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 149028238  11 RGPKLKGAPPSHYYENFLEKKGPCDQDYRKFWAGLQGLAICFYNSNRDLQPLEKLDLRLFSKLKDEALLGSSHDTTyHFS 90
Cdd:cd13268    1 RQERPKIQLPPCYYEGFLEKKRPKDREYRKLWTELCGTTLFFYNDKKDTQYVEKLDLSALESLTDEISRGRNLDAA-RFT 79

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*..
gi 149028238  91 LVLRDQEVKFKVESLESCEMWKGFILTVVELRVPSNLTLLPGHMYMM 137
Cdd:cd13268   80 LVLKDEEVKFKAENLESREEWKGFILTVTELSVPTSLTLLPGQIHML 126

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 149028238  11 RGPKLKGAPPSHYYENFLEKKGPCDQDYRKFWAGLQGLAICFYNSNRDLQPLEKLDLRLFSKLKDEALLGSSHDTTyHFS 90
Cdd:cd13268    1 RQERPKIQLPPCYYEGFLEKKRPKDREYRKLWTELCGTTLFFYNDKKDTQYVEKLDLSALESLTDEISRGRNLDAA-RFT 79

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*..
gi 149028238  91 LVLRDQEVKFKVESLESCEMWKGFILTVVELRVPSNLTLLPGHMYMM 137
Cdd:cd13268   80 LVLKDEEVKFKAENLESREEWKGFILTVTELSVPTSLTLLPGQIHML 126

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 149028238  11 RGPKLKGAPPSHYYENFLEKKGPCDQDYRKFWAGLQGLAICFYNSNRDLQPLEKLDLRLFSKLKDEALLGSSHDTTyHFS 90
Cdd:cd13268    1 RQERPKIQLPPCYYEGFLEKKRPKDREYRKLWTELCGTTLFFYNDKKDTQYVEKLDLSALESLTDEISRGRNLDAA-RFT 79

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*..
gi 149028238  91 LVLRDQEVKFKVESLESCEMWKGFILTVVELRVPSNLTLLPGHMYMM 137
Cdd:cd13268   80 LVLKDEEVKFKAENLESREEWKGFILTVTELSVPTSLTLLPGQIHML 126

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
                 ....*....|....*....|....*....|....*....|....*..
gi 149028238 153 PWCFLQVSRLEAQLLLERYPECGNLLLRPGGDGkDSVSVTTRQILNG 199
Cdd:cd09939    1 PACFYTVSRKEATELLERNPSCGNMLLRPGSDS-RNYSVTTRQEINI 46

Src homology 2 domain found in Signal-transducing adaptor protein 2 (STAP2); STAP2 is a signal-transducing adaptor protein. It is composed of a Pleckstrin homology (PH) and SH2 domains along with several tyrosine phosphorylation sites. 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
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 149028238  96 QEVKFKVESLESCEMWKgfiltvvELRVPSNLTLLPGHMYMMAEVLAKEEVRRAAEV 152
Cdd:cd10404    1 PSCFLKVSRLEAQLLLE-------RYPECGNLLLRPGGDGADGVSVTTRQMLNGTPV 50