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 1676323754 309 LGRLRGFEGKLTAQGKLLGQDTFWVTEPEAGglLSSRGRERRVFLFEQIIIFSEALGGGvRGGTQPGYVYKNSIKVSCLG 388
Cdd:cd13241     1 VGRLQGFDGKITAQGKLLLQGTLLVSEPSAG--LLQKGKERRVFLFEQIIIFSEILGKK-TQFSNPGYIYKNHIKVNKMS 77

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1676323754 389 LEGNLQGDPCRFALTSRGPEGGIQRYVLQAADPAISQAWIKHVAQILESQRDFLNALQSPIEY 451
Cdd:cd13241    78 LEENVDGDPLRFALKSRDPNNPSETFILQAASPEVRQEWVDTINQILDTQRDFLKALQSPIAY 140

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 1676323754 309 LGRLRGFEGKLTAQGKLLGQDTFWVTEPEAGglLSSRGRERRVFLFEQIIIFSEALGGGvRGGTQPGYVYKNSIKVSCLG 388
Cdd:cd13241     1 VGRLQGFDGKITAQGKLLLQGTLLVSEPSAG--LLQKGKERRVFLFEQIIIFSEILGKK-TQFSNPGYIYKNHIKVNKMS 77

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1676323754 389 LEGNLQGDPCRFALTSRGPEGGIQRYVLQAADPAISQAWIKHVAQILESQRDFLNALQSPIEY 451
Cdd:cd13241    78 LEENVDGDPLRFALKSRDPNNPSETFILQAASPEVRQEWVDTINQILDTQRDFLKALQSPIAY 140

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 1676323754 163 YVLSELVETEKMYVDDLGQIVEGYMATMAAQGVPESLRGRDRIvFGNIQQIYEWHRDyFLQELQRCLKDPDW----LAQL 238
Cdd:cd00160     3 EVIKELLQTERNYVRDLKLLVEVFLKPLDKELLPLSPEEVELL-FGNIEEIYEFHRI-FLKSLEERVEEWDKsgprIGDV 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1676323754 239 FIKHE-------------------LRQQL----------------GHRLQLNDLLIKPVQRIMKYQLLLKDFLKYYNRAG 283
Cdd:cd00160    81 FLKLApffkiyseycsnhpdalelLKKLKkfnkffqeflekaeseCGRLKLESLLLKPVQRLTKYPLLLKELLKHTPDGH 160

                         170       180
                  ....*....|....*....|.
gi 1676323754 284 MDTADLEQAVEVMCFVPKRCN 304
Cdd:cd00160   161 EDREDLKKALEAIKEVASQVN 181

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 1676323754 309 LGRLRGFEGKLTAQGKLLGQDTFWVTEPEAGglLSSRGRERRVFLFEQIIIFSEALGGGvRGGTQPGYVYKNSIKVSCLG 388
Cdd:cd13241     1 VGRLQGFDGKITAQGKLLLQGTLLVSEPSAG--LLQKGKERRVFLFEQIIIFSEILGKK-TQFSNPGYIYKNHIKVNKMS 77

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1676323754 389 LEGNLQGDPCRFALTSRGPEGGIQRYVLQAADPAISQAWIKHVAQILESQRDFLNALQSPIEY 451
Cdd:cd13241    78 LEENVDGDPLRFALKSRDPNNPSETFILQAASPEVRQEWVDTINQILDTQRDFLKALQSPIAY 140

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 1676323754 163 YVLSELVETEKMYVDDLGQIVEGYMATMAAQGVPESLRGRDRIvFGNIQQIYEWHRDyFLQELQRCLKDPDW----LAQL 238
Cdd:cd00160     3 EVIKELLQTERNYVRDLKLLVEVFLKPLDKELLPLSPEEVELL-FGNIEEIYEFHRI-FLKSLEERVEEWDKsgprIGDV 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1676323754 239 FIKHE-------------------LRQQL----------------GHRLQLNDLLIKPVQRIMKYQLLLKDFLKYYNRAG 283
Cdd:cd00160    81 FLKLApffkiyseycsnhpdalelLKKLKkfnkffqeflekaeseCGRLKLESLLLKPVQRLTKYPLLLKELLKHTPDGH 160

                         170       180
                  ....*....|....*....|.
gi 1676323754 284 MDTADLEQAVEVMCFVPKRCN 304
Cdd:cd00160   161 EDREDLKKALEAIKEVASQVN 181

Puratrophin-1 pleckstrin homology (PH) domain; Puratrophin-1 (also called Purkinje cell atrophy-associated protein 1 or PLEKHG4/Pleckstrin homology domain-containing family G member 4) contains a spectrin repeat, a RhoGEF (DH) domain, and a PH domain. It is thought to function in intracellular signaling and cytoskeleton dynamics at the Golgi. Puratrophin-1 is expressed in kidney, Leydig cells in the testis, epithelial cells in the prostate gland and Langerhans islet in the pancreas. A single nucleotide substitution in the puratrophin-1 gene were once thought to result in autosomal dominant cerebellar ataxia (ADCA), but now it has been demonstrated that this ataxia is a result of defects in the BEAN gene. Puratrophin contains a domain architecture similar to that of Dbl family members Dbs and Trio. 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 1676323754 304 NDMMTLGRLRGFEGKLTAQGKLLGQDTFWVTEpeaggllSSRGRERRVFLFEQIIIFSEAlgggvrGGTQPG---YVYKN 380
Cdd:cd13242     8 NDLLAMDSIRGCDVNLKEQGQLLRQDEFLVWQ-------GRKKCLRHVFLFEDLILFSKP------KKTPGGkdvYIYKH 74

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 1676323754 381 SIKVSCLGLEGNLQGDPCRFALTSRGPEGGiQRYVLQAADPAISQAWIKHVAQILESQ 438
Cdd:cd13242    75 SIKTSDIGLTENVGDSGLKFEIWFRRRKAR-DTYILQATSPEIKQAWTSDIAKLLWKQ 131

Triple functional domain pleckstrin homology pleckstrin homology (PH) domain, repeat 1; RhoGEFs, Kalirin and Trio, the mammalian homologs of Drosophila Trio and Caenorhabditis elegans UNC-73 regulate a novel step in secretory granule maturation. Their signaling modulates the extent to which regulated cargo enter and remain in the regulated secretory pathway. This allows for fine tuning of peptides released by a single secretory cell type with impaired signaling leading to pathological states. Trio plays an essential role in regulating the actin cytoskeleton during axonal guidance and branching. Kalirin and Trio are encoded by separate genes in mammals and by a single one in invertebrates. Kalirin and Trio share the same complex multidomain structure and display several splice variants. The longest Kalirin and Trio proteins have a Sec14 domain, a stretch of spectrin repeats, a RhoGEF(DH)/PH cassette (also called GEF1), an SH3 domain, a second RhoGEF(DH)/PH cassette (also called GEF2), a second SH3 domain, Ig/FNIII domains, and a kinase domain. The first RhoGEF(DH)/PH cassette catalyzes exchange on Rac1 and RhoG while the second RhoGEF(DH)/PH cassette is specific for RhoA. Kalirin and Trio are closely related to p63RhoGEF and have PH domains of similar function. 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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1676323754 312 LRGFEGKLTAQGKLLGQDTFWVTEPEAgglLSSRGRERRVFLFEQIIIFSEALGGGVRggtQPGYVYKNSIKVSCLGLEG 391
Cdd:cd13240     2 LEGCDEDLDSLGEVILQDSFQVWDPKQ---LIRKGRERHVFLFELCLVFSKEVKDSNG---KSKYIYKSRLMTSEIGVTE 75

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*
gi 1676323754 392 NLQGDPCRFALTSRGPEGGIQRYVLQAADPAISQAWIKHVAQILE 436
Cdd:cd13240    76 HIEGDPCKFALWTGRVPTSDNKIVLKASSLEVKQTWVKKLREVIQ 120

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 1676323754 289 LEQAVEVMCFVPKRCNDMM-----------TLGRLRGFEGK-LTAQGKLLGQDTFwvtepeaggLLSSRGRERRVFLFEQ 356
Cdd:cd13243     4 VEEALDTMTQVAWHINDMKrkhehavrvqeIQSLLDGWEGPeLTTYGDLVLEGTF---------RMAGAKNERLLFLFDK 74

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1676323754 357 IIIFSEALGGGvrggtqpGYVYKNSIKVSCLGLEGNLQGDPCRFALTSRG-PEggiQRYVLQAADPAISQAWIKHVAQ-I 434
Cdd:cd13243    75 MLLITKKREDG-------ILQYKTHIMCSNLMLSESIPKEPLSFQVLPFDnPK---LQYTLQAKNQEQKRLWTQEIKRlI 144

                  ...
gi 1676323754 435 LES 437
Cdd:cd13243   145 LEN 147

unc89 pleckstrin homology (PH) domain; unc89 is a myofibrillar protein. unc89-B the largest isoform is composed of 53 immunoglobulin (Ig) domains, 2 Fn3 domains, a triplet of SH3, DH and PH domains at its N-terminus, and 2 protein kinase domains (PK1 and PK2) at its C-terminus. unc-89 mutants display disorganization of muscle A-bands, and usually lack M-lines. The COOH-terminal region of obscurin, the human homolog of unc89, interacts via two specific Ig-like domains with the NH(2)-terminal Z-disk region of titin, a protein that connects the Z line to the M line in the sarcomere and contributes to the contraction of striated muscle. obscurin is also thought to be involved in Ca2+/calmodulin via its IQ domains, as well as G protein-coupled signal transduction in the sarcomere via its RhoGEF/DH domain. The DH-PH region of OBSCN and unc89, the C. elegans homolog, has exchange activity for RhoA and Rho-1 respectively, but not for the small GTPases homologous to Cdc42 or Rac. 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 1676323754 317 GKLtaqGKLLGQDTFWVTEPEaggllsSRGRERRVFLFEQIIIFSEalgggVRGGTQPGYVY--KNSIKVSCLGLEgNLQ 394
Cdd:cd13325     4 HKL---GRLLRHDWFTVTDGE------GKAKERYLFLFKSRILITK-----VRRISEDRSVFilKDIIRLPEVNVK-QHP 68

                          90       100       110
                  ....*....|....*....|....*....|....*....
gi 1676323754 395 GDPCRFALTSRGPEGGIQRYVLQAADPAISQAWIKHVAQ 433
Cdd:cd13325    69 DDERTFELQPKLPAFGILPIDFKAHKDEIKDYWLNEIEE 107