIKFQNIVVEILIEH 559
Cdd:cd04395   176 tHMPDQCKIVETLIQH 191

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 2024496457 384 EVGFkFVRKCINAVETKGISTEGVYRTVGSNIQVQKLLNAFFDPKcpGDVDLqsSEWDIKTITSSLKFYLRNLSEPVMTY 463
Cdd:cd04378    15 EVPF-IIKKCTSEIENRALGVQGIYRVSGSKARVEKLCQAFENGK--DLVEL--SELSPHDISSVLKLFLRQLPEPLILF 89

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024496457 464 KLHKELV-LAAKSENLDYRLGA-------------IHALVYKLPDKNREMLELLIRHLVNVCEHSRENLMSPSNMGVIFG 529
Cdd:cd04378    90 RLYNDFIaLAKEIQRDTEEDKApntpievnriirkLKDLLRQLPASNYNTLQHLIAHLYRVAEQFEENKMSPNNLGIVFG 169

                         170       180       190
                  ....*....|....*....|....*....|....
gi 2024496457 530 PTLMR----AQEDTVAAMMNIKFQNIVVEILIEH 559
Cdd:cd04378   170 PTLIRprpgDADVSLSSLVDYGYQARLVEFLITN 203

The Bin/Amphiphysin/Rvs (BAR) domain, a dimerization module that binds membranes and detects membrane curvature; BAR domains are dimerization, lipid binding and curvature sensing modules found in many different proteins with diverse functions including organelle biogenesis, membrane trafficking or remodeling, and cell division and migration. Mutations in BAR containing proteins have been linked to diseases and their inactivation in cells leads to altered membrane dynamics. A BAR domain with an additional N-terminal amphipathic helix (an N-BAR) can drive membrane curvature. These N-BAR domains are found in amphiphysins and endophilins, among others. BAR domains are also frequently found alongside domains that determine lipid specificity, such as the Pleckstrin Homology (PH) and Phox Homology (PX) domains which are present in beta centaurins (ACAPs and ASAPs) and sorting nexins, respectively. A FES-CIP4 Homology (FCH) domain together with a coiled coil region is called the F-BAR domain and is present in Pombe/Cdc15 homology (PCH) family proteins, which include Fes/Fes tyrosine kinases, PACSIN or syndapin, CIP4-like proteins, and srGAPs, among others. The Inverse (I)-BAR or IRSp53/MIM homology Domain (IMD) is found in multi-domain proteins, such as IRSp53 and MIM, that act as scaffolding proteins and transducers of a variety of signaling pathways that link membrane dynamics and the underlying actin cytoskeleton. BAR domains form dimers that bind to membranes, induce membrane bending and curvature, and may also be involved in protein-protein interactions. The I-BAR domain induces membrane protrusions in the opposite direction compared to classical BAR and F-BAR domains, which produce membrane invaginations. BAR domains that also serve as protein interaction domains include those of arfaptin and OPHN1-like proteins, among others, which bind to Rac and Rho GAP domains, respectively.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024496457  28 ELERTNKFIKDVIKDGNALIAAIRSYSSAVQKFSQTLQSFQFDFIGDTLTDdeinIAESFKEFAELLQEVELERSMMVQN 107
Cdd:cd07307     1 KLDELEKLLKKLIKDTKKLLDSLKELPAAAEKLSEALQELGKELPDLSNTD----LGEALEKFGKIQKELEEFRDQLEQK 76

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024496457 108 ASDLLIKPLENFRKEQIGFTKERKKKFEKDGEKFYSMLDRHLHLS-SKKKESQLQEADLQVDKERHNFFESSLEYVYQIQ 186
Cdd:cd07307    77 LENKVIEPLKEYLKKDLKEIKKRRKKLDKARLDYDAAREKLKKLRkKKKDSSKLAEAEEELQEAKEKYEELREELIEDLN 156

                         170       180       190
                  ....*....|....*....|....*....|....*...
gi 2024496457 187 EVQESKKFSIVEPVLAFLHSLFTYNNLTVELTQDFLPY 224
Cdd:cd07307   157 KLEEKRKELFLSLLLSFIEAQSEFFKEVLKILEQLLPY 194

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 2024496457 390 VRKCINAVETKGISTEGVYRTVGSNIQVQKLLNAF----FDPKCPGDVDlqssewDIKTITSSLKFYLRNLSEPVMTYKL 465
Cdd:cd04386    24 IEACVMCLLETGMNEEGLFRVGGGASKLKRLKAALdagtFSLPLDEFYS------DPHAVASALKSYLRELPDPLLTYNL 97

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024496457 466 HKELVLAAKSENLDYRLGAIHALVYKLPDKNREMLELLIRHLVNVCEHSRENLMSPSNMGVIFGPTLMRAQEDTVAAMMN 545
Cdd:cd04386    98 YEDWVQAANKPDEDERLQAIWRILNKLPRENRDNLRYLIKFLSKLAQKSDENKMSPSNIAIVLAPNLLWAKNEGSLAEMA 177

                         170       180
                  ....*....|....*....|....
gi 2024496457 546 IKFQ---NIVVEILIEHFGKIYSG 566
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 2024496457 389 FVRKCINAVETKGISTEGVYRTVGSNIQVQKLLNAFFDPkcpGDVDLQSSEWDIKTITSSLKFYLRNLSEPVMTYKLHKE 468
Cdd:cd04373    18 FLEKCVEFIEATGLETEGIYRVSGNKTHLDSLQKQFDQD---HNLDLVSKDFTVNAVAGALKSFFSELPDPLIPYSMHLE 94

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024496457 469 LVLAAKSENLDYRLGAIHALVYKLPDKNREMLELLIRHLVNVCEHSRENLMSPSNMGVIFGPTLMRAQEDTVAAMMNIKF 548
Cdd:cd04373    95 LVEAAKINDREQRLHALKELLKKFPPENFDVFKYVITHLNKVSQNSKVNLMTSENLSICFWPTLMRPDFTSMEALSATRI 174

                  ....*....
gi 2024496457 549 QNIVVEILI 557
Cdd:cd04373   175 YQTIIETFI 183

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 2024496457 390 VRKCINAVETKGISTEGVYRTVGsNIQVQKLLNAFFDPKCPgdVDLQSSEwDIKTITSSLKFYLRNLSEPVMTYKLHKEL 469
Cdd:cd04404    27 VRETVEYLQAHALTTEGIFRRSA-NTQVVKEVQQKYNMGEP--VDFDQYE-DVHLPAVILKTFLRELPEPLLTFDLYDDI 102

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2024496457 470 VLAAKSENLDyRLGAIHALVYKLPDKNREMLELLIRHLVNVCEHSRENLMSPSNMGVIFGPTLMRA--QEDTVAAMMNIk 547
Cdd:cd04404   103 VGFLNVDKEE-RVERVKQLLQTLPEENYQVLKYLIKFLVQVSAHSDQNKMTNSNLAVVFGPNLLWAkdASMSLSAINPI- 180

                         170
                  ....*....|....*..
gi 2024496457 548 fqNIVVEILIEHFGKIY 564
Cdd:cd04404   181 --NTFTKFLLDHQDEIF 195

RhoGAP_myosin_IXB: RhoGAP (GTPase-activator protein [GAP] for Rho-like small GTPases) domain present in myosins IXB. Class IX myosins contain a characteristic head domain, a neck domain and a tail domain which contains a C6H2-zinc binding motif and a Rho-GAP 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 2024496457 390 VRKCINAVETKGISTEGVYRTVGSNIQVQKLLNAFfdPKCPGDVDLQssEWDIKTITSSLKFYLRNLSEPVMTYKLHKEL 469
Cdd:cd04407    19 LEKLLEHVEMHGLYTEGIYRKSGSANRMKELHQLL--QADPENVKLE--NYPIHAITGLLKQWLRELPEPLMTFAQYNDF 94