Cloned out of library/PAK-interactive exchange factor pleckstrin homology (PH) domain; There are two forms of Pix proteins: alpha Pix (also called Rho guanine nucleotide exchange factor (GEF) 6/90Cool-2) and beta Pix (GEF7/p85Cool-1). betaPix contains an N-terminal SH3 domain, a RhoGEF/DH domain, a PH domain, a GIT1 binding domain (GBD), and a C-terminal coiled-coil (CC) domain. alphaPix differs in that it contains a calponin homology (CH) domain, which interacts with beta-parvin, N-terminal to the SH3 domain. alphaPix is an exchange factor for Rac1 and Cdc42 and mediates Pak activation on cell adhesion to fibronectin. Mutations in alphaPix can cause X-linked mental retardation. alphaPix also interacts with Huntington's disease protein (htt), and enhances the aggregation of mutant htt (muthtt) by facilitating SDS-soluble muthtt-muthtt interactions. The DH-PH domain of a Pix was required for its binding to htt. In the majority of Rho GEF proteins, the DH-PH domain is responsible for the exchange activity. 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 1003701532 224 VTYMSQVLIQCAGSEEKNERYLLLFPNVLLMLSASPRMSGFIYQGKLPTTGMTITKLEDSENHRNAFEISGSMIERILVS 303
Cdd:cd01225     1 VIHMSQVAVQNTGCQEKKERYFLLFPHVLLMLSASPRMSGFIYEGKLPLTGISVNRLEDTEGIKNAFEISGPLIERIVVI 80

                          90
                  ....*....|....*....
gi 1003701532 304 CNNQQDLQEWVEHLQKQTK 322
Cdd:cd01225    81 CNSQQDQQEWLEHLQQQTK 99

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 1003701532  16 RKVVLQNILETENEYSKELQTVLSTYLRPLQTSEK-LSSANISYLMGNLEEICSFQQMLVQSLEECTKL-PEAQQRVGGC 93
Cdd:cd00160     1 RQEVIKELLQTERNYVRDLKLLVEVFLKPLDKELLpLSPEEVELLFGNIEEIYEFHRIFLKSLEERVEEwDKSGPRIGDV 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1003701532  94 FLNLMPQMKTlYLTYCANHPSAVNVLTEHSEELGEFME--TKGASSPGILVLTTGLSKPFMRLDKYPTLLKELERHMEDY 171
Cdd:cd00160    81 FLKLAPFFKI-YSEYCSNHPDALELLKKLKKFNKFFQEflEKAESECGRLKLESLLLKPVQRLTKYPLLLKELLKHTPDG 159

                         170       180
                  ....*....|....*....|..
gi 1003701532 172 HTDRQDIQKSMAAFKNLSAQCQ 193
Cdd:cd00160   160 HEDREDLKKALEAIKEVASQVN 181

Cloned out of library/PAK-interactive exchange factor pleckstrin homology (PH) domain; There are two forms of Pix proteins: alpha Pix (also called Rho guanine nucleotide exchange factor (GEF) 6/90Cool-2) and beta Pix (GEF7/p85Cool-1). betaPix contains an N-terminal SH3 domain, a RhoGEF/DH domain, a PH domain, a GIT1 binding domain (GBD), and a C-terminal coiled-coil (CC) domain. alphaPix differs in that it contains a calponin homology (CH) domain, which interacts with beta-parvin, N-terminal to the SH3 domain. alphaPix is an exchange factor for Rac1 and Cdc42 and mediates Pak activation on cell adhesion to fibronectin. Mutations in alphaPix can cause X-linked mental retardation. alphaPix also interacts with Huntington's disease protein (htt), and enhances the aggregation of mutant htt (muthtt) by facilitating SDS-soluble muthtt-muthtt interactions. The DH-PH domain of a Pix was required for its binding to htt. In the majority of Rho GEF proteins, the DH-PH domain is responsible for the exchange activity. 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 1003701532 224 VTYMSQVLIQCAGSEEKNERYLLLFPNVLLMLSASPRMSGFIYQGKLPTTGMTITKLEDSENHRNAFEISGSMIERILVS 303
Cdd:cd01225     1 VIHMSQVAVQNTGCQEKKERYFLLFPHVLLMLSASPRMSGFIYEGKLPLTGISVNRLEDTEGIKNAFEISGPLIERIVVI 80

                          90
                  ....*....|....*....
gi 1003701532 304 CNNQQDLQEWVEHLQKQTK 322
Cdd:cd01225    81 CNSQQDQQEWLEHLQQQTK 99

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 1003701532  16 RKVVLQNILETENEYSKELQTVLSTYLRPLQTSEK-LSSANISYLMGNLEEICSFQQMLVQSLEECTKL-PEAQQRVGGC 93
Cdd:cd00160     1 RQEVIKELLQTERNYVRDLKLLVEVFLKPLDKELLpLSPEEVELLFGNIEEIYEFHRIFLKSLEERVEEwDKSGPRIGDV 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1003701532  94 FLNLMPQMKTlYLTYCANHPSAVNVLTEHSEELGEFME--TKGASSPGILVLTTGLSKPFMRLDKYPTLLKELERHMEDY 171
Cdd:cd00160    81 FLKLAPFFKI-YSEYCSNHPDALELLKKLKKFNKFFQEflEKAESECGRLKLESLLLKPVQRLTKYPLLLKELLKHTPDG 159

                         170       180
                  ....*....|....*....|..
gi 1003701532 172 HTDRQDIQKSMAAFKNLSAQCQ 193
Cdd:cd00160   160 HEDREDLKKALEAIKEVASQVN 181

RhoGEF domain; Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases Also called Dbl-homologous (DH) domain. It appears that pfam00169 domains invariably occur C-terminal to RhoGEF/DH domains.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1003701532  19 VLQNILETENEYSKELQTVLSTYLRPLQTSEKLSSANISYLMGNLEEICSFQQMLVqsLEECTKLPEAQQRVGGCFLNLM 98
Cdd:pfam00621   1 VIKELLQTERSYVRDLEILVEVFLPPNSKPLSESEEEIKTIFSNIEEIYELHRQLL--LEELLKEWISIQRIGDIFLKFA 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1003701532  99 PQMKtLYLTYCANHPSAVNVLTEHSEELGEFM----ETKGASSPGILVLTTGLSKPFMRLDKYPTLLKELERHMEDYHTD 174
Cdd:pfam00621  79 PGFK-VYSTYCSNYPKALKLLKKLLKKNPKFRafleELEANPECRGLDLNSFLIKPVQRIPRYPLLLKELLKHTPPDHPD 157

                         170
                  ....*....|....*...
gi 1003701532 175 RQDIQKSMAAFKNLSAQC 192
Cdd:pfam00621 158 YEDLKKALEAIKEVAKQI 175

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1003701532 242 ERYLLLFPNVLLMLSASPRMSGFIYQGKLPTTGMTITKL--EDSENHRNAFEISGSMI---ERILVSCNNQQDLQEWVEH 316
Cdd:pfam00169  20 KRYFVLFDGSLLYYKDDKSGKSKEPKGSISLSGCEVVEVvaSDSPKRKFCFELRTGERtgkRTYLLQAESEEERKDWIKA 99

                  ....*.
gi 1003701532 317 LQKQTK 322
Cdd:pfam00169 100 IQSAIR 105

large tegument protein UL36; Provisional

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1003701532  329 PTIKPHSVPSHTLPSHPVTPSSKHADSKPAPLTPAYHTLPHPSHHGT-PHTTINWGPLEPPKTPKPWSLSclRPAPPLRP 407
Cdd:PHA03247  2771 PPAAPAAGPPRRLTRPAVASLSESRESLPSPWDPADPPAAVLAPAAAlPPAASPAGPLPPPTSAQPTAPP--PPPGPPPP 2848

                           90       100       110
                   ....*....|....*....|....*....|....*
gi 1003701532  408 SAALCYK----EDLSKSPktmkkllPKRKPERKPS 438
Cdd:PHA03247  2849 SLPLGGSvapgGDVRRRP-------PSRSPAAKPA 2876

Cloned out of library/PAK-interactive exchange factor pleckstrin homology (PH) domain; There are two forms of Pix proteins: alpha Pix (also called Rho guanine nucleotide exchange factor (GEF) 6/90Cool-2) and beta Pix (GEF7/p85Cool-1). betaPix contains an N-terminal SH3 domain, a RhoGEF/DH domain, a PH domain, a GIT1 binding domain (GBD), and a C-terminal coiled-coil (CC) domain. alphaPix differs in that it contains a calponin homology (CH) domain, which interacts with beta-parvin, N-terminal to the SH3 domain. alphaPix is an exchange factor for Rac1 and Cdc42 and mediates Pak activation on cell adhesion to fibronectin. Mutations in alphaPix can cause X-linked mental retardation. alphaPix also interacts with Huntington's disease protein (htt), and enhances the aggregation of mutant htt (muthtt) by facilitating SDS-soluble muthtt-muthtt interactions. The DH-PH domain of a Pix was required for its binding to htt. In the majority of Rho GEF proteins, the DH-PH domain is responsible for the exchange activity. 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 1003701532 224 VTYMSQVLIQCAGSEEKNERYLLLFPNVLLMLSASPRMSGFIYQGKLPTTGMTITKLEDSENHRNAFEISGSMIERILVS 303
Cdd:cd01225     1 VIHMSQVAVQNTGCQEKKERYFLLFPHVLLMLSASPRMSGFIYEGKLPLTGISVNRLEDTEGIKNAFEISGPLIERIVVI 80

                          90
                  ....*....|....*....
gi 1003701532 304 CNNQQDLQEWVEHLQKQTK 322
Cdd:cd01225    81 CNSQQDQQEWLEHLQQQTK 99

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 1003701532  16 RKVVLQNILETENEYSKELQTVLSTYLRPLQTSEK-LSSANISYLMGNLEEICSFQQMLVQSLEECTKL-PEAQQRVGGC 93
Cdd:cd00160     1 RQEVIKELLQTERNYVRDLKLLVEVFLKPLDKELLpLSPEEVELLFGNIEEIYEFHRIFLKSLEERVEEwDKSGPRIGDV 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1003701532  94 FLNLMPQMKTlYLTYCANHPSAVNVLTEHSEELGEFME--TKGASSPGILVLTTGLSKPFMRLDKYPTLLKELERHMEDY 171
Cdd:cd00160    81 FLKLAPFFKI-YSEYCSNHPDALELLKKLKKFNKFFQEflEKAESECGRLKLESLLLKPVQRLTKYPLLLKELLKHTPDG 159

                         170       180
                  ....*....|....*....|..
gi 1003701532 172 HTDRQDIQKSMAAFKNLSAQCQ 193
Cdd:cd00160   160 HEDREDLKKALEAIKEVASQVN 181

RhoGEF domain; Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases Also called Dbl-homologous (DH) domain. It appears that pfam00169 domains invariably occur C-terminal to RhoGEF/DH domains.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1003701532  19 VLQNILETENEYSKELQTVLSTYLRPLQTSEKLSSANISYLMGNLEEICSFQQMLVqsLEECTKLPEAQQRVGGCFLNLM 98
Cdd:pfam00621   1 VIKELLQTERSYVRDLEILVEVFLPPNSKPLSESEEEIKTIFSNIEEIYELHRQLL--LEELLKEWISIQRIGDIFLKFA 78

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1003701532  99 PQMKtLYLTYCANHPSAVNVLTEHSEELGEFM----ETKGASSPGILVLTTGLSKPFMRLDKYPTLLKELERHMEDYHTD 174
Cdd:pfam00621  79 PGFK-VYSTYCSNYPKALKLLKKLLKKNPKFRafleELEANPECRGLDLNSFLIKPVQRIPRYPLLLKELLKHTPPDHPD 157

                         170
                  ....*....|....*...
gi 1003701532 175 RQDIQKSMAAFKNLSAQC 192
Cdd:pfam00621 158 YEDLKKALEAIKEVAKQI 175

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 1003701532  236 GSEEKNERYLLLFPNVLLMLSASPRMSGFIYQGKLPTTGMTITKLEDSEN--HRNAFEISGSMIERILVSCNNQQDLQEW 313
Cdd:smart00233  14 GKKSWKKRYFVLFNSTLLYYKSKKDKKSYKPKGSIDLSGCTVREAPDPDSskKPHCFEIKTSDRKTLLLQAESEEEREKW 93

                   ....*....
gi 1003701532  314 VEHLQKQTK 322
Cdd:smart00233  94 VEALRKAIA 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 1003701532 200 ELE-LQILTEAIRNWEGDDIKTlgnvtymSQVLIQCAGSEEKN------ERYLLLFPNVLLMLSASP-RMSGFIYQGKLP 271
Cdd:cd01224     3 NLEkLAAWQSTVEGWEGEDLSD-------RSSELIHSGELTKIsagraqERTFFLFDHQLVYCKKDLlRRKNYIYKGRID 75

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1003701532 272 TTGMTITKLEDSENH------RNAFEISGSMIER-ILVSCNNQQDLQEWVEHLQK 319
Cdd:cd01224    76 TDNMEIEDLPDGKDDesgvtvKNAWKIYNASKNKwYVLCAKSAEEKQRWLEAFAE 130

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1003701532    7 QSVQKTRRGRKVVLQNILETENEYSKELQTVLSTYLRPLQTSEKLSSAN----ISYLMGNLEEICSFQQMLVQSLEECTK 82
Cdd:COG5422    476 ESLPKQEIKRQEAIYEVIYTERDFVKDLEYLRDTWIKPLEESNIIPENArrnfIKHVFANINEIYAVNSKLLKALTNRQC 555

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1003701532   83 LPEAQQRVGGCFLNLMPQMKTlYLTYCANHPSAVNVLTEHSEELGEFM----ETKGASSPGILVLTTGLSKPFMRLDKYP 158
Cdd:COG5422    556 LSPIVNGIADIFLDYVPKFEP-FIKYGASQPYAKYEFEREKSVNPNFArfdhEVERLDESRKLELDGYLTKPTTRLARYP 634

                          170       180       190
                   ....*....|....*....|....*....|.
gi 1003701532  159 TLLKELERHMEDYHTDRQDIQKSMAAFKNLS 189
Cdd:COG5422    635 LLLEEVLKFTDPDNPDTEDIPKVIDMLREFL 665

large tegument protein UL36; Provisional

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1003701532  329 PTIKPHSVPSHTLPSHPVTPSSKHADSKPAPLTPAYHTLPHPSHHGT-PHTTINWGPLEPPKTPKPWSLSclRPAPPLRP 407
Cdd:PHA03247  2771 PPAAPAAGPPRRLTRPAVASLSESRESLPSPWDPADPPAAVLAPAAAlPPAASPAGPLPPPTSAQPTAPP--PPPGPPPP 2848

                           90       100       110
                   ....*....|....*....|....*....|....*
gi 1003701532  408 SAALCYK----EDLSKSPktmkkllPKRKPERKPS 438
Cdd:PHA03247  2849 SLPLGGSvapgGDVRRRP-------PSRSPAAKPA 2876

FYVE, RhoGEF and PH domain containing/faciogenital dysplasia family proteins, N-terminal Pleckstrin homology (PH) domain; In general, FGDs have a RhoGEF (DH) domain, followed by an N-terminal PH domain, a FYVE domain and a C-terminal PH domain. All FGDs are guanine nucleotide exchange factors that activates the Rho GTPase Cdc42, an important regulator of membrane trafficking. The RhoGEF domain is responsible for GEF catalytic activity, while the N-terminal PH domain is involved in intracellular targeting of the DH domain. Mutations in the FGD1 gene are responsible for the X-linked disorder known as faciogenital dysplasia (FGDY). 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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1003701532 242 ERYLLLFPNVLLMlsASPRMSGFIYQGKLPTT----GMTITKLEDsENHRNAFEISGSmiERIL-VSCNNQQDLQEWVE 315
Cdd:cd13328    17 PRYLFLFNDMLLY--CVPKLSLVGQKFSVRNRldvaGMKVREPVN-ENYPHTFKISGK--ERSLeLQASSAEEKDEWIQ 90

FYVE, RhoGEF and PH domain containing/faciogenital dysplasia proteins 5 and 6, N-terminal Pleckstrin Homology (PH) domain; FGD5 regulates promotes angiogenesis of vascular endothelial growth factor (VEGF) in vascular endothelial cells, including network formation, permeability, directional movement, and proliferation. The specific function of FGD6 is unknown. In general, FGDs have a RhoGEF (DH) domain, followed by a PH domain, a FYVE domain and a C-terminal PH domain. All FGDs are guanine nucleotide exchange factors that activate the Rho GTPase Cdc42, an important regulator of membrane trafficking. The RhoGEF domain is responsible for GEF catalytic activity, while the PH domain is involved in intracellular targeting of the DH 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 1003701532 239 EKNERYLLLFPNVLLMLSASPRMSGFIYQGKLPTTGMTITKLEDSENhRNAFEISgSMIERILVSCNNQQDLQEWVEHLQ 318
Cdd:cd13389    27 EMQPRYFFLFNDCLLYTTPVQSSGMLKLNNELPLSGMKVKLPEDEEY-SNEFQII-STKRSFTLIASSEEERDEWVKALS 104

                  .
gi 1003701532 319 K 319
Cdd:cd13389   105 R 105

Atrophin-1 family; Atrophin-1 is the protein product of the dentatorubral-pallidoluysian atrophy (DRPLA) gene. DRPLA OMIM:125370 is a progressive neurodegenerative disorder. It is caused by the expansion of a CAG repeat in the DRPLA gene on chromosome 12p. This results in an extended polyglutamine region in atrophin-1, that is thought to confer toxicity to the protein, possibly through altering its interactions with other proteins. The expansion of a CAG repeat is also the underlying defect in six other neurodegenerative disorders, including Huntington's disease. One interaction of expanded polyglutamine repeats that is thought to be pathogenic is that with the short glutamine repeat in the transcriptional coactivator CREB binding protein, CBP. This interaction draws CBP away from its usual nuclear location to the expanded polyglutamine repeat protein aggregates that are characteriztic of the polyglutamine neurodegenerative disorders. This interferes with CBP-mediated transcription and causes cytotoxicity.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1003701532 329 PTIKPHSVPSHTLPSHPVTPSSKHADSKPAPLTP-----AYHTLPHPSHHGT----PHtTINWGP--LEPPKTPKPWSLS 397
Cdd:pfam03154 223 STAAPHTLIQQTPTLHPQRLPSPHPPLQPMTQPPppsqvSPQPLPQPSLHGQmppmPH-SLQTGPshMQHPVPPQPFPLT 301

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|...
gi 1003701532 398 CLRP---APPLRPSAALCYKEDLSKSPKTMKKLLPKRKPERKP 437
Cdd:pfam03154 302 PQSSqsqVPPGPSPAAPGQSQQRIHTPPSQSQLQSQQPPREQP 344