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 291045194 189 LENIDKIAQWQASVLDWEGEDILDRSSELIYTGEMAWIYqpYGRNQQRVFFLFDHQMVLCKKDLIRRDILYYKGRIDMDK 268
Cdd:cd01224    1 MENLEKLAAWQSTVEGWEGEDLSDRSSELIHSGELTKIS--AGRAQERTFFLFDHQLVYCKKDLLRRKNYIYKGRIDTDN 78

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 291045194 269 YEVVDIEDGRDDDFNVSMKNAFKLHNKETEEIHLFFAKKLEEKIRWLRAFREERKMVQED 328
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 291045194 189 LENIDKIAQWQASVLDWEGEDILDRSSELIYTGEMAWIYqpYGRNQQRVFFLFDHQMVLCKKDLIRRDILYYKGRIDMDK 268
Cdd:cd01224    1 MENLEKLAAWQSTVEGWEGEDLSDRSSELIHSGELTKIS--AGRAQERTFFLFDHQLVYCKKDLLRRKNYIYKGRIDTDN 78

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 291045194 269 YEVVDIEDGRDDDFNVSMKNAFKLHNKETEEIHLFFAKKLEEKIRWLRAFREERKMVQED 328
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 291045194   2 RANVINEIMSTERHYIKHLKDICEGYLKQCRKRRDMFSDEQLKVIFGNIEDIYRFQMGFVRDLEKQYNNDDPHLSEIGPC 81
Cdd:cd00160    1 RQEVIKELLQTERNYVRDLKLLVEVFLKPLDKELLPLSPEEVELLFGNIEEIYEFHRIFLKSLEERVEEWDKSGPRIGDV 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 291045194  82 FLEHQDGFWIYSEYCNNHLDACMELSKLMKDSryqHFFEACRLLQQ--MIDIAIDGFLLTPVQKICKYPLQLAELLKYTA 159
Cdd:cd00160   81 FLKLAPFFKIYSEYCSNHPDALELLKKLKKFN---KFFQEFLEKAEseCGRLKLESLLLKPVQRLTKYPLLLKELLKHTP 157

                        170       180
                 ....*....|....*....|....
gi 291045194 160 QDHSDYRYVAAALAVMRNVTQQIN 183
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 291045194   217 LIYTGEMAWIYQPYGRN-QQRVFFLFDHQMVLCKKDLIRRDILYyKGRIDMDKYEVVDIEDGRDDDfnvsMKNAFKLHNK 295
Cdd:smart00233   1 VIKEGWLYKKSGGGKKSwKKRYFVLFNSTLLYYKSKKDKKSYKP-KGSIDLSGCTVREAPDPDSSK----KPHCFEIKTS 75

                           90       100
                   ....*....|....*....|....*
gi 291045194   296 eTEEIHLFFAKKLEEKIRWLRAFRE 320
Cdd:smart00233  76 -DRKTLLLQAESEEEREKWVEALRK 99

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 291045194  234 QQRVFFLFDHQMVLCKKDLIRRDiLYYKGRIDMDKYEVVDIEDgrDDDFNVSMKNAFKLHNKETEEIHLFFAKKLEEKIR 313
Cdd:pfam00169  19 KKRYFVLFDGSLLYYKDDKSGKS-KEPKGSISLSGCEVVEVVA--SDSPKRKFCFELRTGERTGKRTYLLQAESEEERKD 95

                  ....*..
gi 291045194  314 WLRAFRE 320
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 291045194 189 LENIDKIAQWQASVLDWEGEDILDRSSELIYTGEMAWIYqpYGRNQQRVFFLFDHQMVLCKKDLIRRDILYYKGRIDMDK 268
Cdd:cd01224    1 MENLEKLAAWQSTVEGWEGEDLSDRSSELIHSGELTKIS--AGRAQERTFFLFDHQLVYCKKDLLRRKNYIYKGRIDTDN 78

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 291045194 269 YEVVDIEDGRDDDFNVSMKNAFKLHNKETEEIHLFFAKKLEEKIRWLRAFREERKMVQED 328
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 291045194   2 RANVINEIMSTERHYIKHLKDICEGYLKQCRKRRDMFSDEQLKVIFGNIEDIYRFQMGFVRDLEKQYNNDDPHLSEIGPC 81
Cdd:cd00160    1 RQEVIKELLQTERNYVRDLKLLVEVFLKPLDKELLPLSPEEVELLFGNIEEIYEFHRIFLKSLEERVEEWDKSGPRIGDV 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 291045194  82 FLEHQDGFWIYSEYCNNHLDACMELSKLMKDSryqHFFEACRLLQQ--MIDIAIDGFLLTPVQKICKYPLQLAELLKYTA 159
Cdd:cd00160   81 FLKLAPFFKIYSEYCSNHPDALELLKKLKKFN---KFFQEFLEKAEseCGRLKLESLLLKPVQRLTKYPLLLKELLKHTP 157

                        170       180
                 ....*....|....*....|....
gi 291045194 160 QDHSDYRYVAAALAVMRNVTQQIN 183
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 291045194   217 LIYTGEMAWIYQPYGRN-QQRVFFLFDHQMVLCKKDLIRRDILYyKGRIDMDKYEVVDIEDGRDDDfnvsMKNAFKLHNK 295
Cdd:smart00233   1 VIKEGWLYKKSGGGKKSwKKRYFVLFNSTLLYYKSKKDKKSYKP-KGSIDLSGCTVREAPDPDSSK----KPHCFEIKTS 75

                           90       100
                   ....*....|....*....|....*
gi 291045194   296 eTEEIHLFFAKKLEEKIRWLRAFRE 320
Cdd:smart00233  76 -DRKTLLLQAESEEEREKWVEALRK 99

Pleckstrin homology domain-containing family G members 1, 2, and 3 pleckstrin homology (PH) domain; PLEKHG1 (also called ARHGEF41), PLEKHG2 (also called ARHGEF42 or CLG/common-site lymphoma/leukemia guanine nucleotide exchange factor2), and PLEKHG3 (also called ARHGEF43) have RhoGEF DH/double-homology domains in tandem with a PH domain which is involved in phospholipid binding. They function as a guanine nucleotide exchange factor (GEF) and are involved in the regulation of Rho protein signal transduction. Mutations in PLEKHG1 have been associated panic disorder (PD), an anxiety disorder characterized by panic attacks and anticipatory anxiety. 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 291045194 168 VAAALAVMRNVTQQINERKRRLENIDKIAQWQASVLDWEGEDILDRSSELIYTGemawiYQPYGRNQQRVFFLFDHQMVL 247
Cdd:cd13243    4 VEEALDTMTQVAWHINDMKRKHEHAVRVQEIQSLLDGWEGPELTTYGDLVLEGT-----FRMAGAKNERLLFLFDKMLLI 78

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 291045194 248 CKKdliRRDILY-YKGRIDMDKYEVVDIEDGRDDDFNVsmknafkLHNKETEEIHLFFAKKLEEKIRWLRAFR 319
Cdd:cd13243   79 TKK---REDGILqYKTHIMCSNLMLSESIPKEPLSFQV-------LPFDNPKLQYTLQAKNQEQKRLWTQEIK 141

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 291045194  234 QQRVFFLFDHQMVLCKKDLIRRDiLYYKGRIDMDKYEVVDIEDgrDDDFNVSMKNAFKLHNKETEEIHLFFAKKLEEKIR 313
Cdd:pfam00169  19 KKRYFVLFDGSLLYYKDDKSGKS-KEPKGSISLSGCEVVEVVA--SDSPKRKFCFELRTGERTGKRTYLLQAESEEERKD 95

                  ....*..
gi 291045194  314 WLRAFRE 320
Cdd:pfam00169  96 WIKAIQS 102

Pleckstrin homology (PH) 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 291045194 225 WIYQPYGRNQQRVFFLFDHQMVLCKKDliRRDILYYKGRIDMDKYEVVDIEDgrdddfNVSMKNAFKLHNKEtEEIHLFF 304
Cdd:cd00821    8 RGGGGLKSWKKRWFVLFEGVLLYYKSK--KDSSYKPKGSIPLSGILEVEEVS------PKERPHCFELVTPD-GRTYYLQ 78

                         90
                 ....*....|....
gi 291045194 305 AKKLEEKIRWLRAF 318
Cdd:cd00821   79 ADSEEERQEWLKAL 92