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 46198230  218 MEKLEVLEEWQSHIEGWEGSNITDTCTEMLMCGVLLKISSGNIQERVFFLFDNLLVYCKRKHRRLKNskastdghrYLFR 297
Cdd:cd01224    1 MENLEKLAAWQSTVEGWEGEDLSDRSSELIHSGELTKISAGRAQERTFFLFDHQLVYCKKDLLRRKN---------YIYK 71

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 46198230  298 GRINTEVMEVENVDDGTADFhsSGHIVVNGWKIHNTAKNKWFVCMAKTPEEKHEWFEAILKERERRK 364
Cdd:cd01224   72 GRIDTDNMEIEDLPDGKDDE--SGVTVKNAWKIYNASKNKWYVLCAKSAEEKQRWLEAFAEEREKVE 136

DEP (Dishevelled, Egl-10, and Pleckstrin) domain 1 found in P-Rex-like proteins. The P-Rex family is the guanine-nucleotide exchange factor (GEF) for the small GTPase Rac that contains an N-terminal RhoGEF domain, two DEP and PDZ domains. Rac-GEF activity is stimulated by phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3), a lipid second messenger, and by the G beta-gamma subunits of heterotrimeric G proteins. The DEP domains are not involved in mediating these stimuli, but may be of importance for basal and stimulated levels Rac-GEF activity.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 46198230  382 GEKLYKMMCRQGNLIKDRKRKLTTFPKCFLGSEFVSWLLEIGEIHRPEEGVHLGQALLENGIIHHVTDKHQFKPEQMLYR 461
Cdd:cd04439    1 GEKLYKMMCKQGSLIKDRRRKLSTFPKCFLGNEFVSWLLEIGEISKPEEGVNLGQALLENGIIHHVSDKHQFKNEQVLYR 80

                 .
gi 46198230  462 F 462
Cdd:cd04439   81 F 81

PDZ domain of regulator of G-protein signaling 12 (RGS12), and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of RGS12, and related domains. RGS12 downregulates GPCR signal transduction by increasing the GTPase activity of G-protein alpha subunits, thereby driving G-proteins into their inactive GDP-bound form. The RGS12 PDZ domain can bind selectively to C-terminal (A/S)-T-X-(L/V) motifs as found within both the CXCR2 IL-8 receptor, and the alternative 3' exon form of RGS12. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This RGS12-like family domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 46198230  676 ETVKIPDSADGLGFQIRGFGPSVVHAVGRGTVAAAAGLHPGQCIIKVNGINVSKETHASVIAHVTACRKYRRPTKQ 751
Cdd:cd06710    1 RTVEIARGRAGYGFTISGQAPCVLSCVVRGSPADVAGLKAGDQILAVNGINVSKASHEDVVKLIGKCTGVLRLVIA 76

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 46198230  218 MEKLEVLEEWQSHIEGWEGSNITDTCTEMLMCGVLLKISSGNIQERVFFLFDNLLVYCKRKHRRLKNskastdghrYLFR 297
Cdd:cd01224    1 MENLEKLAAWQSTVEGWEGEDLSDRSSELIHSGELTKISAGRAQERTFFLFDHQLVYCKKDLLRRKN---------YIYK 71

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 46198230  298 GRINTEVMEVENVDDGTADFhsSGHIVVNGWKIHNTAKNKWFVCMAKTPEEKHEWFEAILKERERRK 364
Cdd:cd01224   72 GRIDTDNMEIEDLPDGKDDE--SGVTVKNAWKIYNASKNKWYVLCAKSAEEKQRWLEAFAEEREKVE 136

DEP (Dishevelled, Egl-10, and Pleckstrin) domain 1 found in P-Rex-like proteins. The P-Rex family is the guanine-nucleotide exchange factor (GEF) for the small GTPase Rac that contains an N-terminal RhoGEF domain, two DEP and PDZ domains. Rac-GEF activity is stimulated by phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3), a lipid second messenger, and by the G beta-gamma subunits of heterotrimeric G proteins. The DEP domains are not involved in mediating these stimuli, but may be of importance for basal and stimulated levels Rac-GEF activity.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 46198230  382 GEKLYKMMCRQGNLIKDRKRKLTTFPKCFLGSEFVSWLLEIGEIHRPEEGVHLGQALLENGIIHHVTDKHQFKPEQMLYR 461
Cdd:cd04439    1 GEKLYKMMCKQGSLIKDRRRKLSTFPKCFLGNEFVSWLLEIGEISKPEEGVNLGQALLENGIIHHVSDKHQFKNEQVLYR 80

                 .
gi 46198230  462 F 462
Cdd:cd04439   81 F 81

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 46198230   24 RVCVLSELQKTERDYVGTLEFLVSAFLHRMNQCaaskvDKNVTEETVKMLFSNIEDILAVHKEFLKVVEECLHPEPNAQQ 103
Cdd:cd00160    1 RQEVIKELLQTERNYVRDLKLLVEVFLKPLDKE-----LLPLSPEEVELLFGNIEEIYEFHRIFLKSLEERVEEWDKSGP 75

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 46198230  104 EVGTCFLHFKDKFRIYDEYCSNHEKAQKLLLELNKirtIRTFLLNCMLLGGRKNIDVPLEGYLVTPIQRICKYPLILKEL 183
Cdd:cd00160   76 RIGDVFLKLAPFFKIYSEYCSNHPDALELLKKLKK---FNKFFQEFLEKAESECGRLKLESLLLKPVQRLTKYPLLLKEL 152

                        170       180
                 ....*....|....*....|....*....
gi 46198230  184 LKRTPRKHSDYAAVMEALQAMKAVCSNIN 212
Cdd:cd00160  153 LKHTPDGHEDREDLKKALEAIKEVASQVN 181

PDZ domain of regulator of G-protein signaling 12 (RGS12), and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of RGS12, and related domains. RGS12 downregulates GPCR signal transduction by increasing the GTPase activity of G-protein alpha subunits, thereby driving G-proteins into their inactive GDP-bound form. The RGS12 PDZ domain can bind selectively to C-terminal (A/S)-T-X-(L/V) motifs as found within both the CXCR2 IL-8 receptor, and the alternative 3' exon form of RGS12. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This RGS12-like family domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 46198230  676 ETVKIPDSADGLGFQIRGFGPSVVHAVGRGTVAAAAGLHPGQCIIKVNGINVSKETHASVIAHVTACRKYRRPTKQ 751
Cdd:cd06710    1 RTVEIARGRAGYGFTISGQAPCVLSCVVRGSPADVAGLKAGDQILAVNGINVSKASHEDVVKLIGKCTGVLRLVIA 76

Domain found in Dishevelled, Egl-10, and Pleckstrin; Domain of unknown function present in signalling proteins that contain PH, rasGEF, rhoGEF, rhoGAP, RGS, PDZ domains. DEP domain in Drosophila dishevelled is essential to rescue planar polarity defects and induce JNK signalling (Cell 94, 109-118).

                            10        20        30        40        50        60        70
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 46198230     390 CRQGNLIKDRKRKLTTFPKCFLGSEFVSWLLEIGEIHRPEEGVHLGQALLENGIIHHVTD--KHQFKPEQMLYRFR 463
Cdd:smart00049    1 PETGLKLRDRKYFLKTYPNCFTGSELVDWLMDNLEIIDREEAVHLGQLLLDEGLIHHVNGpnKHTFKDSKALYRFT 76

Domain found in Dishevelled, Egl-10, and Pleckstrin; Domain of unknown function present in signalling proteins that contain PH, rasGEF, rhoGEF, rhoGAP, RGS, PDZ domains. DEP domain in Drosophila dishevelled is essential to rescue planar polarity defects and induce JNK signalling (Cell 94, 109-118).

                            10        20        30        40        50        60
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 46198230     497 IRDKDYHLRTYKSVVMANKLIDWLIAQGDCRTREEAMIFGVGLCDNGFMHHVLEKSE--FKDEPLLFRF 563
Cdd:smart00049    7 LRDRKYFLKTYPNCFTGSELVDWLMDNLEIIDREEAVHLGQLLLDEGLIHHVNGPNKhtFKDSKALYRF 75

Domain present in PSD-95, Dlg, and ZO-1/2; Also called DHR (Dlg homologous region) or GLGF (relatively well conserved tetrapeptide in these domains). Some PDZs have been shown to bind C-terminal polypeptides; others appear to bind internal (non-C-terminal) polypeptides. Different PDZs possess different binding specificities.

                            10        20        30        40        50        60        70
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 46198230     675 RETVKIPDSADGLGFQIRGFGPS----VVHAVGRGTVAAAAGLHPGQCIIKVNGINVSKETHASVIAHVTACR 743
Cdd:smart00228    2 PRLVELEKGGGGLGFSLVGGKDEgggvVVSSVVPGSPAAKAGLRVGDVILEVNGTSVEGLTHLEAVDLLKKAG 74

PDZ domains of the Na+/H+ exchange regulatory cofactor (NHERF) family (NHERF1-4), and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of the Na+/H+ exchange regulatory cofactor (NHERF) family of multi-PDZ-domain-containing scaffolding proteins (NHERF1-4), and related domains. The NHERF family includes NHERF1 (also known as EBP50), NHERF2 (also known as E3KARP; TKA-1; SIP-1), NHERF3 (also known as CAP70; CLAMP; Napi-Cap-1; PDZD1) and NHERF4 (also known as IKEPP; PDZK2; Napi-Cap-2). NHERF1 and NHERF2 have tandem PDZ domains (PDZ1-2); NHERF3 and NHERF4 have four PDZ domains (PDZ1-4). NHERFs are involved in the regulation of multiple receptors or transporters, such as type II sodium-phosphate cotransporter (Npt2a), purinergic P2Y1 receptor P2Y1R, the beta2-adrenergic receptor (beta2-AR), parathyroid hormone receptor type 1 (PTHR), the lysophosphatidic acid receptors (LPARs), sodium-hydrogen exchanger 3 (NHE3), and cystic fibrosis transmembrane conductance regulator (CFTR). NHERF-PDZ1 domain interaction partners include Npt2a, purinergic P2Y1 receptor, beta2-AR, CFTR, PTHR, NH3, G-protein-coupled receptor kinase 6 (GRK6A), platelet-derived growth factor receptor (PDGFR), B1 subunit of the H+ATPase, cholesterol, receptor for activated C-kinase RACK1, aquaporin 9, among others. The NHERF PDZ2 domain interacts with fewer proteins: NHERF1 PDZ2 binds Npt2a, PTHR, beta-catenin, aquaporin 9, and RACK1; NHERF2 PDZ2 binds LPA2, P2Y1R, and NHE3, cGMP-dependent protein kinase type II (cGKII). NHERF4 PDZ1 and PDZ4 bind the epithelial Ca(2+) channels TRPV5 and TRPV6. NHERF2/NHERF3 heterodimerization is mediated by PDZ domains of NHERF2 and the C-terminal PDZ domain recognition motif of NHERF3. NHERF4 regulates several transporters mediating influx of xenobiotics and nutrients in the small intestine. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This NHERF-like family domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 46198230  595 LIKSNEGsYGFGL--EDKNKVPIIKLVEKGSNAEMAGMEVGKKIFAINGDLV 644
Cdd:cd06768    5 LVKGPEG-YGFNLhaEKGRPGHFIREVDPGSPAERAGLKDGDRLVEVNGENV 55

PDZ domain; This entry represents the PDZ domain from a wide variety of proteins.

                           10        20        30
                   ....*....|....*....|....*....|....*..
gi 46198230    698 VVHAVGRGTVAAAAGLHPGQCIIKVNGINVSKETHAS 734
Cdd:pfam17820    1 VVTAVVPGSPAERAGLRVGDVILAVNGKPVRSLEDVA 37

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 46198230  218 MEKLEVLEEWQSHIEGWEGSNITDTCTEMLMCGVLLKISSGNIQERVFFLFDNLLVYCKRKHRRLKNskastdghrYLFR 297
Cdd:cd01224    1 MENLEKLAAWQSTVEGWEGEDLSDRSSELIHSGELTKISAGRAQERTFFLFDHQLVYCKKDLLRRKN---------YIYK 71

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 46198230  298 GRINTEVMEVENVDDGTADFhsSGHIVVNGWKIHNTAKNKWFVCMAKTPEEKHEWFEAILKERERRK 364
Cdd:cd01224   72 GRIDTDNMEIEDLPDGKDDE--SGVTVKNAWKIYNASKNKWYVLCAKSAEEKQRWLEAFAEEREKVE 136

DEP (Dishevelled, Egl-10, and Pleckstrin) domain 1 found in P-Rex-like proteins. The P-Rex family is the guanine-nucleotide exchange factor (GEF) for the small GTPase Rac that contains an N-terminal RhoGEF domain, two DEP and PDZ domains. Rac-GEF activity is stimulated by phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3), a lipid second messenger, and by the G beta-gamma subunits of heterotrimeric G proteins. The DEP domains are not involved in mediating these stimuli, but may be of importance for basal and stimulated levels Rac-GEF activity.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 46198230  382 GEKLYKMMCRQGNLIKDRKRKLTTFPKCFLGSEFVSWLLEIGEIHRPEEGVHLGQALLENGIIHHVTDKHQFKPEQMLYR 461
Cdd:cd04439    1 GEKLYKMMCKQGSLIKDRRRKLSTFPKCFLGNEFVSWLLEIGEISKPEEGVNLGQALLENGIIHHVSDKHQFKNEQVLYR 80

                 .
gi 46198230  462 F 462
Cdd:cd04439   81 F 81

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 46198230   24 RVCVLSELQKTERDYVGTLEFLVSAFLHRMNQCaaskvDKNVTEETVKMLFSNIEDILAVHKEFLKVVEECLHPEPNAQQ 103
Cdd:cd00160    1 RQEVIKELLQTERNYVRDLKLLVEVFLKPLDKE-----LLPLSPEEVELLFGNIEEIYEFHRIFLKSLEERVEEWDKSGP 75

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 46198230  104 EVGTCFLHFKDKFRIYDEYCSNHEKAQKLLLELNKirtIRTFLLNCMLLGGRKNIDVPLEGYLVTPIQRICKYPLILKEL 183
Cdd:cd00160   76 RIGDVFLKLAPFFKIYSEYCSNHPDALELLKKLKK---FNKFFQEFLEKAESECGRLKLESLLLKPVQRLTKYPLLLKEL 152

                        170       180
                 ....*....|....*....|....*....
gi 46198230  184 LKRTPRKHSDYAAVMEALQAMKAVCSNIN 212
Cdd:cd00160  153 LKHTPDGHEDREDLKKALEAIKEVASQVN 181

PDZ domain of regulator of G-protein signaling 12 (RGS12), and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of RGS12, and related domains. RGS12 downregulates GPCR signal transduction by increasing the GTPase activity of G-protein alpha subunits, thereby driving G-proteins into their inactive GDP-bound form. The RGS12 PDZ domain can bind selectively to C-terminal (A/S)-T-X-(L/V) motifs as found within both the CXCR2 IL-8 receptor, and the alternative 3' exon form of RGS12. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This RGS12-like family domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 46198230  676 ETVKIPDSADGLGFQIRGFGPSVVHAVGRGTVAAAAGLHPGQCIIKVNGINVSKETHASVIAHVTACRKYRRPTKQ 751
Cdd:cd06710    1 RTVEIARGRAGYGFTISGQAPCVLSCVVRGSPADVAGLKAGDQILAVNGINVSKASHEDVVKLIGKCTGVLRLVIA 76

Domain found in Dishevelled, Egl-10, and Pleckstrin (DEP); The DEP domain is responsible for mediating intracellular protein targeting and regulation of protein stability in the cell. The DEP domain is present in a number of signaling molecules, including Regulator of G protein Signaling (RGS) proteins, and has been implicated in membrane targeting. New findings in yeast, however, demonstrate a major role for a DEP domain in mediating the interaction of an RGS protein to the C-terminal tail of a GPCR, thus placing RGS in close proximity with its substrate G protein alpha subunit.

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 46198230    393 GNLIKDRKRKLTTFPKCFLGSEFVSWLLEIGEIHRPEEGVHLGQALLENGIIHHVTDKH-QFKPEQMLYRF 462
Cdd:pfam00610    1 GVKLKDRRKHLKTYPNCFTGSEAVDWLMDNLEIITREEAVELGQLLLDQGLIHHVGDKHgLFKDSYYFYRF 71

DEP (Dishevelled, Egl-10, and Pleckstrin) domain 2 found in DEP6-like proteins. DEP6 proteins contain two DEP and a PDZ domain. Their function is unknown.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 46198230  381 QGEKLY-KMMCRQGNLIKDRKRKLTTFPKCFLGSEFVSWLLEIGEIHRPEEGVHLGQALLENGIIHHVTDKHQFKPEQML 459
Cdd:cd04441    3 RGQRLYeKLMSTENSILQVREEEGVKYERTFVGSEFIDWLLQEGEAESRREAVQLCRRLLEHGIIQHVSNKHHFFDSNLL 82

                 ...
gi 46198230  460 YRF 462
Cdd:cd04441   83 YQF 85

Domain found in Dishevelled, Egl-10, and Pleckstrin (DEP); The DEP domain is responsible for mediating intracellular protein targeting and regulation of protein stability in the cell. The DEP domain is present in a number of signaling molecules, including Regulator of G protein Signaling (RGS) proteins, and has been implicated in membrane targeting. New findings in yeast, however, demonstrate a major role for a DEP domain in mediating the interaction of an RGS protein to the C-terminal tail of a GPCR, thus placing RGS in close proximity with its substrate G protein alpha subunit.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 46198230    497 IRDKDYHLRTYKSVVMANKLIDWLIAQGDCRTREEAMIFGVGLCDNGFMHHVLEK-SEFKDEPLLFRF 563
Cdd:pfam00610    4 LKDRRKHLKTYPNCFTGSEAVDWLMDNLEIITREEAVELGQLLLDQGLIHHVGDKhGLFKDSYYFYRF 71

DEP domain, named after Dishevelled, Egl-10, and Pleckstrin, where this domain was first discovered. The function of this domain is still not clear, but it is believed to be important for the membrane association of the signaling proteins in which it is present. New studies show that the DEP domain of Sst2, a yeast RGS protein is necessary and sufficient for receptor interaction.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 46198230  485 LYCRLHSLFTPVIRDKDYHLRTYKSVVMANKLIDWLIAQGDCRTREEAMIFGVGLCDNGFMHHVL-EKSEFKDEPLLFR 562
Cdd:cd04371    3 VRIMLDSDSGVPIKDRKYHLKTYPNCFTGSELVDWLLDNLEAITREEAVELGQALLKHGLIHHVSdDKHTFRDSYALYR 81

Domain found in Dishevelled, Egl-10, and Pleckstrin; Domain of unknown function present in signalling proteins that contain PH, rasGEF, rhoGEF, rhoGAP, RGS, PDZ domains. DEP domain in Drosophila dishevelled is essential to rescue planar polarity defects and induce JNK signalling (Cell 94, 109-118).

                            10        20        30        40        50        60
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 46198230     497 IRDKDYHLRTYKSVVMANKLIDWLIAQGDCRTREEAMIFGVGLCDNGFMHHVLEKSE--FKDEPLLFRF 563
Cdd:smart00049    7 LRDRKYFLKTYPNCFTGSELVDWLMDNLEIIDREEAVHLGQLLLDEGLIHHVNGPNKhtFKDSKALYRF 75

DEP (Dishevelled, Egl-10, and Pleckstrin) domain 1 found in DEP6-like proteins. DEP6 proteins contain two DEP and a PDZ domain. Their function is unknown.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 46198230  482 GVRLYCRLHSlfTPVIRDKDYHLRTYKSVVMANKLIDWLIAQGDCRTREEAMIFGVGLCDNGFMHHVL-EKSEFKDEPLL 560
Cdd:cd04442    2 GEQLRLRLHE--AKVIKDRRHHLRTYPNCFVGKELIDWLIEHKEASDRETAIKIMQKLLDHSIIHHVCdEHKEFKDAKLF 79

                 ...
gi 46198230  561 FRF 563
Cdd:cd04442   80 YRF 82

DEP (Dishevelled, Egl-10, and Pleckstrin) domain 2 found in P-Rex-like proteins. The P-Rex family is the guanine-nucleotide exchange factor (GEF) for the small GTPase Rac that contains an N-terminal RhoGEF domain, two DEP and PDZ domains. Rac-GEF activity is stimulated by phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3), a lipid second messenger, and the G beta-gamma subunits of heterotrimeric G proteins. The DEP domains are not involved in mediating these stimuli, but may be of importance for basal and stimulated levels Rac-GEF activity.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 46198230  378 ISEQGEKLYkmmCRQGNL----IKDRKRKLTTFPKCFLGSEFVSWLLEIGEIHRPEEGVHLGQALLENGIIHHVTDKHQF 453
Cdd:cd04440    5 IMSKGVRLY---CRLHSLftpvVKDRDYHLKTYKSVVPASKLVDWLLAQGDCRTREEAVILGVGLCNNGFMHHVLEKSEF 81

                         90
                 ....*....|..
gi 46198230  454 KPEQMLYRFRYD 465
Cdd:cd04440   82 KDEPLLFRFYAD 93

PDZ domain 2 of delphilin (L-delphilin isoform), and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain 2 of delphilin (also known as glutamate receptor, ionotropic, delta 2-interacting protein 1, L-delphilin). Delphilin, a postsynaptic protein which it is selectively expressed at cerebellar Purkinje cells, links the glutamate receptor delta 2 subunit (GluRdelta2) with the actin cytoskeleton and various signaling molecules. Two alternatively spliced isoforms of delphilin have been characterized: L-delphilin has two PDZ domains, PDZ1 and PDZ2, and S-delphilin has a single PDZ domain (PDZ2). These two isoforms are differently palmitoylated and may be involved in controlling GluRdelta2 signaling in Purkinje cells. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This delphilin-like family PDZ2 domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 46198230  686 GLGFQIRGFGPSVVHAVGRGTVAAAAGLHPGQCIIKVNGINVSKETHASVIA 737
Cdd:cd06744   10 SFGFTLRGHAPVYIESVDPGSAAERAGLKPGDRILFLNGLDVRNCSHDKVVS 61

DEP (Dishevelled, Egl-10, and Pleckstrin) domain found in GPR155-like proteins. GRP155-like proteins, also known as PGR22, contain an N-terminal permease domain, a central transmembrane region and a C-terminal DEP domain. They are orphan receptors of the class B G protein-coupled receptors. Their function is unknown.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 46198230  496 VIRDKDYHLRTYKSVVMANKLIDWLIAQGDCRTREEAMIFGVGLCDNGFMHHVLEKSEFKDEPLLFRF 563
Cdd:cd04443   16 IVKDRRCGLRTYKGVFCGCDLVSWLIEVGLAQDRGEAVLYGRRLLQGGVLQHITNEHHFRDENLLYRF 83

DEP (Dishevelled, Egl-10, and Pleckstrin) domain 2 found in DEP6-like proteins. DEP6 proteins contain two DEP and a PDZ domain. Their function is unknown.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 46198230  481 KGVRLYCRLHSLFTPVIRDKDYHLRTYKSVVMANKLIDWLIAQGDCRTREEAMIFGVGLCDNGFMHHVLEKSEFKDEPLL 560
Cdd:cd04441    3 RGQRLYEKLMSTENSILQVREEEGVKYERTFVGSEFIDWLLQEGEAESRREAVQLCRRLLEHGIIQHVSNKHHFFDSNLL 82

                 ...
gi 46198230  561 FRF 563
Cdd:cd04441   83 YQF 85

DEP (Dishevelled, Egl-10, and Pleckstrin) domain found in Epac-like proteins. Epac (exchange proteins directly activated by cAMP) proteins are GEFs (guanine-nucleotide-exchange factors) for the small GTPases, Rap1 and Rap2. They are directly regulated by cyclic AMP, a second messenger that plays a role in the control of diverse cellular processes, such as cell adhesion and insulin secretion. Epac-like proteins share a common domain architecture, containing RasGEF, DEP and CAP-effector (cAMP binding) domains. The DEP domain is involved in membrane localization.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 46198230  496 VIRDKDYHLRTYKSVVMANKLIDWLIAQGDC-RTREEAMIFGVGLCDNGFMHHVLEKSEFKDEPLLFRFFSDEE 568
Cdd:cd04437   16 LIRDRKYHLRTYRQCCVGTELVDWLLQQSPCvQSRSQAVGMWQVLLEEGVLLHVDQELHFQDKYQFYRFSDDEC 89

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 46198230     246 MLMCGVLLKISSGNI---QERVFFLFDNLLVYCKRKHRRLKNSKastdghrylfRGRINTEVMEVENVDDGTADFHSsgh 322
Cdd:smart00233    1 VIKEGWLYKKSGGGKkswKKRYFVLFNSTLLYYKSKKDKKSYKP----------KGSIDLSGCTVREAPDPDSSKKP--- 67

                            90       100       110
                    ....*....|....*....|....*....|....
gi 46198230     323 ivvNGWKIHnTAKNKWFVCMAKTPEEKHEWFEAI 356
Cdd:smart00233   68 ---HCFEIK-TSDRKTLLLQAESEEEREKWVEAL 97

Son of Sevenless (SOS) Pleckstrin homology (PH) domain; SOS is a Ras guanine nucleotide exchange factor. SOS is thought to transmit signals from activated receptor tyrosine kinases to the Ras signaling pathway. SOS contains a histone domain, Dbl-homology (DH), a PH domain, Rem domain, Cdc25 domain, and a Grb2 binding domain. The SOS PH domain binds to phosphatidylinositol-4,5-bisphosphate (PIP2) and phosphatidic acid (PA). SOS is dependent on Ras binding to the allosteric site via its histone domain for both a lower level of activity (Ras GDP) and maximal activity (Ras GTP). The DH domain blocks the allosteric Ras binding site in SOS. The PH domain is closely associated with the DH domain and the action of the DH-PH unit gates a reciprocal interaction between Ras and SOS. The C-terminal proline-rich domain of SOS binds to the adapter protein Grb2 which localizes the Sos protein to the plasma membrane and diminishes the negative effect of the C-terminal domain on the guanine nucleotide exchange activity of the CDC25-homology domain of SOS. 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 46198230  242 TCTEMLMCGVLLKISSGN-IQERVFFLFDNLLVYCKRKHRRLKNSKASTDghrYLFRGRINTEVMEVENVDDgTADfhss 320
Cdd:cd01261    2 CCNEFIMEGTLGKVGSGKrKTERHAFLFDGLLLLCKSNRRRTSTGGPKPE---YRLKEKFFIRKVEINDLED-TEE---- 73

                         90       100       110
                 ....*....|....*....|....*....|..
gi 46198230  321 ghiVVNGWKIHNTAKNKWfVCMAKTPEEKHEW 352
Cdd:cd01261   74 ---LKNAFEIVPRDQPSV-ILFAKSAEEKNNW 101

PDZ domain 1 of delphilin (L-delphilin isoform), and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain 1 of delphilin (also known as glutamate receptor, ionotropic, delta 2-interacting protein 1, L-delphilin). Delphilin, a postsynaptic protein which is selectively expressed at cerebellar Purkinje cells, links the glutamate receptor delta 2 subunit (GluRdelta2) with the actin cytoskeleton and various signaling molecules. Two alternatively spliced isoforms of delphilin have been characterized: L-delphilin has two PDZ domains, PDZ1 and PDZ2, and S-delphilin has a single PDZ domain (PDZ2). These two isoforms are differently palmitoylated and may be involved in controlling GluRdelta2 signaling in Purkinje cells. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This delphilin-like family PDZ1 domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 46198230  688 GFQIRGFGPSVVHAVGRGTVAAAAGLHPGQCIIKVNGINVSKETHASVIAHVTACRK 744
Cdd:cd06743   12 GFSIGGSGPCYILSVEEGSSAHAAGLQPGDQILELDGQDVSSLSCEAIIALARRCPS 68