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 71274148  273 YDVVLDAIDTMQRVAWHINDMKRKHEHAVRLQEIQSLLTNWKGPDLTSYGELVLEGTFRIQRAKNERTLFLFDKLLLITK 352
Cdd:cd13243    1 RSVVEEALDTMTQVAWHINDMKRKHEHAVRVQEIQSLLDGWEGPELTTYGDLVLEGTFRMAGAKNERLLFLFDKMLLITK 80

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 71274148  353 KRDD-TFTYKAHILCGNLMLVEVIPKEPLSFSVFHYKNPKLQHTVQAKSQQDKRLWVLHLKRLILEN 418
Cdd:cd13243   81 KREDgILQYKTHIMCSNLMLSESIPKEPLSFQVLPFDNPKLQYTLQAKNQEQKRLWTQEIKRLILEN 147

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 71274148  273 YDVVLDAIDTMQRVAWHINDMKRKHEHAVRLQEIQSLLTNWKGPDLTSYGELVLEGTFRIQRAKNERTLFLFDKLLLITK 352
Cdd:cd13243    1 RSVVEEALDTMTQVAWHINDMKRKHEHAVRVQEIQSLLDGWEGPELTTYGDLVLEGTFRMAGAKNERLLFLFDKMLLITK 80

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 71274148  353 KRDD-TFTYKAHILCGNLMLVEVIPKEPLSFSVFHYKNPKLQHTVQAKSQQDKRLWVLHLKRLILEN 418
Cdd:cd13243   81 KREDgILQYKTHIMCSNLMLSESIPKEPLSFQVLPFDNPKLQYTLQAKNQEQKRLWTQEIKRLILEN 147

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 71274148  115 DRVVQEILETERTYVQDLKSIVEDYLDCIrDQTKLPLGTEERSALFGNIQDIYHFNSELLQDLENC----ENDPVAIAEC 190
Cdd:cd00160    2 QEVIKELLQTERNYVRDLKLLVEVFLKPL-DKELLPLSPEEVELLFGNIEEIYEFHRIFLKSLEERveewDKSGPRIGDV 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71274148  191 FVSKSEEFHIYTQYCTNYPRSVAVLTECMRNKilaKFFRE---RQETLKHSLPLGSYLLKPVQRILKYHLLLHEIENHLD 267
Cdd:cd00160   81 FLKLAPFFKIYSEYCSNHPDALELLKKLKKFN---KFFQEfleKAESECGRLKLESLLLKPVQRLTKYPLLLKELLKHTP 157

                        170       180
                 ....*....|....*....|....
gi 71274148  268 KDTEGYDVVLDAIDTMQRVAWHIN 291
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 71274148     324 LVLEGTFRIQRAKN-----ERTLFLFDKLLLITKKRDDT--FTYKAHILCGNLMLVEV----IPKEPLSFSVFHykNPKL 392
Cdd:smart00233    1 VIKEGWLYKKSGGGkkswkKRYFVLFNSTLLYYKSKKDKksYKPKGSIDLSGCTVREApdpdSSKKPHCFEIKT--SDRK 78

                            90       100
                    ....*....|....*....|...
gi 71274148     393 QHTVQAKSQQDKRLWVLHLKRLI 415
Cdd:smart00233   79 TLLLQAESEEEREKWVEALRKAI 101

PH domain; PH stands for pleckstrin homology.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71274148    322 GELVLEGTFRIQRAKnERTLFLFDKLLLITKKRDDT--FTYKAHILCGNLMLVEVI----PKEPLSFSV-FHYKNPKLQH 394
Cdd:pfam00169    5 GWLLKKGGGKKKSWK-KRYFVLFDGSLLYYKDDKSGksKEPKGSISLSGCEVVEVVasdsPKRKFCFELrTGERTGKRTY 83

                           90       100
                   ....*....|....*....|.
gi 71274148    395 TVQAKSQQDKRLWVLHLKRLI 415
Cdd:pfam00169   84 LLQAESEEERKDWIKAIQSAI 104

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 71274148  273 YDVVLDAIDTMQRVAWHINDMKRKHEHAVRLQEIQSLLTNWKGPDLTSYGELVLEGTFRIQRAKNERTLFLFDKLLLITK 352
Cdd:cd13243    1 RSVVEEALDTMTQVAWHINDMKRKHEHAVRVQEIQSLLDGWEGPELTTYGDLVLEGTFRMAGAKNERLLFLFDKMLLITK 80

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 71274148  353 KRDD-TFTYKAHILCGNLMLVEVIPKEPLSFSVFHYKNPKLQHTVQAKSQQDKRLWVLHLKRLILEN 418
Cdd:cd13243   81 KREDgILQYKTHIMCSNLMLSESIPKEPLSFQVLPFDNPKLQYTLQAKNQEQKRLWTQEIKRLILEN 147

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 71274148  115 DRVVQEILETERTYVQDLKSIVEDYLDCIrDQTKLPLGTEERSALFGNIQDIYHFNSELLQDLENC----ENDPVAIAEC 190
Cdd:cd00160    2 QEVIKELLQTERNYVRDLKLLVEVFLKPL-DKELLPLSPEEVELLFGNIEEIYEFHRIFLKSLEERveewDKSGPRIGDV 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71274148  191 FVSKSEEFHIYTQYCTNYPRSVAVLTECMRNKilaKFFRE---RQETLKHSLPLGSYLLKPVQRILKYHLLLHEIENHLD 267
Cdd:cd00160   81 FLKLAPFFKIYSEYCSNHPDALELLKKLKKFN---KFFQEfleKAESECGRLKLESLLLKPVQRLTKYPLLLKELLKHTP 157

                        170       180
                 ....*....|....*....|....
gi 71274148  268 KDTEGYDVVLDAIDTMQRVAWHIN 291
Cdd:cd00160  158 DGHEDREDLKKALEAIKEVASQVN 181

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 71274148  298 EHAVRLQEIQSLLTNWKGPDL--TSYgELVLEGTF-RIQRAKN-ERTLFLFDKLLLITKK---RDDTFTYKAHILCgNLM 370
Cdd:cd01224    2 ENLEKLAAWQSTVEGWEGEDLsdRSS-ELIHSGELtKISAGRAqERTFFLFDHQLVYCKKdllRRKNYIYKGRIDT-DNM 79

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|.
gi 71274148  371 LVEVIPKEPLSFSVFHYKNP-KLQ-------HTVQAKSQQDKRLWVLHLKR 413
Cdd:cd01224   80 EIEDLPDGKDDESGVTVKNAwKIYnasknkwYVLCAKSAEEKQRWLEAFAE 130

p63RhoGEF pleckstrin homology (PH) domain, repeat 2; The guanine nucleotide exchange factor p63RhoGEF is an effector of the heterotrimeric G protein, Galphaq and linking Galphaq-coupled receptors (GPCRs) to the activation of RhoA. The Dbl(DH) and PH domains of p63RhoGEF interact with the effector-binding site and the C-terminal region of Galphaq and appear to relieve autoinhibition of the catalytic DH domain by the PH domain. Trio, Duet, and p63RhoGEF are shown to constitute a family of Galphaq effectors that appear to activate RhoA both in vitro and in intact cells. Dbs is a guanine nucleotide exchange factor (GEF), which contains spectrin repeats, a rhoGEF (DH) domain and a PH domain. The Dbs PH domain participates in binding to both the Cdc42 and RhoA GTPases. Trio plays an essential role in regulating the actin cytoskeleton during axonal guidance and branching. Trio is a multidomain signaling protein that contains two RhoGEF(DH)-PH domains in tandem. 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 71274148  318 LTSYGELVLEGTF--------RIQRAKnERTLFLFDKLL----LITKKR---DDTFTYKAHILCGNLMLVEVIPKEPLSF 382
Cdd:cd13241   11 ITAQGKLLLQGTLlvsepsagLLQKGK-ERRVFLFEQIIifseILGKKTqfsNPGYIYKNHIKVNKMSLEENVDGDPLRF 89

                         90       100       110
                 ....*....|....*....|....*....|....*....
gi 71274148  383 sVFHYKNPKLQH---TVQAKSQQDKRLWVLHLKRlILEN 418
Cdd:cd13241   90 -ALKSRDPNNPSetfILQAASPEVRQEWVDTINQ-ILDT 126

Shape and Conjugation Deficiency 1 Pleckstrin homology (PH) domain; Fission yeast Scd1 is an exchange factor for Cdc42 and an effector of Ras1, the homolog of the human H-Ras. Scd2/Bem1 mediates Cdc42 activation by binding to Scd1/Cdc24 and to Cdc42. Ras1 regulates Scd1/Cdc24/Ral1, which is a putative guanine nucleotide exchange factor for Cdc42, a member of the Rho family of Ras-like proteins. Cdc42 then activates the Shk1/Orb2 protein kinase. Scd1 interacts with Klp5 and Klp6 kinesins to mediate cytokinesis. 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
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 71274148  294 KRKHEHAVRLQEIQSLLTNWKGPDLTSYGELVLEGTFRIQRAKNER--TLFLFDKLLLITK 352
Cdd:cd13246    1 QRRAENQQVVDDLKARVEDWKGHSLDSFGELLLHDTFTVRKDDSEReyHVYLFERILLCCK 61

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 71274148     324 LVLEGTFRIQRAKN-----ERTLFLFDKLLLITKKRDDT--FTYKAHILCGNLMLVEV----IPKEPLSFSVFHykNPKL 392
Cdd:smart00233    1 VIKEGWLYKKSGGGkkswkKRYFVLFNSTLLYYKSKKDKksYKPKGSIDLSGCTVREApdpdSSKKPHCFEIKT--SDRK 78

                            90       100
                    ....*....|....*....|...
gi 71274148     393 QHTVQAKSQQDKRLWVLHLKRLI 415
Cdd:smart00233   79 TLLLQAESEEEREKWVEALRKAI 101

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 71274148  322 GELVLEGTFRIQRAKnERTLFLFDKLLLITK-KRDDTFTYKAHI-LCGNLMLVEVIPKE-PLSFSVFHYKNPKlqHTVQA 398
Cdd:cd00821    3 GYLLKRGGGGLKSWK-KRWFVLFEGVLLYYKsKKDSSYKPKGSIpLSGILEVEEVSPKErPHCFELVTPDGRT--YYLQA 79

                         90
                 ....*....|...
gi 71274148  399 KSQQDKRLWVLHL 411
Cdd:cd00821   80 DSEEERQEWLKAL 92

PH domain; PH stands for pleckstrin homology.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 71274148    322 GELVLEGTFRIQRAKnERTLFLFDKLLLITKKRDDT--FTYKAHILCGNLMLVEVI----PKEPLSFSV-FHYKNPKLQH 394
Cdd:pfam00169    5 GWLLKKGGGKKKSWK-KRYFVLFDGSLLYYKDDKSGksKEPKGSISLSGCEVVEVVasdsPKRKFCFELrTGERTGKRTY 83

                           90       100
                   ....*....|....*....|.
gi 71274148    395 TVQAKSQQDKRLWVLHLKRLI 415
Cdd:pfam00169   84 LLQAESEEERKDWIKAIQSAI 104