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 584029909   4 RTRRPRDQLPNCYYEGYMEKRSFNDETSQKLWTALCGNTLFFFNDKKDCDYIEKLDLSGFISVTDETRQDRNLDAARFNL 83
Cdd:cd13268    1 RQERPKIQLPPCYYEGFLEKKRPKDREYRKLWTELCGTTLFFYNDKKDTQYVEKLDLSALESLTDEISRGRNLDAARFTL 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*..
gi 584029909  84 RLKGGNIKFTVPNAEVREFWKGYIQAVAELAVPTSLNLLPGQIHMLK 130
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 584029909   4 RTRRPRDQLPNCYYEGYMEKRSFNDETSQKLWTALCGNTLFFFNDKKDCDYIEKLDLSGFISVTDETRQDRNLDAARFNL 83
Cdd:cd13268    1 RQERPKIQLPPCYYEGFLEKKRPKDREYRKLWTELCGTTLFFYNDKKDTQYVEKLDLSALESLTDEISRGRNLDAARFTL 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*..
gi 584029909  84 RLKGGNIKFTVPNAEVREFWKGYIQAVAELAVPTSLNLLPGQIHMLK 130
Cdd:cd13268   81 VLKDEEVKFKAENLESREEWKGFILTVTELSVPTSLTLLPGQIHMLK 127

SH2 domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 584029909  165 YH-NVSRLEAELLLDREVKRGNLLLRPgSDGS--SFAVSTRQDLDsplVKHYRVIRKHDGGFIIDvePKVTCDTLHDVIS 241
Cdd:pfam00017   2 YHgKISRQEAERLLLNGKPDGTFLVRE-SESTpgGYTLSVRDDGK---VKHYKIQSTDNGGYYIS--GGVKFSSLAELVE 75

                  .
gi 584029909  242 Y 242
Cdd:pfam00017  76 H 76

Src homology 2 domains; Src homology 2 domains bind phosphotyrosine-containing polypeptides via 2 surface pockets. Specificity is provided via interaction with residues that are distinct from the phosphotyrosine. Only a single occurrence of a SH2 domain has been found in S. cerevisiae.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 584029909   164 CYH-NVSRLEAELLLdREVKRGNLLLRP-GSDGSSFAVSTRQDldsPLVKHYRVIRKHDGGFiiDVEPKVTCDTLHDVIS 241
Cdd:smart00252   3 WYHgFISREEAEKLL-KNEGDGDFLVRDsESSPGDYVLSVRVK---GKVKHYRIRRNEDGKF--YLEGGRKFPSLVELVE 76

                   ....*...
gi 584029909   242 YLVTSTDG 249
Cdd:smart00252  77 HYQKNSLG 84

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 584029909   4 RTRRPRDQLPNCYYEGYMEKRSFNDETSQKLWTALCGNTLFFFNDKKDCDYIEKLDLSGFISVTDETRQDRNLDAARFNL 83
Cdd:cd13268    1 RQERPKIQLPPCYYEGFLEKKRPKDREYRKLWTELCGTTLFFYNDKKDTQYVEKLDLSALESLTDEISRGRNLDAARFTL 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*..
gi 584029909  84 RLKGGNIKFTVPNAEVREFWKGYIQAVAELAVPTSLNLLPGQIHMLK 130
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 584029909 162 PACYHNVSRLEAELLLDREVKRGNLLLRPGSDGSSFAVSTRQDLDSPLVKHYRVIRKHDGGFIIDVEPkVTCDTLHDVIS 241
Cdd:cd09939    1 PACFYTVSRKEATELLERNPSCGNMLLRPGSDSRNYSVTTRQEINIPVIRHYKVMSVGQNYTIELEKP-VTCPNLFSVIN 79

                         90
                 ....*....|....*
gi 584029909 242 YLVTSTDGVLIPLII 256
Cdd:cd09939   80 YFVKETRGNLRPFIL 94

Src homology 2 (SH2) domain found in the Src family of non-receptor tyrosine kinases; The Src family kinases are nonreceptor tyrosine kinases that have been implicated in pathways regulating proliferation, angiogenesis, invasion and metastasis, and bone metabolism. It is thought that transforming ability of Src is linked to its ability to activate key signaling molecules in these pathways, rather than through direct activity. As such blocking Src activation has been a target for drug companies. Src family members can be divided into 3 groups based on their expression pattern: 1) Src, Fyn, and Yes; 2) Blk, Fgr, Hck, Lck, and Lyn; and 3) Frk-related kinases Frk/Rak and Iyk/Bsk Of these, cellular c-Src is the best studied and most frequently implicated in oncogenesis. The c-Src contains five distinct regions: a unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail, as do the other members of the family. Src exists in both active and inactive conformations. Negative regulation occurs through phosphorylation of Tyr, resulting in an intramolecular association between phosphorylated Tyr and the SH2 domain of SRC, which locks the protein in a closed conformation. Further stabilization of the inactive state occurs through interactions between the SH3 domain and a proline-rich stretch of residues within the kinase domain. Conversely, dephosphorylation of Tyr allows SRC to assume an open conformation. Full activity requires additional autophosphorylation of a Tyr residue within the catalytic domain. Loss of the negative-regulatory C-terminal segment has been shown to result in increased activity and transforming potential. Phosphorylation of the C-terminal Tyr residue by C-terminal Src kinase (Csk) and Csk homology kinase results in increased intramolecular interactions and consequent Src inactivation. Specific phosphatases, protein tyrosine phosphatase a (PTPa) and the SH-containing phosphatases SHP1/SHP2, have also been shown to take a part in Src activation. Src is also activated by direct binding of focal adhesion kinase (Fak) and Crk-associated substrate (Cas) to the SH2 domain. SRC activity can also be regulated by numerous receptor tyrosine kinases (RTKs), such as Her2, epidermal growth factor receptor (EGFR), fibroblast growth factor receptor, platelet-derived growth factor receptor (PDGFR), and vascular endothelial growth factor receptor (VEGFR). 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 584029909 167 NVSRLEAE-LLLDREVKRGNLLLRPG-SDGSSFAVSTRqDLDS---PLVKHYRVIRKHDGGFIIdvEPKVTCDTLHDVIS 241
Cdd:cd09933    9 KIKRKDAEkLLLAPGNPRGTFLIRESeTTPGAYSLSVR-DGDDargDTVKHYRIRKLDNGGYYI--TTRATFPTLQELVQ 85

                 ....*...
gi 584029909 242 YLVTSTDG 249
Cdd:cd09933   86 HYSKDADG 93

Src homology 2 (SH2) domain in lymphocyte cell kinase (Lck); Lck is a member of the Src non-receptor type tyrosine kinase family of proteins. It is expressed in the brain, T-cells, and NK cells. The unique domain of Lck mediates its interaction with two T-cell surface molecules, CD4 and CD8. It associates with their cytoplasmic tails on CD4 T helper cells and CD8 cytotoxic T cells to assist signaling from the T cell receptor (TCR) complex. When the T cell receptor is engaged by the specific antigen presented by MHC, Lck phosphorylase the intracellular chains of the CD3 and zeta-chains of the TCR complex, allowing ZAP-70 to bind them. Lck then phosphorylates and activates ZAP-70, which in turn phosphorylates Linker of Activated T cells (LAT), a transmembrane protein that serves as a docking site for proteins including: Shc-Grb2-SOS, PI3K, and phospholipase C (PLC). The tyrosine phosphorylation cascade culminates in the intracellular mobilization of a calcium ions and activation of important signaling cascades within the lymphocyte, including the Ras-MEK-ERK pathway, which goes on to activate certain transcription factors such as NFAT, NF-kappaB, and AP-1. These transcription factors regulate the production cytokines such as Interleukin-2 that promote long-term proliferation and differentiation of the activated lymphocytes. The N-terminal tail of Lck is myristoylated and palmitoylated and it tethers the protein to the plasma membrane of the cell. Lck also contains a SH3 domain, a SH2 domain, and a C-terminal tyrosine kinase domain. Lck has 2 phosphorylation sites, the first an autophosphorylation site that is linked to activation of the protein and the second which is phosphorylated by Csk, which inhibits it. Lck is also inhibited by SHP-1 dephosphorylation and by Cbl ubiquitin ligase, which is part of the ubiquitin-mediated pathway. 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 584029909 162 PACYHNVSRLEAE--LLLDREVKRGNLLLRPGSDGSSFAVSTRqDLD---SPLVKHYRVIRKHDGGFIIdvEPKVTCDTL 236
Cdd:cd10362    4 PWFFKNLSRNDAErqLLAPGNTHGSFLIRESETTAGSFSLSVR-DFDqnqGEVVKHYKIRNLDNGGFYI--SPRITFPGL 80

                         90
                 ....*....|....
gi 584029909 237 HDVISYLVTSTDGV 250
Cdd:cd10362   81 HELVRHYTNASDGL 94

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 584029909    16 YYEGYMEKRSFNDETS-QKLWTALCGNTLFFFNDKK---DCDYIEKLDLSGfISVTDETRQDRNLDAARFNLRLKGGN-I 90
Cdd:smart00233   2 IKEGWLYKKSGGGKKSwKKRYFVLFNSTLLYYKSKKdkkSYKPKGSIDLSG-CTVREAPDPDSSKKPHCFEIKTSDRKtL 80

                           90       100
                   ....*....|....*....|.
gi 584029909    91 KFTVPNAEVREFWKGYIQAVA 111
Cdd:smart00233  81 LLQAESEEEREKWVEALRKAI 101

Src homology 2 (SH2) domain found in the Src oncogene at 42A (Src42); Src42 is a member of the Src non-receptor type tyrosine kinase family of proteins. The integration of receptor tyrosine kinase-induced RAS and Src42 signals by Connector eNhancer of KSR (CNK) as a two-component input is essential for RAF activation in Drosophila. Src42 is present in a wide variety of organisms including: California sea hare, pea aphid, yellow fever mosquito, honey bee, Panamanian leafcutter ant, and sea urchin. Src42 has a unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail, as do the other members of the family. Like the other members of the Src family the SH2 domain in addition to binding the target, also plays an autoinhibitory role by binding to its C-terminal tail. 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 584029909 162 PACYHNVSRLEAE-LLLDREVKRGNLLLRPG-SDGSSFAVSTRqdlDSPLVKHYRVIRKHDGGFIIdvEPKVTCDTLHDV 239
Cdd:cd10370    4 PWYFGKIKRIEAEkKLLLPENEHGAFLIRDSeSRHNDYSLSVR---DGDTVKHYRIRQLDEGGFFI--ARRTTFRTLQEL 78

                         90
                 ....*....|....*
gi 584029909 240 ISYLVTSTDGVLIPL 254
Cdd:cd10370   79 VEHYSKDSDGLCVNL 93

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 584029909 165 YH-NVSRLEAELLLDREVKRGNLLLRPGSDGS-SFAVSTRQDldsPLVKHYRVirKHDGG-FIIDvepKVTCDTLHDVIS 241
Cdd:cd09932    7 FHaNLTREQAEEMLMRVPRDGAFLVRPSETDPnSFAISFRAE---GKIKHCRI--KQEGRlFVIG---TSQFESLVELVS 78

                 .
gi 584029909 242 Y 242
Cdd:cd09932   79 Y 79

Src homology 2 (SH2) domain found in HCK; HCK is a member of the Src non-receptor type tyrosine kinase family of proteins and is expressed in hemopoietic cells. HCK is proposed to couple the Fc receptor to the activation of the respiratory burst. It may also play a role in neutrophil migration and in the degranulation of neutrophils. It has two different translational starts that have different subcellular localization. HCK has been shown to interact with BCR gene, ELMO1 Cbl gene, RAS p21 protein activator 1, RASA3, Granulocyte colony-stimulating factor receptor, ADAM15 and RAPGEF1. Like the other members of the Src family the SH2 domain in addition to binding the target, also plays an autoinhibitory role by binding to its C-terminal tail. In general SH2 domains are involved in signal transduction. HCK has a unique N-terminal domain, an SH3 domain, an SH2 domain, a kinase domain and a regulatory tail, as do the other members of the family. 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 584029909 165 YHNVSRLEAEL-LLDREVKRGNLLLRPG-SDGSSFAVSTRqDLDS---PLVKHYRVIRKHDGGFIIdvEPKVTCDTLHDV 239
Cdd:cd10363    7 FKGISRKDAERqLLAPGNMLGSFMIRDSeTTKGSYSLSVR-DYDPqhgDTVKHYKIRTLDNGGFYI--SPRSTFSTLQEL 83

                         90
                 ....*....|.
gi 584029909 240 ISYLVTSTDGV 250
Cdd:cd10363   84 VDHYKKGNDGL 94

Src homology 2 (SH2) domain found in Tec protein, Txk; A member of the Tec protein tyrosine kinase Txk is expressed in thymus, spleen, lymph node, T lymphocytes, NK cells, mast cell lines, and myeloid cell line. Txk plays a role in TCR signal transduction, T cell development, and selection which is analogous to the function of Itk. Txk has been shown to interact with IFN-gamma. Unlike most of the Tec family members Txk lacks a PH domain. Instead Txk has a unique region containing a palmitoylated cysteine string which has a similar membrane tethering function as the PH domain. Txk also has a zinc-binding motif, a SH3 domain, a SH2 domain, and a protein kinase catalytic domain. The TH domain consists of a Zn2+-binding Btk motif and a proline-rich region. The Btk motif is found in Tec kinases, Ras GAP, and IGBP and crucial to the function of the PH domain. It is not present in Txk which is not surprising since it lacks a PH domain. The type 1 splice form of the Drosophila homolog also lacks both the PH domain and the Btk motif. The proline-rich regions are highly conserved for the most part with the exception of Bmx whose residues surrounding the PXXP motif are not conserved (TH-like) and Btk29A which is entirely unique with large numbers of glycine residues (TH-extended). Tec family members all lack a C-terminal tyrosine having an autoinhibitory function in its phosphorylated state. 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
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 584029909 165 YH-NVSRLEAELLLDREVKRGNLLLRPGSDGSSFAVS----TRQDLDSPlVKHYRVIRKHDG 221
Cdd:cd10398    9 YHkNITRNQAERLLRQESKEGAFIVRDSRHLGSYTISvftrARRSTEAS-IKHYQIKKNDSG 69

Pleckstrin homology (PH) 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        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 584029909  17 YEGYMEKRS-FNDETSQKLWTALCGNTLFFFNDKKDCDY--IEKLDLSGFISVTDETRQDRNldaARFNLRLKGG-NIKF 92
Cdd:cd00821    1 KEGYLLKRGgGGLKSWKKRWFVLFEGVLLYYKSKKDSSYkpKGSIPLSGILEVEEVSPKERP---HCFELVTPDGrTYYL 77

                         90
                 ....*....|.
gi 584029909  93 TVPNAEVREFW 103
Cdd:cd00821   78 QADSEEERQEW 88