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 6912272   15 FQERLKITALPLYFEGFLLIKRSGYREYEHYWTELRGTTLFFYTDKKSIIYVDKLDIVDLTCLTEQNSTEKN--CAKFTL 92
Cdd:cd13268   1 RQERPKIQLPPCYYEGFLEKKRPKDREYRKLWTELCGTTLFFYNDKKDTQYVEKLDLSALESLTDEISRGRNldAARFTL 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*..
gi 6912272   93 VLPKEEVQLKTENTESGEEWRGFILTVTELSVPQNVSLLPGQVIKLH 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 6912272   15 FQERLKITALPLYFEGFLLIKRSGYREYEHYWTELRGTTLFFYTDKKSIIYVDKLDIVDLTCLTEQNSTEKN--CAKFTL 92
Cdd:cd13268   1 RQERPKIQLPPCYYEGFLEKKRPKDREYRKLWTELCGTTLFFYNDKKDTQYVEKLDLSALESLTDEISRGRNldAARFTL 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*..
gi 6912272   93 VLPKEEVQLKTENTESGEEWRGFILTVTELSVPQNVSLLPGQVIKLH 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 6912272      29 EGFLLIKRSGY-REYEHYWTELRGTTLFFYTDKKSIIYVDKLDIVDLTCLT----EQNSTEKNCAKFTLVLP-KEEVQLK 102
Cdd:smart00233   4 EGWLYKKSGGGkKSWKKRYFVLFNSTLLYYKSKKDKKSYKPKGSIDLSGCTvreaPDPDSSKKPHCFEIKTSdRKTLLLQ 83

                           90
                   ....*....|
gi 6912272     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 6912272   15 FQERLKITALPLYFEGFLLIKRSGYREYEHYWTELRGTTLFFYTDKKSIIYVDKLDIVDLTCLTEQNSTEKN--CAKFTL 92
Cdd:cd13268   1 RQERPKIQLPPCYYEGFLEKKRPKDREYRKLWTELCGTTLFFYNDKKDTQYVEKLDLSALESLTDEISRGRNldAARFTL 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*..
gi 6912272   93 VLPKEEVQLKTENTESGEEWRGFILTVTELSVPQNVSLLPGQVIKLH 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 6912272  176 PACFYTVSRKEATEMLQKNPSLGNMILRPGSDSRNYSITIRQEIDIPRIKHYKVMSVGQNYTIELEKPVTLPNLFSVIDY 255
Cdd:cd09939   1 PACFYTVSRKEATELLERNPSCGNMLLRPGSDSRNYSVTTRQEINIPVIRHYKVMSVGQNYTIELEKPVTCPNLFSVINY 80

                        90
                ....*....|...
gi 6912272  256 FVKETRGNLRPFI 268
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 6912272  182 VSRKEATEMLQKNPSlGNMILRPGSDSRN-YSITIRQEIDipRIKHYKVMSVGQNYTIELEKPVTLPNLFSVIDYF 256
Cdd:cd00173   7 ISREEAERLLRGKPD-GTFLVRESSSEPGdYVLSVRSGDG--KVKHYLIERNEGGYYLLGGSGRTFPSLPELVEHY 79

C-terminal Src homology 2 (C-SH2) domain in Phospholipase C gamma; Phospholipase C gamma is a signaling molecule that is recruited to the C-terminal tail of the receptor upon autophosphorylation of a highly conserved tyrosine. PLCgamma is composed of a Pleckstrin homology (PH) domain followed by an elongation factor (EF) domain, 2 catalytic regions of PLC domains that flank 2 tandem SH2 domains (N-SH2, C-SH2), and ending with a SH3 domain and C2 domain. N-SH2 SH2 domain-mediated interactions represent a crucial step in transmembrane signaling by receptor tyrosine kinases. SH2 domains recognize phosphotyrosine (pY) in the context of particular sequence motifs in receptor phosphorylation sites. Both N-SH2 and C-SH2 have a very similar binding affinity to pY. But in growth factor stimulated cells these domains bind to different target proteins. N-SH2 binds to pY containing sites in the C-terminal tails of tyrosine kinases and other receptors. Recently it has been shown that this interaction is mediated by phosphorylation-independent interactions between a secondary binding site found exclusively on the N-SH2 domain and a region of the FGFR1 tyrosine kinase domain. This secondary site on the SH2 cooperates with the canonical pY site to regulate selectivity in mediating a specific cellular process. C-SH2 binds to an intramolecular site on PLCgamma itself which allows it to hydrolyze phosphatidylinositol-4,5-bisphosphate into diacylglycerol and inositol triphosphate. These then activate protein kinase C and release calcium. 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 6912272  181 TVSRKEATEMLQKNPSLGNMILRP-GSDSRNYSITIRQEidiPRIKHYKVMSVGQNYTI---ELEkpvtlpNLFSVIDYF 256
Cdd:cd09932  10 NLTREQAEEMLMRVPRDGAFLVRPsETDPNSFAISFRAE---GKIKHCRIKQEGRLFVIgtsQFE------SLVELVSYY 80

                ..
gi 6912272  257 VK 258
Cdd:cd09932  81 EK 82

N-terminal Src homology 2 (SH2) domain found in Spt6; N-terminal SH2 domain in Spt6. Spt6 is an essential transcription elongation factor and histone chaperone that binds the C-terminal repeat domain (CTD) of RNA polymerase II. Spt6 contains a tandem SH2 domain with a novel structure and CTD-binding mode. The tandem SH2 domain binds to a serine 2-phosphorylated CTD peptide in vitro, whereas its N-terminal SH2 subdomain does not. CTD binding requires a positively charged crevice in the C-terminal SH2 subdomain, which lacks the canonical phospho-binding pocket of SH2 domains. The tandem SH2 domain is apparently required for transcription elongation in vivo as its deletion in cells is lethal in the presence of 6-azauracil. 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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 6912272  179 FYTVSRKEATEMLQKNPSlGNMILRPGSDSRNY-SITIR------QEIDIPRIKHYKVMSVGQNYTIELEK 242
Cdd:cd09918   5 FKNVNYKQAEAYLKSKDV-GEVVIRPSSKGVDHlTVTWKvadgvyQHIDIEELNKENPFSLGKELIIGGEE 74

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 6912272      29 EGFLLIKRSGY-REYEHYWTELRGTTLFFYTDKKSIIYVDKLDIVDLTCLT----EQNSTEKNCAKFTLVLP-KEEVQLK 102
Cdd:smart00233   4 EGWLYKKSGGGkKSWKKRYFVLFNSTLLYYKSKKDKKSYKPKGSIDLSGCTvreaPDPDSSKKPHCFEIKTSdRKTLLLQ 83

                           90
                   ....*....|
gi 6912272     103 TENTESGEEW 112
Cdd:smart00233  84 AESEEEREKW 93

SH2 domain;

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 6912272    182 VSRKEATEMLQKNPSLGNMILRPgSDSR--NYSITIRQEidiPRIKHYKVMSVGQ 234
Cdd:pfam00017   6 ISRQEAERLLLNGKPDGTFLVRE-SESTpgGYTLSVRDD---GKVKHYKIQSTDN 56