Pleckstrin homology-like domain; The PH-like family includes the PH domain, both the Shc-like and IRS-like PTB domains, the ran-binding domain, the EVH1 domain, a domain in neurobeachin and the third domain of FERM. All of these domains have a PH fold, but lack significant sequence similarity. They are generally involved in targeting to protein to the appropriate cellular location or interacting with a binding partner. This domain family possesses multiple functions including the ability to bind inositol phosphates and to other proteins.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767926127 474 AVTECPDDIGKLGKLLLHGPFSVWTIHKDRYKMKDlIRFKPSQRQIYLFERGIVFCKIRmepGDQGLSPHYSFKKTMKLM 553
Cdd:cd01227    1 AITGYDGNLGDLGKLLMQGSFNVWTEHKKGHTKKL-ARFKPMQRHIFLYEKAVLFCKKR---GENGEAPSYSYKNSLNTT 76

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|
gi 767926127 554 TLSIRQLGRGSHRKFEIASRNGLEKYILQAASKEIRDCWFSEISKLLMEQ 603
Cdd:cd01227   77 AVGLTENVKGDTKKFEIWLNGREEVFIIQAPTPEIKAAWVKAIRQVLLSQ 126

DBL's big sister protein pleckstrin homology (PH) domain; Dbs (also called MCF2-transforming sequence-like protein 2) 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. 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 767926127 474 AVTECPDDIGKLGKLLLHGPFSVWTIHKDRYKMKDlIRFKPSQRQIYLFERGIVFCKIRmepGDQGLSPHYSFKKTMKLM 553
Cdd:cd01227    1 AITGYDGNLGDLGKLLMQGSFNVWTEHKKGHTKKL-ARFKPMQRHIFLYEKAVLFCKKR---GENGEAPSYSYKNSLNTT 76

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|
gi 767926127 554 TLSIRQLGRGSHRKFEIASRNGLEKYILQAASKEIRDCWFSEISKLLMEQ 603
Cdd:cd01227   77 AVGLTENVKGDTKKFEIWLNGREEVFIIQAPTPEIKAAWVKAIRQVLLSQ 126

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 767926127  270 IIRDLLETEEIYIKEIKSIIDGYITPmdfiwlKHLIPDVLQNNKDFLFGNIRELYEFHNRTFLKELEKCAENPELLAHCF 349
Cdd:pfam00621   1 VIKELLQTERSYVRDLEILVEVFLPP------NSKPLSESEEEIKTIFSNIEEIYELHRQLLLEELLKEWISIQRIGDIF 74

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767926127  350 LKRKEDLQIYFKYHKNLPRARAIWQECQD-----CAYFGVCQRQLD-HNLPLFKYLKGPSQRLIKYQMLLKGLLDFESPE 423
Cdd:pfam00621  75 LKFAPGFKVYSTYCSNYPKALKLLKKLLKknpkfRAFLEELEANPEcRGLDLNSFLIKPVQRIPRYPLLLKELLKHTPPD 154

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|...
gi 767926127  424 DMEidpgelggsakdgpkrtkdsafSTELQQALAVIEDLIKSC 466
Cdd:pfam00621 155 HPD----------------------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 767926127   504 YKMKDLIRFKPSQRQIYLFERGIVFCKIRMEPGDqglsphYSFKKTMKLMTLSIRQLGRGSHRK----FEIASRNGlEKY 579
Cdd:smart00233   8 YKKSGGGKKSWKKRYFVLFNSTLLYYKSKKDKKS------YKPKGSIDLSGCTVREAPDPDSSKkphcFEIKTSDR-KTL 80

                           90       100
                   ....*....|....*....|.
gi 767926127   580 ILQAASKEIRDCWFSEISKLL 600
Cdd:smart00233  81 LLQAESEEEREKWVEALRKAI 101

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767926127  504 YKMKDLIRFKPSQRQIYLFERGIVFCKirmepgDQGLSPHYSFKKTMKLMTLSIRQLGRGSHRK----FEI--ASRNGLE 577
Cdd:pfam00169   8 LKKGGGKKKSWKKRYFVLFDGSLLYYK------DDKSGKSKEPKGSISLSGCEVVEVVASDSPKrkfcFELrtGERTGKR 81

                          90       100
                  ....*....|....*....|...
gi 767926127  578 KYILQAASKEIRDCWFSEISKLL 600
Cdd:pfam00169  82 TYLLQAESEEERKDWIKAIQSAI 104

DBL's big sister protein pleckstrin homology (PH) domain; Dbs (also called MCF2-transforming sequence-like protein 2) 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. 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 767926127 474 AVTECPDDIGKLGKLLLHGPFSVWTIHKDRYKMKDlIRFKPSQRQIYLFERGIVFCKIRmepGDQGLSPHYSFKKTMKLM 553
Cdd:cd01227    1 AITGYDGNLGDLGKLLMQGSFNVWTEHKKGHTKKL-ARFKPMQRHIFLYEKAVLFCKKR---GENGEAPSYSYKNSLNTT 76

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|
gi 767926127 554 TLSIRQLGRGSHRKFEIASRNGLEKYILQAASKEIRDCWFSEISKLLMEQ 603
Cdd:cd01227   77 AVGLTENVKGDTKKFEIWLNGREEVFIIQAPTPEIKAAWVKAIRQVLLSQ 126

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 767926127  270 IIRDLLETEEIYIKEIKSIIDGYITPmdfiwlKHLIPDVLQNNKDFLFGNIRELYEFHNRTFLKELEKCAENPELLAHCF 349
Cdd:pfam00621   1 VIKELLQTERSYVRDLEILVEVFLPP------NSKPLSESEEEIKTIFSNIEEIYELHRQLLLEELLKEWISIQRIGDIF 74

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767926127  350 LKRKEDLQIYFKYHKNLPRARAIWQECQD-----CAYFGVCQRQLD-HNLPLFKYLKGPSQRLIKYQMLLKGLLDFESPE 423
Cdd:pfam00621  75 LKFAPGFKVYSTYCSNYPKALKLLKKLLKknpkfRAFLEELEANPEcRGLDLNSFLIKPVQRIPRYPLLLKELLKHTPPD 154

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|...
gi 767926127  424 DMEidpgelggsakdgpkrtkdsafSTELQQALAVIEDLIKSC 466
Cdd:pfam00621 155 HPD----------------------YEDLKKALEAIKEVAKQI 175

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 767926127 468 LAVDlaAVTECPDDIGKLGKLLLHGPFSVWtihkdrykmkdlIRFKPSQRQIYLFERGIVFCKIRMEPGDQGLsphYSFK 547
Cdd:cd13242   11 LAMD--SIRGCDVNLKEQGQLLRQDEFLVW------------QGRKKCLRHVFLFEDLILFSKPKKTPGGKDV---YIYK 73

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 767926127 548 KTMKLMTLSIRQLGRGSHRKFEI--ASRNGLEKYILQAASKEIRDCWFSEISKLLMEQQNNIK 608
Cdd:cd13242   74 HSIKTSDIGLTENVGDSGLKFEIwfRRRKARDTYILQATSPEIKQAWTSDIAKLLWKQAIRNR 136

Obscurin pleckstrin homology (PH) domain; Obscurin (also called Obscurin-RhoGEF; Obscurin-myosin light chain kinase/Obscurin-MLCK) is a giant muscle protein that is concentrated at the peripheries of Z-disks and M-lines. It binds small ankyrin I, a component of the sarcoplasmic reticulum (SR) membrane. It is associated with the contractile apparatus through binding with titin and sarcomeric myosin. It plays important roles in the organization and assembly of the myofibril and the SR. Obscurin has been observed as alternatively-spliced isoforms. The major isoform in sleletal muscle, approximately 800 kDa in size, is composed of many adhesion modules and signaling domains. It harbors 49 Ig and 2 FNIII repeats at the N-terminues, a complex middle region with additional Ig domains, an IQ motif, and a conserved SH3 domain near RhoGEF and PH domains, and a non-modular C-terminus with phosphorylation motifs. The obscurin gene also encodes two kinase domains, which are not part of the 800 kDa form of the protein, but is part of smaller spliced products that present in heart muscle. 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 767926127 479 PDDIGKLGKLLLHGPFSVWTiHKDRYKMKDlirfKPSQRQIYLFERGIVFCKIRMEPGDQGLSphYSFKKTMKLMTLSIR 558
Cdd:cd13239    6 PAPLQALGEPIRQGHFTVWE-EAPEVKTSS----RGHHRHVFLFKNCVVICKPKRDSRTDTVT--YVFKNKMKLSDIDVK 78

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|
gi 767926127 559 QLGRGSHRKFEI--ASRNGLEKYILQAASKEIRDCWFSEISKLlmeQQNN 606
Cdd:cd13239   79 DTVEGDDRSFGLwhEHRGSVRKYTLQARSAIIKSSWLKDLRDL---QQRL 125

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 767926127 478 CPDDIGKLGKLLLHGPFSVWtihkdryKMKDLIRfKPSQRQIYLFERGIVFCKirmEPGDQGLSPHYSFKktMKLMTLSI 557
Cdd:cd13240    5 CDEDLDSLGEVILQDSFQVW-------DPKQLIR-KGRERHVFLFELCLVFSK---EVKDSNGKSKYIYK--SRLMTSEI 71

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|
gi 767926127 558 RQLGR--GSHRKFEIASR---NGLEKYILQAASKEIRDCWFSEISKLLME 602
Cdd:cd13240   72 GVTEHieGDPCKFALWTGrvpTSDNKIVLKASSLEVKQTWVKKLREVIQE 121

Spectrin repeats;

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 767926127     2 HVEQILKEHKKLEEKSQEPLEKAQLLALVGDQLIQSHHYAADAIRPRCVELRHLCDDFingnKKKWDILGKSLE 75
Cdd:smart00150  32 SVEALLKKHEAFEAELEAHEERVEALNELGEQLIEEGHPDAEEIEERLEELNERWEEL----KELAEERRQKLE 101

PH domain; PH stands for pleckstrin homology.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767926127  504 YKMKDLIRFKPSQRQIYLFERGIVFCKirmepgDQGLSPHYSFKKTMKLMTLSIRQLGRGSHRK----FEI--ASRNGLE 577
Cdd:pfam00169   8 LKKGGGKKKSWKKRYFVLFDGSLLYYK------DDKSGKSKEPKGSISLSGCEVVEVVASDSPKrkfcFELrtGERTGKR 81

                          90       100
                  ....*....|....*....|...
gi 767926127  578 KYILQAASKEIRDCWFSEISKLL 600
Cdd:pfam00169  82 TYLLQAESEEERKDWIKAIQSAI 104