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 62511232  15 FQERLKITALPLYFEGFLLVKRSDHQEYKHYWTELRGTTLFFYTDKKSTIYVGKLDIIDLVCLTGQHSTEKN--CAKFTL 92
Cdd:cd13268   1 RQERPKIQLPPCYYEGFLEKKRPKDREYRKLWTELCGTTLFFYNDKKDTQYVEKLDLSALESLTDEISRGRNldAARFTL 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*..
gi 62511232  93 VLPKEEVHVKTENTESGEEWRGFILTVTELTVPQHVSLLPGQVIRLH 139
Cdd:cd13268  81 VLKDEEVKFKAENLESREEWKGFILTVTELSVPTSLTLLPGQIHMLK 127

BCR downstream signaling 1 Pleckstrin homology (PH) domain; Brdg1 is thought to function as a docking protein acting downstream of Tec, a protein tyrosine kinases (PTK), in B-cell antigen receptor (BCR) signaling. BRDG1 contains a proline-rich (PR) motif which is thought to bind SH3 or WW domains, a PH domain, and multiple tyrosine residues which are potential target sites for SH2 domains. Since PH domains bind phospholipids it is thought to be involved in the tethering of Tec and BRDG1 to the cell membrane.Tec and Pyk2, but not Btk, Bmx, Lyn, Syk, or c-Abl, induces phosphorylation of BRDG1 on tyrosine residues. Efficient phosphorylation requires both the PH and SH2 domains of BRDG1 and the kinase domain of Tec. The overexpression of BRDG1 increases theBCR-mediated activation of cAMP-response element binding protein (CREB). Phosphorylated BRDG1 is hypothesized to recruit CREB either directly or through its recruitment of downstream effectors which then recruit CREB. 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 62511232  15 FQERLKITALPLYFEGFLLVKRSDHQEYKHYWTELRGTTLFFYTDKKSTIYVGKLDIIDLVCLTGQHSTEKN--CAKFTL 92
Cdd:cd13268   1 RQERPKIQLPPCYYEGFLEKKRPKDREYRKLWTELCGTTLFFYNDKKDTQYVEKLDLSALESLTDEISRGRNldAARFTL 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*..
gi 62511232  93 VLPKEEVHVKTENTESGEEWRGFILTVTELTVPQHVSLLPGQVIRLH 139
Cdd:cd13268  81 VLKDEEVKFKAENLESREEWKGFILTVTELSVPTSLTLLPGQIHMLK 127

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 62511232     29 EGFLLVKRSDH-QEYKHYWTELRGTTLFFYTDKKSTIYVGKLDIIDLVCLTGQHSTEKNCAK----FTLVLPKEEVHV-K 102
Cdd:smart00233   4 EGWLYKKSGGGkKSWKKRYFVLFNSTLLYYKSKKDKKSYKPKGSIDLSGCTVREAPDPDSSKkphcFEIKTSDRKTLLlQ 83

                           90
                   ....*....|
gi 62511232    103 TENTESGEEW 112
Cdd:smart00233  84 AESEEEREKW 93

BCR downstream signaling 1 Pleckstrin homology (PH) domain; Brdg1 is thought to function as a docking protein acting downstream of Tec, a protein tyrosine kinases (PTK), in B-cell antigen receptor (BCR) signaling. BRDG1 contains a proline-rich (PR) motif which is thought to bind SH3 or WW domains, a PH domain, and multiple tyrosine residues which are potential target sites for SH2 domains. Since PH domains bind phospholipids it is thought to be involved in the tethering of Tec and BRDG1 to the cell membrane.Tec and Pyk2, but not Btk, Bmx, Lyn, Syk, or c-Abl, induces phosphorylation of BRDG1 on tyrosine residues. Efficient phosphorylation requires both the PH and SH2 domains of BRDG1 and the kinase domain of Tec. The overexpression of BRDG1 increases theBCR-mediated activation of cAMP-response element binding protein (CREB). Phosphorylated BRDG1 is hypothesized to recruit CREB either directly or through its recruitment of downstream effectors which then recruit CREB. 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 62511232  15 FQERLKITALPLYFEGFLLVKRSDHQEYKHYWTELRGTTLFFYTDKKSTIYVGKLDIIDLVCLTGQHSTEKN--CAKFTL 92
Cdd:cd13268   1 RQERPKIQLPPCYYEGFLEKKRPKDREYRKLWTELCGTTLFFYNDKKDTQYVEKLDLSALESLTDEISRGRNldAARFTL 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*..
gi 62511232  93 VLPKEEVHVKTENTESGEEWRGFILTVTELTVPQHVSLLPGQVIRLH 139
Cdd:cd13268  81 VLKDEEVKFKAENLESREEWKGFILTVTELSVPTSLTLLPGQIHMLK 127

Src homology 2 domain found in Signal-transducing adaptor protein (STAP) family; STAP1 and STAP2 are signal-transducing adaptor proteins. They are composed of a Pleckstrin homology (PH) and SH2 domains along with several tyrosine phosphorylation sites. STAP-1 is an ortholog of BRDG1 (BCR downstream signaling 1). STAP1 protein functions as a docking protein acting downstream of Tec tyrosine kinase in B cell antigen receptor signaling. The protein is phosphorylated by Tec and participates in a positive feedback loop, increasing Tec activity. STAP1 has been shown to interact with C19orf2, an unconventional prefoldin RPB5 interactor. The STAP2 protein is the substrate of breast tumor kinase, an Src-type non-receptor tyrosine kinase that mediates the interactions linking proteins involved in signal transduction pathways. STAP2 has alternative splicing variants. STAP2 has been shown to interact with tyrosine-protein kinase 6 (PTK6). In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 62511232 178 PECFYAVSRKEATAMLEKNPSWGNMILRPGSDSKNYSITIRQEIEMPRIKHFKVTRTGNNYTIELEKPVTLPNLFSVIDY 257
Cdd:cd09939   1 PACFYTVSRKEATELLERNPSCGNMLLRPGSDSRNYSVTTRQEINIPVIRHYKVMSVGQNYTIELEKPVTCPNLFSVINY 80

                        90
                ....*....|...
gi 62511232 258 FVKETRGNLRPFI 270
Cdd:cd09939  81 FVKETRGNLRPFI 93

Src homology 2 (SH2) domain; In general, SH2 domains are involved in signal transduction; they bind pTyr-containing polypeptide ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites. They are present in a wide array of proteins including: adaptor proteins (Nck1, Crk, Grb2), scaffolds (Slp76, Shc, Dapp1), kinases (Src, Syk, Fps, Tec), phosphatases (Shp-1, Shp-2), transcription factors (STAT1), Ras signaling molecules (Ras-Gap), ubiquitination factors (c-Cbl), cytoskeleton regulators (Tensin), signal regulators (SAP), and phospholipid second messengers (PLCgamma), amongst others.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 62511232 184 VSRKEATAMLEKNPSwGNMILRPGSDSKN-YSITIRQEieMPRIKHFKVTRTGNNYTIELEKPVTLPNLFSVIDYF 258
Cdd:cd00173   7 ISREEAERLLRGKPD-GTFLVRESSSEPGdYVLSVRSG--DGKVKHYLIERNEGGYYLLGGSGRTFPSLPELVEHY 79

ArfGAP with RhoGAP domain, ankyrin repeat and PH domain Pleckstrin homology (PH) domain, repeat 3; ARAP proteins (also called centaurin delta) are phosphatidylinositol 3,4,5-trisphosphate-dependent GTPase-activating proteins that modulate actin cytoskeleton remodeling by regulating ARF and RHO family members. They bind phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) and phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4,5)P2) binding. There are 3 mammalian ARAP proteins: ARAP1, ARAP2, and ARAP3. All ARAP proteins contain a N-terminal SAM (sterile alpha motif) domain, 5 PH domains, an ArfGAP domain, 2 ankyrin domain, A RhoGap domain, and a Ras-associating domain. This hierarchy contains the third PH domain in ARAP. 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 62511232  25 PLYFEGFL---------LVKRSDHQEYKHYWTELRGTTLFFYTDKKSTIYVGKLDIIDLVCL----TGQHSTEKNCAKFT 91
Cdd:cd13256   1 SVFHSGFLykspsaakpTLERRAREEFSRRWCVLEDGFLSYYESERSPEPNGEIDVSEIVCLavspPDTHPGDGFPFTFE 80

                        90       100
                ....*....|....*....|..
gi 62511232  92 LVLPKEEV-HVKTENTESGEEW 112
Cdd:cd13256  81 LYLESERLyLFGLETAEALHEW 102

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 62511232     29 EGFLLVKRSDH-QEYKHYWTELRGTTLFFYTDKKSTIYVGKLDIIDLVCLTGQHSTEKNCAK----FTLVLPKEEVHV-K 102
Cdd:smart00233   4 EGWLYKKSGGGkKSWKKRYFVLFNSTLLYYKSKKDKKSYKPKGSIDLSGCTVREAPDPDSSKkphcFEIKTSDRKTLLlQ 83

                           90
                   ....*....|
gi 62511232    103 TENTESGEEW 112
Cdd:smart00233  84 AESEEEREKW 93

T-lymphoma invasion and metastasis 1 and 2 Pleckstrin Homology (PH) domain, N-terminal domain; Tiam1 activates Rac GTPases to induce membrane ruffling and cell motility while Tiam2 (also called STEF (SIF (still life) and Tiam1 like-exchange factor) contributes to neurite growth. Tiam1/2 are Dbl-family of GEFs that possess a Dbl(DH) domain with a PH domain in tandem. DH-PH domain catalyzes the GDP/GTP exchange reaction in the GTPase cycle and facillitating the switch between inactive GDP-bound and active GTP-bound states. Tiam1/2 possess two PH domains, which are often referred to as PHn and PHc domains. The DH-PH tandem domain is made up of the PHc domain while the PHn is part of a novel N-terminal PHCCEx domain which is made up of the PHn domain, a coiled coil region(CC), and an extra region (Ex). PHCCEx mediates binding to plasma membranes and signalling proteins in the activation of Rac GTPases. The PH domain resembles the beta-spectrin PH domain, suggesting non-canonical phosphatidylinositol binding. CC and Ex form a positively charged surface for protein binding. There are 2 motifs in Tiam1/2-interacting proteins that bind to the PHCCEx domain: Motif-I in CD44, ephrinBs, and the NMDA receptor and Motif-II in Par3 and JIP2.Neither of these fall in the PHn 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
                ....*....|....*....|....*....|....*....|....*.
gi 62511232  26 LYFEGFLLVKRSDHQE------YKHYWTELRGTTLFFY-TDKKSTI 64
Cdd:cd01230   9 LSVKNFLVHKKNKKVElatrrkWKKYWVCLKGCTLLFYeCDERSGI 54