Collybistin/APC-stimulated guanine nucleotide exchange factor pleckstrin homology (PH) domain; Collybistin (also called PEM2) is homologous to the Dbl proteins ASEF (also called ARHGEF4/RhoGEF4) and SPATA13 (Spermatogenesis-associated protein 13; also called ASEF2). It activates CDC42 specifically and not any other Rho-family GTPases. Collybistin consists of an SH3 domain, followed by a RhoGEF/DH and PH domain. In Dbl proteins, the DH and PH domains catalyze the exchange of GDP for GTP in Rho GTPases, allowing them to signal to downstream effectors. It induces submembrane clustering of the receptor-associated peripheral membrane protein gephyrin, which is thought to form a scaffold underneath the postsynaptic membrane linking receptors to the cytoskeleton. It also acts as a tumor suppressor that links adenomatous polyposis coli (APC) protein, a negative regulator of the Wnt signaling pathway and promotes the phosphorylation and degradation of beta-catenin, to Cdc42. Autoinhibition of collybistin is accomplished by the binding of its SH3 domain with both the RhoGEF and PH domains to block access of Cdc42 to the GTPase-binding site. Inactivation promotes cancer progression. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1222014525 231 LENIDKIAQWQASVLDWEGEDILDRSSELIYTGEMAWIYqpYGRNQQRVFFLFDHQMVLCKKDLIRRDILYYKGRIDMDK 310
Cdd:cd01224     1 MENLEKLAAWQSTVEGWEGEDLSDRSSELIHSGELTKIS--AGRAQERTFFLFDHQLVYCKKDLLRRKNYIYKGRIDTDN 78

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1222014525 311 YEVVDIEDGRDDDFNVSMKNAFKLHNKETEEIHLFFAKKLEEKIRWLRAFREERKMVQED 370
Cdd:cd01224    79 MEIEDLPDGKDDESGVTVKNAWKIYNASKNKWYVLCAKSAEEKQRWLEAFAEEREKVEKD 138

Collybistin/APC-stimulated guanine nucleotide exchange factor pleckstrin homology (PH) domain; Collybistin (also called PEM2) is homologous to the Dbl proteins ASEF (also called ARHGEF4/RhoGEF4) and SPATA13 (Spermatogenesis-associated protein 13; also called ASEF2). It activates CDC42 specifically and not any other Rho-family GTPases. Collybistin consists of an SH3 domain, followed by a RhoGEF/DH and PH domain. In Dbl proteins, the DH and PH domains catalyze the exchange of GDP for GTP in Rho GTPases, allowing them to signal to downstream effectors. It induces submembrane clustering of the receptor-associated peripheral membrane protein gephyrin, which is thought to form a scaffold underneath the postsynaptic membrane linking receptors to the cytoskeleton. It also acts as a tumor suppressor that links adenomatous polyposis coli (APC) protein, a negative regulator of the Wnt signaling pathway and promotes the phosphorylation and degradation of beta-catenin, to Cdc42. Autoinhibition of collybistin is accomplished by the binding of its SH3 domain with both the RhoGEF and PH domains to block access of Cdc42 to the GTPase-binding site. Inactivation promotes cancer progression. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1222014525 231 LENIDKIAQWQASVLDWEGEDILDRSSELIYTGEMAWIYqpYGRNQQRVFFLFDHQMVLCKKDLIRRDILYYKGRIDMDK 310
Cdd:cd01224     1 MENLEKLAAWQSTVEGWEGEDLSDRSSELIHSGELTKIS--AGRAQERTFFLFDHQLVYCKKDLLRRKNYIYKGRIDTDN 78

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1222014525 311 YEVVDIEDGRDDDFNVSMKNAFKLHNKETEEIHLFFAKKLEEKIRWLRAFREERKMVQED 370
Cdd:cd01224    79 MEIEDLPDGKDDESGVTVKNAWKIYNASKNKWYVLCAKSAEEKQRWLEAFAEEREKVEKD 138

Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases; Also called Dbl-homologous (DH) domain. It appears that PH domains invariably occur C-terminal to RhoGEF/DH domains.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1222014525  44 RANVINEIMSTERHYIKHLKDICEGYLKQCRKRRDMFSDEQLKVIFGNIEDIYRFQMGFVRDLEKQYNNDDPHLSEIGPC 123
Cdd:cd00160     1 RQEVIKELLQTERNYVRDLKLLVEVFLKPLDKELLPLSPEEVELLFGNIEEIYEFHRIFLKSLEERVEEWDKSGPRIGDV 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1222014525 124 FLEHQDGFWIYSEYCNNHLDACMELSKLMKDSryqHFFEACRLLQQ--MIDIAIDGFLLTPVQKICKYPLQLAELLKYTA 201
Cdd:cd00160    81 FLKLAPFFKIYSEYCSNHPDALELLKKLKKFN---KFFQEFLEKAEseCGRLKLESLLLKPVQRLTKYPLLLKELLKHTP 157

                         170       180
                  ....*....|....*....|....
gi 1222014525 202 QDHSDYRYVAAALAVMRNVTQQIN 225
Cdd:cd00160   158 DGHEDREDLKKALEAIKEVASQVN 181

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 1222014525  259 LIYTGEMAWIYQPYGRN-QQRVFFLFDHQMVLCKKDLIRRDILYyKGRIDMDKYEVVDIEDGRDDDfnvsMKNAFKLHNK 337
Cdd:smart00233   1 VIKEGWLYKKSGGGKKSwKKRYFVLFNSTLLYYKSKKDKKSYKP-KGSIDLSGCTVREAPDPDSSK----KPHCFEIKTS 75

                           90       100
                   ....*....|....*....|....*
gi 1222014525  338 eTEEIHLFFAKKLEEKIRWLRAFRE 362
Cdd:smart00233  76 -DRKTLLLQAESEEEREKWVEALRK 99

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1222014525 276 QQRVFFLFDHQMVLCKKDLIRRDiLYYKGRIDMDKYEVVDIEDgrDDDFNVSMKNAFKLHNKETEEIHLFFAKKLEEKIR 355
Cdd:pfam00169  19 KKRYFVLFDGSLLYYKDDKSGKS-KEPKGSISLSGCEVVEVVA--SDSPKRKFCFELRTGERTGKRTYLLQAESEEERKD 95

                  ....*..
gi 1222014525 356 WLRAFRE 362
Cdd:pfam00169  96 WIKAIQS 102

Collybistin/APC-stimulated guanine nucleotide exchange factor pleckstrin homology (PH) domain; Collybistin (also called PEM2) is homologous to the Dbl proteins ASEF (also called ARHGEF4/RhoGEF4) and SPATA13 (Spermatogenesis-associated protein 13; also called ASEF2). It activates CDC42 specifically and not any other Rho-family GTPases. Collybistin consists of an SH3 domain, followed by a RhoGEF/DH and PH domain. In Dbl proteins, the DH and PH domains catalyze the exchange of GDP for GTP in Rho GTPases, allowing them to signal to downstream effectors. It induces submembrane clustering of the receptor-associated peripheral membrane protein gephyrin, which is thought to form a scaffold underneath the postsynaptic membrane linking receptors to the cytoskeleton. It also acts as a tumor suppressor that links adenomatous polyposis coli (APC) protein, a negative regulator of the Wnt signaling pathway and promotes the phosphorylation and degradation of beta-catenin, to Cdc42. Autoinhibition of collybistin is accomplished by the binding of its SH3 domain with both the RhoGEF and PH domains to block access of Cdc42 to the GTPase-binding site. Inactivation promotes cancer progression. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1222014525 231 LENIDKIAQWQASVLDWEGEDILDRSSELIYTGEMAWIYqpYGRNQQRVFFLFDHQMVLCKKDLIRRDILYYKGRIDMDK 310
Cdd:cd01224     1 MENLEKLAAWQSTVEGWEGEDLSDRSSELIHSGELTKIS--AGRAQERTFFLFDHQLVYCKKDLLRRKNYIYKGRIDTDN 78

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1222014525 311 YEVVDIEDGRDDDFNVSMKNAFKLHNKETEEIHLFFAKKLEEKIRWLRAFREERKMVQED 370
Cdd:cd01224    79 MEIEDLPDGKDDESGVTVKNAWKIYNASKNKWYVLCAKSAEEKQRWLEAFAEEREKVEKD 138

Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases; Also called Dbl-homologous (DH) domain. It appears that PH domains invariably occur C-terminal to RhoGEF/DH domains.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1222014525  44 RANVINEIMSTERHYIKHLKDICEGYLKQCRKRRDMFSDEQLKVIFGNIEDIYRFQMGFVRDLEKQYNNDDPHLSEIGPC 123
Cdd:cd00160     1 RQEVIKELLQTERNYVRDLKLLVEVFLKPLDKELLPLSPEEVELLFGNIEEIYEFHRIFLKSLEERVEEWDKSGPRIGDV 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1222014525 124 FLEHQDGFWIYSEYCNNHLDACMELSKLMKDSryqHFFEACRLLQQ--MIDIAIDGFLLTPVQKICKYPLQLAELLKYTA 201
Cdd:cd00160    81 FLKLAPFFKIYSEYCSNHPDALELLKKLKKFN---KFFQEFLEKAEseCGRLKLESLLLKPVQRLTKYPLLLKELLKHTP 157

                         170       180
                  ....*....|....*....|....
gi 1222014525 202 QDHSDYRYVAAALAVMRNVTQQIN 225
Cdd:cd00160   158 DGHEDREDLKKALEAIKEVASQVN 181

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 1222014525  259 LIYTGEMAWIYQPYGRN-QQRVFFLFDHQMVLCKKDLIRRDILYyKGRIDMDKYEVVDIEDGRDDDfnvsMKNAFKLHNK 337
Cdd:smart00233   1 VIKEGWLYKKSGGGKKSwKKRYFVLFNSTLLYYKSKKDKKSYKP-KGSIDLSGCTVREAPDPDSSK----KPHCFEIKTS 75

                           90       100
                   ....*....|....*....|....*
gi 1222014525  338 eTEEIHLFFAKKLEEKIRWLRAFRE 362
Cdd:smart00233  76 -DRKTLLLQAESEEEREKWVEALRK 99

RhoGEF, Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases [Signal transduction mechanisms];

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1222014525   35 RPLQNRDQMRANVINEIMSTERHYIKHLKDICEGYLKQCRKRRDMFSD---EQLKVIFGNIEDIYRFQMGFVRDLEKQyN 111
Cdd:COG5422    476 ESLPKQEIKRQEAIYEVIYTERDFVKDLEYLRDTWIKPLEESNIIPENarrNFIKHVFANINEIYAVNSKLLKALTNR-Q 554

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1222014525  112 NDDPHLSEIGPCFLEHQDGFWIYSEYCNNHLDACMEL----SKLMKDSRYQHFFEACRLLQQMidiAIDGFLLTPVQKIC 187
Cdd:COG5422    555 CLSPIVNGIADIFLDYVPKFEPFIKYGASQPYAKYEFerekSVNPNFARFDHEVERLDESRKL---ELDGYLTKPTTRLA 631

                          170       180       190
                   ....*....|....*....|....*....|....*...
gi 1222014525  188 KYPLQLAELLKYTAQDHSDYRYVAAALAVMRNVTQQIN 225
Cdd:COG5422    632 RYPLLLEEVLKFTDPDNPDTEDIPKVIDMLREFLSRLN 669

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1222014525 276 QQRVFFLFDHQMVLCKKDLIRRDiLYYKGRIDMDKYEVVDIEDgrDDDFNVSMKNAFKLHNKETEEIHLFFAKKLEEKIR 355
Cdd:pfam00169  19 KKRYFVLFDGSLLYYKDDKSGKS-KEPKGSISLSGCEVVEVVA--SDSPKRKFCFELRTGERTGKRTYLLQAESEEERKD 95

                  ....*..
gi 1222014525 356 WLRAFRE 362
Cdd:pfam00169  96 WIKAIQS 102

Vav pleckstrin homology (PH) domain; Vav acts as a guanosine nucleotide exchange factor (GEF) for Rho/Rac proteins. They control processes including T cell activation, phagocytosis, and migration of cells. The Vav subgroup of Dbl GEFs consists of three family members (Vav1, Vav2, and Vav3) in mammals. Vav1 is preferentially expressed in the hematopoietic system, while Vav2 and Vav3 are described by broader expression patterns. Mammalian Vav proteins consist of a calponin homology (CH) domain, an acidic region, a catalytic Dbl homology (DH) domain, a PH domain, a zinc finger cysteine rich domain (C1/CRD), and an SH2 domain, flanked by two SH3 domains. In invertebrates such as Drosophila and C. elegans, Vav is missing the N-terminal SH3 domain. The DH domain is involved in RhoGTPase recognition and selectivity and stimulates the reorganization of the switch regions for GDP/GTP exchange. The PH domain is implicated in directing membrane localization, allosteric regulation of guanine nucleotide exchange activity, and as a phospholipid- dependent regulator of GEF activity. Vavs bind RhoGTPases including Rac1, RhoA, RhoG, and Cdc42, while other members of the GEF family are specific for a single RhoGTPase. This promiscuity is thought to be a result of its CRD. PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner. They share little sequence conservation, but all have a common fold, which is electrostatically polarized. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity. PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane. A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes.polarized. PH domains also have diverse functions. They are often involved in targeting proteins to the plasma membrane, but only a few (less than 10%) display strong specificity in binding inositol phosphates. Any specificity is usually determined by loop regions or insertions in the N-terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signaling proteins such as serine/threonine kinases, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, cytoskeletal associated molecules, and in lipid associated enzymes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1222014525 276 QQRVFFLFDHQMVLCKKdlIRRDILYYKGRIDMDKYEVVDIEDGRDDDFNVSMKNAFKLHNKETEEIHLFFAKKLEEKIR 355
Cdd:cd01223    36 KDRYAFLFDKVLLICKS--LRGDQYEYKEIINLSEYRIEDDPSRRTLKRDKRWSYQFLLVHKQGKTAYTLYAKTEELKKK 113

                  ....*..
gi 1222014525 356 WLRAFRE 362
Cdd:cd01223   114 WMEAIEM 120