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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1158943420 413 DLEDEQDLNP-QWYVGQVTRGQAEGCLRQVNMDGAFLVRDSSKRSSIQPYTLMVLYQDKVYNIQIRCEQN--EFLLGTGL 489
Cdd:cd09929     1 SAEEEADLLPkEWYAGNIDRKEAEEALRRSNKDGTFLVRDSSGKDSSQPYTLMVLYNDKVYNIQIRFLENtrQYALGTGL 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....
gi 1158943420 490 KVSETYPMVAHIIAHYRQSPLLLIDAKNRgsGQQSQCPLiYPAG 533
Cdd:cd09929    81 RGEETFSSVAEIIEHHQKTPLLLIDGKDN--TKDSTCLL-YAAG 121

transcriptional regulator ICP4; Provisional

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1158943420  149 PPSEAPEEIPHQLRAAKPLADGEYIDSTPHRNTARSHPPPTTQRPGAGPPIPSASHPSLLQPPPPRREQSPQHPGRITGK 228
Cdd:PHA03307    67 PPTGPPPGPGTEAPANESRSTPTWSLSTLAPASPAREGSPTPPGPSSPDPPPPTPPPASPPPSPAPDLSEMLRPVGSPGP 146

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1158943420  229 LPATSSnaaPAPPVDRRRKPTKLDRTRLAESPIPATKLNTTNMPAPHSWRPQAEERGPDPPRMPKPPLPVSSSVSRSSSS 308
Cdd:PHA03307   147 PPAASP---PAAGASPAAVASDAASSRQAALPLSSPEETARAPSSPPAEPPPSTPPAAASPRPPRRSSPISASASSPAPA 223

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1158943420  309 VGRAPlnNNRYVPDARNEVQDDVPMSKPYNSNTFPRPGHPRAVLPGLSlhSDGFPPNIASTASLPSKLQALQASISPRSS 388
Cdd:PHA03307   224 PGRSA--ADDAGASSSDSSSSESSGCGWGPENECPLPRPAPITLPTRI--WEASGWNGPSSRPGPASSSSSPRERSPSPS 299

                          250       260
                   ....*....|....*....|....*
gi 1158943420  389 PRIVPDRHIMPPPPPMQASIPPPAD 413
Cdd:PHA03307   300 PSSPGSGPAPSSPRASSSSSSSRES 324

Src homology 2 (SH2) domain found in B-cell linker (BLNK) protein and SH2 domain-containing leukocyte protein of 76 kDa (SLP-76); BLNK (also known as SLP-65 or BASH) is an important adaptor protein expressed in B-lineage cells. BLNK consists of a N-terminal sterile alpha motif (SAM) domain and a C-terminal SH2 domain. BLNK is a cytoplasmic protein, but a part of it is bound to the plasma membrane through an N-terminal leucine zipper motif and transiently bound to a cytoplasmic domain of Iga through its C-terminal SH2 domain upon B cell antigen receptor (BCR)-stimulation. A non-ITAM phosphotyrosine in Iga is necessary for the binding with the BLNK SH2 domain and/or for normal BLNK function in signaling and B cell activation. Upon phosphorylation BLNK binds Btk and PLCgamma2 through their SH2 domains and mediates PLCgamma2 activation by Btk. BLNK also binds other signaling molecules such as Vav, Grb2, Syk, and HPK1. BLNK has been shown to be necessary for BCR-mediated Ca2+ mobilization, for the activation of mitogen-activated protein kinases such as ERK, JNK, and p38 in a chicken B cell line DT40, and for activation of transcription factors such as NF-AT and NF-kappaB in human or mouse B cells. BLNK is involved in B cell development, B cell survival, activation, proliferation, and T-independent immune responses. BLNK is structurally homologous to SLP-76. SLP-76 and (linker for activation of T cells) LAT are adaptor/linker proteins in T cell antigen receptor activation and T cell development. BLNK interacts with many downstream signaling proteins that interact directly with both SLP-76 and LAT. New data suggest functional complementation of SLP-76 and LAT in T cell antigen receptor function with BLNK in BCR function. 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 1158943420 413 DLEDEQDLNP-QWYVGQVTRGQAEGCLRQVNMDGAFLVRDSSKRSSIQPYTLMVLYQDKVYNIQIRCEQN--EFLLGTGL 489
Cdd:cd09929     1 SAEEEADLLPkEWYAGNIDRKEAEEALRRSNKDGTFLVRDSSGKDSSQPYTLMVLYNDKVYNIQIRFLENtrQYALGTGL 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....
gi 1158943420 490 KVSETYPMVAHIIAHYRQSPLLLIDAKNRgsGQQSQCPLiYPAG 533
Cdd:cd09929    81 RGEETFSSVAEIIEHHQKTPLLLIDGKDN--TKDSTCLL-YAAG 121

SH2 domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1158943420 424 WYVGQVTRGQAEGCLRQVNMDGAFLVRDSSkrSSIQPYTLMVLYQDKVYNIQIRCEQNEFLLGTGlkvSETYPMVAHIIA 503
Cdd:pfam00017   1 WYHGKISRQEAERLLLNGKPDGTFLVRESE--STPGGYTLSVRDDGKVKHYKIQSTDNGGYYISG---GVKFSSLAELVE 75

                  ..
gi 1158943420 504 HY 505
Cdd:pfam00017  76 HY 77

transcriptional regulator ICP4; Provisional

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1158943420  149 PPSEAPEEIPHQLRAAKPLADGEYIDSTPHRNTARSHPPPTTQRPGAGPPIPSASHPSLLQPPPPRREQSPQHPGRITGK 228
Cdd:PHA03307    67 PPTGPPPGPGTEAPANESRSTPTWSLSTLAPASPAREGSPTPPGPSSPDPPPPTPPPASPPPSPAPDLSEMLRPVGSPGP 146

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1158943420  229 LPATSSnaaPAPPVDRRRKPTKLDRTRLAESPIPATKLNTTNMPAPHSWRPQAEERGPDPPRMPKPPLPVSSSVSRSSSS 308
Cdd:PHA03307   147 PPAASP---PAAGASPAAVASDAASSRQAALPLSSPEETARAPSSPPAEPPPSTPPAAASPRPPRRSSPISASASSPAPA 223

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1158943420  309 VGRAPlnNNRYVPDARNEVQDDVPMSKPYNSNTFPRPGHPRAVLPGLSlhSDGFPPNIASTASLPSKLQALQASISPRSS 388
Cdd:PHA03307   224 PGRSA--ADDAGASSSDSSSSESSGCGWGPENECPLPRPAPITLPTRI--WEASGWNGPSSRPGPASSSSSPRERSPSPS 299

                          250       260
                   ....*....|....*....|....*
gi 1158943420  389 PRIVPDRHIMPPPPPMQASIPPPAD 413
Cdd:PHA03307   300 PSSPGSGPAPSSPRASSSSSSSRES 324

Src homology 2 (SH2) domain found in B-cell linker (BLNK) protein and SH2 domain-containing leukocyte protein of 76 kDa (SLP-76); BLNK (also known as SLP-65 or BASH) is an important adaptor protein expressed in B-lineage cells. BLNK consists of a N-terminal sterile alpha motif (SAM) domain and a C-terminal SH2 domain. BLNK is a cytoplasmic protein, but a part of it is bound to the plasma membrane through an N-terminal leucine zipper motif and transiently bound to a cytoplasmic domain of Iga through its C-terminal SH2 domain upon B cell antigen receptor (BCR)-stimulation. A non-ITAM phosphotyrosine in Iga is necessary for the binding with the BLNK SH2 domain and/or for normal BLNK function in signaling and B cell activation. Upon phosphorylation BLNK binds Btk and PLCgamma2 through their SH2 domains and mediates PLCgamma2 activation by Btk. BLNK also binds other signaling molecules such as Vav, Grb2, Syk, and HPK1. BLNK has been shown to be necessary for BCR-mediated Ca2+ mobilization, for the activation of mitogen-activated protein kinases such as ERK, JNK, and p38 in a chicken B cell line DT40, and for activation of transcription factors such as NF-AT and NF-kappaB in human or mouse B cells. BLNK is involved in B cell development, B cell survival, activation, proliferation, and T-independent immune responses. BLNK is structurally homologous to SLP-76. SLP-76 and (linker for activation of T cells) LAT are adaptor/linker proteins in T cell antigen receptor activation and T cell development. BLNK interacts with many downstream signaling proteins that interact directly with both SLP-76 and LAT. New data suggest functional complementation of SLP-76 and LAT in T cell antigen receptor function with BLNK in BCR function. 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 1158943420 413 DLEDEQDLNP-QWYVGQVTRGQAEGCLRQVNMDGAFLVRDSSKRSSIQPYTLMVLYQDKVYNIQIRCEQN--EFLLGTGL 489
Cdd:cd09929     1 SAEEEADLLPkEWYAGNIDRKEAEEALRRSNKDGTFLVRDSSGKDSSQPYTLMVLYNDKVYNIQIRFLENtrQYALGTGL 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....
gi 1158943420 490 KVSETYPMVAHIIAHYRQSPLLLIDAKNRgsGQQSQCPLiYPAG 533
Cdd:cd09929    81 RGEETFSSVAEIIEHHQKTPLLLIDGKDN--TKDSTCLL-YAAG 121

SH2 domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1158943420 424 WYVGQVTRGQAEGCLRQVNMDGAFLVRDSSkrSSIQPYTLMVLYQDKVYNIQIRCEQNEFLLGTGlkvSETYPMVAHIIA 503
Cdd:pfam00017   1 WYHGKISRQEAERLLLNGKPDGTFLVRESE--STPGGYTLSVRDDGKVKHYKIQSTDNGGYYISG---GVKFSSLAELVE 75

                  ..
gi 1158943420 504 HY 505
Cdd:pfam00017  76 HY 77

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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1158943420 424 WYVGQVTRGQAEGCLRQVNmDGAFLVRDSSkrSSIQPYTLMVLYQ-DKVYNIQIRCEQNEFLLGTGLKVseTYPMVAHII 502
Cdd:cd00173     2 WFHGSISREEAERLLRGKP-DGTFLVRESS--SEPGDYVLSVRSGdGKVKHYLIERNEGGYYLLGGSGR--TFPSLPELV 76

                  ...
gi 1158943420 503 AHY 505
Cdd:cd00173    77 EHY 79

C-terminal Src homology 2 (C-SH2) domain found in SH2 domain Phosphatases (SHP) proteins; The SH2 domain phosphatases (SHP-1, SHP-2/Syp, Drosophila corkscrew (csw), and Caenorhabditis elegans Protein Tyrosine Phosphatase (Ptp-2)) are cytoplasmic signaling enzymes. They are both targeted and regulated by interactions of their SH2 domains with phosphotyrosine docking sites. These proteins contain two SH2 domains (N-SH2, C-SH2) followed by a tyrosine phosphatase (PTP) domain, and a C-terminal extension. Shp1 and Shp2 have two tyrosyl phosphorylation sites in their C-tails, which are phosphorylated differentially by receptor and nonreceptor PTKs. Csw retains the proximal tyrosine and Ptp-2 lacks both sites. Shp-binding proteins include receptors, scaffolding adapters, and inhibitory receptors. Some of these bind both Shp1 and Shp2 while others bind only one. Most proteins that bind a Shp SH2 domain contain one or more immuno-receptor tyrosine-based inhibitory motifs (ITIMs): [SIVL]xpYxx[IVL]. Shp1 N-SH2 domain blocks the catalytic domain and keeps the enzyme in the inactive conformation, and is thus believed to regulate the phosphatase activity of SHP-1. Its C-SH2 domain is thought to be involved in searching for phosphotyrosine activators. The SHP2 N-SH2 domain is a conformational switch; it either binds and inhibits the phosphatase, or it binds phosphoproteins and activates the enzyme. The C-SH2 domain contributes binding energy and specificity, but it does not have a direct role in activation. Csw SH2 domain function is essential, but either SH2 domain can fulfill this requirement. The role of the csw SH2 domains during Sevenless receptor tyrosine kinase (SEV) signaling is to bind Daughter of Sevenless rather than activated SEV. Ptp-2 acts in oocytes downstream of sheath/oocyte gap junctions to promote major sperm protein (MSP)-induced MAP Kinase (MPK-1) phosphorylation. Ptp-2 functions in the oocyte cytoplasm, not at the cell surface to inhibit multiple RasGAPs, resulting in sustained Ras activation. It is thought that MSP triggers PTP-2/Ras activation and ROS production to stimulate MPK-1 activity essential for oocyte maturation and that secreted MSP domains and Cu/Zn superoxide dismutases function antagonistically to control ROS and MAPK signaling. 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 1158943420 424 WYVGQVTRGQAEGCLRQVNMDGAFLVRDSskRSSIQPYTLMVLY-QDKVYNIQIRCEQNEFLLGTGlkvsETYPMVAHII 502
Cdd:cd09931     2 WFHGHLSGKEAEKLLLEKGKPGSFLVRES--QSKPGDFVLSVRTdDDKVTHIMIRCQGGKYDVGGG----EEFDSLTDLV 75

                  ....*....
gi 1158943420 503 AHYRQSPLL 511
Cdd:cd09931    76 EHYKKNPMV 84

Src homology 2 (SH2) domain found in Nck; Nck proteins are adaptors that modulate actin cytoskeleton dynamics by linking proline-rich effector molecules to tyrosine kinases or phosphorylated signaling intermediates. There are two members known in this family: Nck1 (Nckalpha) and Nck2 (Nckbeta and Growth factor receptor-bound protein 4 (Grb4)). They are characterized by having 3 SH3 domains and a C-terminal SH2 domain. Nck1 and Nck2 have overlapping functions as determined by gene knockouts. Both bind receptor tyrosine kinases and other tyrosine-phosphorylated proteins through their SH2 domains. In addition they also bind distinct targets. Neuronal signaling proteins: EphrinB1, EphrinB2, and Disabled-1 (Dab-1) all bind to Nck-2 exclusively. And in the case of PDGFR, Tyr(P)751 binds to Nck1 while Tyr(P)1009 binds to Nck2. Nck1 and Nck2 have a role in the infection process of enteropathogenic Escherichia coli (EPEC). Their SH3 domains are involved in recruiting and activating the N-WASP/Arp2/3 complex inducing actin polymerization resulting in the production of pedestals, dynamic bacteria-presenting protrusions of the plasma membrane. A similar thing occurs in the vaccinia virus where motile plasma membrane projections are formed beneath the virus. Recently it has been shown that the SH2 domains of both Nck1 and Nck2 bind the G-protein coupled receptor kinase-interacting protein 1 (GIT1) in a phosphorylation-dependent manner. 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 1158943420 423 QWYVGQVTRGQAEGCLRQVNMDGAFLVRDSskRSSIQPYTLMVLYQDKVYNIQIRCEQNEFLLGtglkvSETYPMVAHII 502
Cdd:cd10408     2 PWYYGKVTRHQAEMALNERGNEGDFLIRDS--ESSPNDFSVSLKAQGKNKHFKVQLKECVYCIG-----QRKFSSMEELV 74

                  ....*....
gi 1158943420 503 AHYRQSPLL 511
Cdd:cd10408    75 EHYKKAPIF 83

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 1158943420 420 LNPQWYVGQVTRGQAEGCLRQVNMDGAFLVRDSSKrsSIQPYTLMVLYQDKVYNIQIRCEQNEFLLGTglkvSETYPMVA 499
Cdd:cd09932     2 ESKEWFHANLTREQAEEMLMRVPRDGAFLVRPSET--DPNSFAISFRAEGKIKHCRIKQEGRLFVIGT----SQFESLVE 75

                          90
                  ....*....|.
gi 1158943420 500 hIIAHYRQSPL 510
Cdd:cd09932    76 -LVSYYEKHPL 85

Src homology 2 (SH2) domain found in the Nck family; Nck proteins are adaptors that modulate actin cytoskeleton dynamics by linking proline-rich effector molecules to tyrosine kinases or phosphorylated signaling intermediates. There are two members known in this family: Nck1 (Nckalpha) and Nck2 (Nckbeta and Growth factor receptor-bound protein 4 (Grb4)). They are characterized by having 3 SH3 domains and a C-terminal SH2 domain. Nck1 and Nck2 have overlapping functions as determined by gene knockouts. Both bind receptor tyrosine kinases and other tyrosine-phosphorylated proteins through their SH2 domains. In addition they also bind distinct targets. Neuronal signaling proteins: EphrinB1, EphrinB2, and Disabled-1 (Dab-1) all bind to Nck-2 exclusively. And in the case of PDGFR, Tyr(P)751 binds to Nck1 while Tyr(P)1009 binds to Nck2. Nck1 and Nck2 have a role in the infection process of enteropathogenic Escherichia coli (EPEC). Their SH3 domains are involved in recruiting and activating the N-WASP/Arp2/3 complex inducing actin polymerization resulting in the production of pedestals, dynamic bacteria-presenting protrusions of the plasma membrane. A similar thing occurs in the vaccinia virus where motile plasma membrane projections are formed beneath the virus. Recently it has been shown that the SH2 domains of both Nck1 and Nck2 bind the G-protein coupled receptor kinase-interacting protein 1 (GIT1) in a phosphorylation-dependent manner. 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 1158943420 424 WYVGQVTRGQAEGCLRQVNMDGAFLVRDSskRSSIQPYTLMVLYQDKVYNIQIRCEQNEFLLGTglkvsETYPMVAHIIA 503
Cdd:cd09943     3 WYYGRITRHQAETLLNEHGHEGDFLIRDS--ESNPGDYSVSLKAPGRNKHFKVQVVDNVYCIGQ-----RKFHTMDELVE 75

                  ....*..
gi 1158943420 504 HYRQSPL 510
Cdd:cd09943    76 HYKKAPI 82

Src homology 2 domain found in Growth factor receptor-bound protein 2 (Grb2) and similar proteins; The adaptor proteins here include homologs Grb2 in humans, Sex muscle abnormal protein 5 (Sem-5) in Caenorhabditis elegans, and Downstream of receptor kinase (drk) in Drosophila melanogaster. They are composed of one SH2 and two SH3 domains. Grb2/Sem-5/drk regulates the Ras pathway by linking the tyrosine kinases to the Ras guanine nucleotide releasing protein Sos, which converts Ras to the active GTP-bound state. The SH2 domain of Grb2/Sem-5/drk binds class II phosphotyrosyl peptides while its SH3 domain binds to Sos and Sos-derived, proline-rich peptides. Besides it function in Ras signaling, Grb2 is also thought to play a role in apoptosis. Unlike most SH2 structures in which the peptide binds in an extended conformation (such that the +3 peptide residue occupies a hydrophobic pocket in the protein, conferring a modest degree of selectivity), Grb2 forms several hydrogen bonds via main chain atoms with the side chain of +2 Asn. 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 1158943420 421 NPQWYVGQVTRGQAEGCLRQVNMDGAFLVRDSskRSSIQPYTLMVLYQDKVYNIQI-RCEQNEFLLGTglkvsETYPMVA 499
Cdd:cd09941     2 PHPWFHGKISRAEAEEILMNQRPDGAFLIRES--ESSPGDFSLSVKFGNDVQHFKVlRDGAGKYFLWV-----VKFNSLN 74

                          90
                  ....*....|
gi 1158943420 500 HIIAHYRQSP 509
Cdd:cd09941    75 ELVDYHRTTS 84

Src homology 2 (SH2) domain found in Abelson murine lymphosarcoma virus (ABL) proteins; ABL-family proteins are highly conserved tyrosine kinases. Each ABL protein contains an SH3-SH2-TK (Src homology 3-Src homology 2-tyrosine kinase) domain cassette, which confers autoregulated kinase activity and is common among nonreceptor tyrosine kinases. Several types of posttranslational modifications control ABL catalytic activity, subcellular localization, and stability, with consequences for both cytoplasmic and nuclear ABL functions. Binding partners provide additional regulation of ABL catalytic activity, substrate specificity, and downstream signaling. By combining this cassette with actin-binding and -bundling domain, ABL proteins are capable of connecting phosphoregulation with actin-filament reorganization. Vertebrate paralogs, ABL1 and ABL2, have evolved to perform specialized functions. ABL1 includes nuclear localization signals and a DNA binding domain which is used to mediate DNA damage-repair functions, while ABL2 has additional binding capacity for actin and for microtubules to enhance its cytoskeletal remodeling functions. SH2 is involved in several autoinhibitory mechanism that constrain the enzymatic activity of the ABL-family kinases. In one mechanism SH2 and SH3 cradle the kinase domain while a cap sequence stabilizes the inactive conformation resulting in a locked inactive state. Another involves phosphatidylinositol 4,5-bisphosphate (PIP2) which binds the SH2 domain through residues normally required for phosphotyrosine binding in the linker segment between the SH2 and kinase domains. The SH2 domain contributes to ABL catalytic activity and target site specificity. It is thought that the ABL catalytic site and SH2 pocket have coevolved to recognize the same sequences. Recent work now supports a hierarchical processivity model in which the substrate target site most compatible with ABL kinase domain preferences is phosphorylated with greatest efficiency. If this site is compatible with the ABL SH2 domain specificity, it will then reposition and dock in the SH2 pocket. This mechanism also explains how ABL kinases phosphorylates poor targets on the same substrate if they are properly positioned and how relatively poor substrate proteins might be recruited to ABL through a complex with strong substrates that can also dock with the SH2 pocket. 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 1158943420 424 WYVGQVTRGQAEGCLRQvNMDGAFLVRDSskRSSIQPYTLMVLYQDKVYNIQIRCEQNEFLLGTGLKVsetYPMVAHIIA 503
Cdd:cd09935     5 WYHGPISRNAAEYLLSS-GINGSFLVRES--ESSPGQYSISLRYDGRVYHYRISEDSDGKVYVTQEHR---FNTLAELVH 78

                          90       100
                  ....*....|....*....|....*...
gi 1158943420 504 HYRQSPLLLIdaknrgsgqqsqCPLIYP 531
Cdd:cd09935    79 HHSKNADGLI------------TTLRYP 94

Src homology 2 (SH2) domain found in Tec protein, Bmx; A member of the Tec protein tyrosine kinase Bmx is expressed in the endothelium of large arteries, fetal endocardium, adult endocardium of the left ventricle, bone marrow, lung, testis, granulocytes, myeloid cell lines, and prostate cell lines. Bmx is involved in the regulation of Rho and serum response factor (SRF). Bmx has been shown to interact with PAK1, PTK2, PTPN21, and RUFY1. Most of the Tec family members have a PH domain (Txk and the short (type 1) splice variant of Drosophila Btk29A are exceptions), a Tec homology (TH) domain, 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. It is crucial for the function of Tec PH domains. It is not present in Txk and the type 1 splice form of the Drosophila homolog. 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
                  ....*....|....*....|....*....|....*....|...
gi 1158943420 424 WYVGQVTRGQAEGCLRQVNMDGAFLVRDSSKrssIQPYTLMVL 466
Cdd:cd10399     8 WFAGNISRSQSEQLLRQKGKEGAFMVRNSSQ---VGMYTVSLF 47

transcriptional regulator ICP4; Provisional

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1158943420  149 PPSEAPEEIPHQLRAAKPLADGEYIDSTPHRNTARSHPPPTTQRPGAGPPIPSASHPSLLQPPPPRREQSPQHPGRITGK 228
Cdd:PHA03307    67 PPTGPPPGPGTEAPANESRSTPTWSLSTLAPASPAREGSPTPPGPSSPDPPPPTPPPASPPPSPAPDLSEMLRPVGSPGP 146

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1158943420  229 LPATSSnaaPAPPVDRRRKPTKLDRTRLAESPIPATKLNTTNMPAPHSWRPQAEERGPDPPRMPKPPLPVSSSVSRSSSS 308
Cdd:PHA03307   147 PPAASP---PAAGASPAAVASDAASSRQAALPLSSPEETARAPSSPPAEPPPSTPPAAASPRPPRRSSPISASASSPAPA 223

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1158943420  309 VGRAPlnNNRYVPDARNEVQDDVPMSKPYNSNTFPRPGHPRAVLPGLSlhSDGFPPNIASTASLPSKLQALQASISPRSS 388
Cdd:PHA03307   224 PGRSA--ADDAGASSSDSSSSESSGCGWGPENECPLPRPAPITLPTRI--WEASGWNGPSSRPGPASSSSSPRERSPSPS 299

                          250       260
                   ....*....|....*....|....*
gi 1158943420  389 PRIVPDRHIMPPPPPMQASIPPPAD 413
Cdd:PHA03307   300 PSSPGSGPAPSSPRASSSSSSSRES 324

N-terminal Src homology 2 (N-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 1158943420 424 WYVGQVTRGQ--AEGCLRQVNM--DGAFLVRDSSkrSSIQPYTLMVLYQDKVYNIQIRCEQNEFLLGTGLKVSETYPMVA 499
Cdd:cd10341     6 WFHGKLGDGRdeAEKLLLEYCEggDGTFLVRESE--TFVGDYTLSFWRNGKVQHCRIRSRQENGEKKYYLTDNLVFDSLY 83

                          90
                  ....*....|.
gi 1158943420 500 HIIAHYRQSPL 510
Cdd:cd10341    84 ELIDYYRQNPL 94

Src homology 2 (SH2) domain found in the growth factor receptor bound, subclass 7 (Grb7) proteins; The Grb family binds to the epidermal growth factor receptor (EGFR, erbB1) via their SH2 domains. There are 3 members of the Grb7 family of proteins: Grb7, Grb10, and Grb14. They are composed of an N-terminal Proline-rich domain, a Ras Associating-like (RA) domain, a Pleckstrin Homology (PH) domain, a phosphotyrosine interaction region (PIR, BPS) and a C-terminal SH2 domain. The SH2 domains of Grb7, Grb10 and Grb14 preferentially bind to a different RTK. Grb7 binds strongly to the erbB2 receptor, unlike Grb10 and Grb14 which bind weakly to it. Grb14 binds to Fibroblast Growth Factor Receptor (FGFR). Grb10 has been shown to interact with many different proteins, including the insulin and IGF1 receptors, platelet-derived growth factor (PDGF) receptor-beta, Ret, Kit, Raf1 and MEK1, and Nedd4. Grb7 family proteins are phosphorylated on serine/threonine as well as tyrosine residues. 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 1158943420 424 WYVGQVTRGQAEGCLRQV-NMDGAFLVRDSskRSSIQPYTLMVLYQDKVYNIQI 476
Cdd:cd09944     7 WFHGGISRDEAARLIRQQgLVDGVFLVRES--QSNPGAFVLSLKHGQKIKHYQI 58

Src homology 2 (SH2) domain found in suppressor of cytokine signaling (SOCS) proteins; SH2 domain found in SOCS proteins. SOCS was first recognized as a group of cytokine-inducible SH2 (CIS) domain proteins comprising eight family members in human (CIS and SOCS1-SOCS7). In addition to the SH2 domain, SOCS proteins have a variable N-terminal domain and a conserved SOCS box in the C-terminal domain. SOCS proteins bind to a substrate via their SH2 domain. The prototypical members, CIS and SOCS1-SOCS3, have been shown to regulate growth hormone signaling in vitro and in a classic negative feedback response compete for binding at phosphotyrosine sites in JAK kinase and receptor pathways to displace effector proteins and target bound receptors for proteasomal degradation. Loss of SOCS activity results in excessive cytokine signaling associated with a variety of hematopoietic, autoimmune, and inflammatory diseases and certain cancers. Members (SOCS4-SOCS7) were identified by their conserved SOCS box, an adapter motif of 3 helices that associates substrate binding domains, such as the SOCS SH2 domain, ankryin, and WD40 with ubiquitin ligase components. These show limited cytokine induction. 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 1158943420 424 WYVGQVTRGQAEGCLRQvNMDGAFLVRDSSKRSSIqpYTLMVLYQDKVYNIQIRCEQNEFLLGTGLKVSETYPM---VAH 500
Cdd:cd10384    12 FYWSTVSGKEANLLLSA-EPAGTFLIRDSSDQRHF--FTLSVKTESGTKNLRIQCEGGSFSLQTDPRSTQPVPRfdcVLK 88

                  ....*....
gi 1158943420 501 IIAHYRQSP 509
Cdd:cd10384    89 LVHHYMPPS 97

Src homology 2 (SH2) domain found in suppressor of cytokine signaling (SOCS) proteins; SH2 domain found in SOCS proteins. SOCS was first recognized as a group of cytokine-inducible SH2 (CIS) domain proteins comprising eight family members in human (CIS and SOCS1-SOCS7). In addition to the SH2 domain, SOCS proteins have a variable N-terminal domain and a conserved SOCS box in the C-terminal domain. SOCS proteins bind to a substrate via their SH2 domain. The prototypical members, CIS and SOCS1-SOCS3, have been shown to regulate growth hormone signaling in vitro and in a classic negative feedback response compete for binding at phosphotyrosine sites in JAK kinase and receptor pathways to displace effector proteins and target bound receptors for proteasomal degradation. Loss of SOCS activity results in excessive cytokine signaling associated with a variety of hematopoietic, autoimmune, and inflammatory diseases and certain cancers. Members (SOCS4-SOCS7) were identified by their conserved SOCS box, an adapter motif of 3 helices that associates substrate binding domains, such as the SOCS SH2 domain, ankryin, and WD40 with ubiquitin ligase components. These show limited cytokine induction. 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 1158943420 424 WYVGQVTRGQAEGCLRQvNMDGAFLVRDSSKRSSIqpYTLMVLYQDKVYNIQIRCEQNEFLLGTGLKVSETYPMVAHII 502
Cdd:cd10388    12 WYWGPMSWEDAEKVLSN-KPDGSFLVRDSSDDRYI--FSLSFRSQGSVHHTRIEQYQGTFSLGSRNKFVDRSQSLVEFI 87

Src homology 2 (SH2) domain found in SLAM-associated protein (SAP) 1a; The X-linked lymphoproliferative syndrome (XLP) gene encodes SAP (also called SH2D1A/DSHP) a protein that consists of a 5 residue N-terminus, a single SH2 domain, and a short 25 residue C-terminal tail. XLP is characterized by an extreme sensitivity to Epstein-Barr virus. Both T and natural killer (NK) cell dysfunctions have been seen in XLP patients. SAP binds the cytoplasmic tail of Signaling lymphocytic activation molecule (SLAM), 2B4, Ly-9, and CD84. SAP is believed to function as a signaling inhibitor, by blocking or regulating binding of other signaling proteins. SAP and the SAP-like protein EAT-2 recognize the sequence motif TIpYXX[VI], which is found in the cytoplasmic domains of a restricted number of T, B, and NK cell surface receptors and are proposed to be natural inhibitors or regulators of the physiological role of a small family of receptors on the surface of these cells. 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 1158943420 425 YVGQVTRGQAEGCLRQVNMDGAFLVRDSSKRSSIqpYTLMVLYQDKVYNiqIRCEQNEfllgTGLKVSETYPMVAHIIAH 504
Cdd:cd10400     6 YHGKISRETGEKLLLAAGLDGSYLLRDSESVPGV--YCLCVLYKGYVYT--YRVSQTE----TGSWSAETAPGVHKRLFR 77

                          90       100
                  ....*....|....*....|....*..
gi 1158943420 505 YRQSpllLIDAKNRgSGQQSQCPLIYP 531
Cdd:cd10400    78 KVKN---LISAFQK-PDQGIVTPLQYP 100

Src homology 2 domain found in SH2 domain-containing adapter proteins B, D, E, and F (SHB, SHD, SHE, SHF); SHB, SHD, SHE, and SHF are SH2 domain-containing proteins that play various roles throughout the cell. SHB functions in generating signaling compounds in response to tyrosine kinase activation. SHB contains proline-rich motifs, a phosphotyrosine binding (PTB) domain, tyrosine phosphorylation sites, and a SH2 domain. SHB mediates certain aspects of platelet-derived growth factor (PDGF) receptor-, fibroblast growth factor (FGF) receptor-, neural growth factor (NGF) receptor TRKA-, T cell receptor-, interleukin-2 (IL-2) receptor- and focal adhesion kinase- (FAK) signaling. SRC-like FYN-Related Kinase FRK/RAK (also named BSK/IYK or GTK) and SHB regulate apoptosis, proliferation and differentiation. SHB promotes apoptosis and is also required for proper mitogenicity, spreading and tubular morphogenesis in endothelial cells. SHB also plays a role in preventing early cavitation of embryoid bodies and reduces differentiation to cells expressing albumin, amylase, insulin and glucagon. SHB is a multifunctional protein that has difference responses in different cells under various conditions. SHE is expressed in heart, lung, brain, and skeletal muscle, while expression of SHD is restricted to the brain. SHF is mainly expressed in skeletal muscle, brain, liver, prostate, testis, ovary, small intestine, and colon. SHD may be a physiological substrate of c-Abl and may function as an adapter protein in the central nervous system. It is also thought to be involved in apoptotic regulation. SHD contains five YXXP motifs, a substrate sequence preferred by Abl tyrosine kinases, in addition to a poly-proline rich region and a C-terminal SH2 domain. SHE contains two pTry protein binding domains, protein interaction domain (PID) and a SH2 domain, followed by a glycine-proline rich region, all of which are N-terminal to the phosphotyrosine binding (PTB) domain. SHF contains four putative tyrosine phosphorylation sites and an SH2 domain. 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 1158943420 424 WYVGQVTRGQAEGCLRqVNMDGAFLVRDSskRSSIQPYTLMVLYQDKVYNIQI-RCEQNEFLLGTGLKVSETYPMVAHii 502
Cdd:cd09945     3 WYHGAITRIEAESLLR-PCKEGSYLVRNS--ESTKQDYSLSLKSAKGFMHMRIqRNETGQYILGQFSRPFETIPEMIR-- 77

                  ....*...
gi 1158943420 503 aHYRQSPL 510
Cdd:cd09945    78 -HYCLNKL 84

large tegument protein UL36; Provisional

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1158943420  149 PPSEAPEEIPHQLRAAKPLadgeyidstphrntarshPPPTTQRPGAGPPIPSASHPsllqPPPPRREQSPQHPGRItGK 228
Cdd:PHA03247  2703 PPPPTPEPAPHALVSATPL------------------PPGPAAARQASPALPAAPAP----PAVPAGPATPGGPARP-AR 2759

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1158943420  229 LPATSSNAAPAPPVDRRRKPT-KLDRTRLAESPIPATKLNTTNMPAPHSWRPQAEERGPDPPRMPKPPLPVSSSVSRSSS 307
Cdd:PHA03247  2760 PPTTAGPPAPAPPAAPAAGPPrRLTRPAVASLSESRESLPSPWDPADPPAAVLAPAAALPPAASPAGPLPPPTSAQPTAP 2839

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1158943420  308 SVGRAPLNNNR-----YVP--DARNEVQDDVPMSKPynsNTFPRPGHPRAVLPGLSLHSDGFPPNIASTASLPSKlqalQ 380
Cdd:PHA03247  2840 PPPPGPPPPSLplggsVAPggDVRRRPPSRSPAAKP---AAPARPPVRRLARPAVSRSTESFALPPDQPERPPQP----Q 2912

                          250       260       270
                   ....*....|....*....|....*....|....*...
gi 1158943420  381 ASISPRSSPRIVPDRHIMPPPPPMQASIPPPADLEDEQ 418
Cdd:PHA03247  2913 APPPPQPQPQPPPPPQPQPPPPPPPRPQPPLAPTTDPA 2950

Src homology 2 domain found in dual adaptor for phosphotyrosine and 3-phosphoinositides ( DAPP1)/B lymphocyte adaptor molecule of 32 kDa (Bam32)-like proteins; DAPP1/Bam32 contains a putative myristoylation site at its N-terminus, followed by a SH2 domain, and a pleckstrin homology (PH) domain at its C-terminus. DAPP1 could potentially be recruited to the cell membrane by any of these domains. Its putative myristoylation site could facilitate the interaction of DAPP1 with the lipid bilayer. Its SH2 domain may also interact with phosphotyrosine residues on membrane-associated proteins such as activated tyrosine kinase receptors. And finally its PH domain exhibits a high-affinity interaction with the PtdIns(3,4,5)P(3) PtdIns(3,4)P(2) second messengers produced at the cell membrane following the activation of PI 3-kinases. DAPP1 is thought to interact with both tyrosine phosphorylated proteins and 3-phosphoinositides and therefore may play a role in regulating the location and/or activity of such proteins(s) in response to agonists that elevate PtdIns(3,4,5)P(3) and PtdIns(3,4)P(2). This protein is likely to play an important role in triggering signal transduction pathways that lie downstream from receptor tyrosine kinases and PI 3-kinase. It is likely that DAPP1 functions as an adaptor to recruit other proteins to the plasma membrane in response to extracellular signals. 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 1158943420 424 WYVGQVTRGQAEGCLRQVNMDGAFLVRDSSKRSSIqpYTLMVLYQDKVYNIQIRCEQNEFLLGtglkVSEtYPMVAHIIA 503
Cdd:cd10355     8 WYHGNLTRHAAEALLLSNGVDGSYLLRNSNEGTGL--FSLSVRAKDSVKHFHVEYTGYSFKFG----FNE-FSSLQDFVK 80

                  ....*...
gi 1158943420 504 HYRQSPLL 511
Cdd:cd10355    81 HFANQPLI 88

Src homology 2 (SH2) domain found in suppressor of cytokine signaling (SOCS) family; SH2 domain found in SOCS proteins. SOCS was first recognized as a group of cytokine-inducible SH2 (CIS) domain proteins comprising eight family members in human (CIS and SOCS1-SOCS7). In addition to the SH2 domain, SOCS proteins have a variable N-terminal domain and a conserved SOCS box in the C-terminal domain. SOCS proteins bind to a substrate via their SH2 domain. The prototypical members, CIS and SOCS1-SOCS3, have been shown to regulate growth hormone signaling in vitro and in a classic negative feedback response compete for binding at phosphotyrosine sites in JAK kinase and receptor pathways to displace effector proteins and target bound receptors for proteasomal degradation. Loss of SOCS activity results in excessive cytokine signaling associated with a variety of hematopoietic, autoimmune, and inflammatory diseases and certain cancers. Members (SOCS4-SOCS7) were identified by their conserved SOCS box, an adapter motif of 3 helices that associates substrate binding domains, such as the SOCS SH2 domain, ankryin, and WD40 with ubiquitin ligase components. These show limited cytokine induction. 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 1158943420 424 WYVGQVTRGQAEGCLRQVNmDGAFLVRDSSKRSSIqpYTLMVLYQDKVYNIQIRCEQNEFLLGTGLKVSETYPMVAHIIA 503
Cdd:cd09923     2 WYWGGITRYEAEELLAGKP-EGTFLVRDSSDSRYL--FSVSFRTYGRTLHARIEYSNGRFSFDSSDPSVPRFPCVVELIE 78

                  ..
gi 1158943420 504 HY 505
Cdd:cd09923    79 HY 80

Src homology 2 (SH2) domain found in tyrosine kinase sarcoma (Src); Src is a member of the Src non-receptor type tyrosine kinase family of proteins. Src is thought to play a role in the regulation of embryonic development and cell growth. Members here include v-Src and c-Src. v-Src lacks the C-terminal inhibitory phosphorylation site and is therefore constitutively active as opposed to normal cellular src (c-Src) which is only activated under certain circumstances where it is required (e.g. growth factor signaling). v-Src is an oncogene whereas c-Src is a proto-oncogene. c-Src consists of three domains, an N-terminal SH3 domain, a central SH2 domain and a tyrosine kinase domain. The SH2 and SH3 domains work together in the auto-inhibition of the kinase domain. The phosphorylation of an inhibitory tyrosine near the c-terminus of the protein produces a binding site for the SH2 domain which then facilitates binding of the SH3 domain to a polyproline site within the linker between the SH2 domain and the kinase domain. Binding of the SH3 domain inactivates the enzyme. This allows for multiple mechanisms for c-Src activation: dephosphorylation of the C-terminal tyrosine by a protein tyrosine phosphatase, binding of the SH2 domain by a competitive phospho-tyrosine residue, or competitive binding of a polyproline binding site to the SH3 domain. Unlike most other Src members Src lacks cysteine residues in the SH4 domain that undergo palmitylation. Serine and threonine phosphorylation sites have also been identified in the unique domains of Src and are believed to modulate protein-protein interactions or regulate catalytic activity. Alternatively spliced forms of Src, which contain 6- or 11-amino acid insertions in the SH3 domain, are expressed in CNS neurons. c-Src 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. 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 1158943420 423 QWYVGQVTRGQAEGCLRQV-NMDGAFLVRDSskRSSIQPYTLMVLYQDKVYNIQIRCEQNEFLLGTGLKVSE--TYPMVA 499
Cdd:cd10365     4 EWYFGKITRRESERLLLNAeNPRGTFLVRES--ETTKGAYCLSVSDFDNAKGLNVKHYKIRKLDSGGFYITSrtQFNSLQ 81

                  ....*...
gi 1158943420 500 HIIAHYRQ 507
Cdd:cd10365    82 QLVAYYSK 89

Src homology 2 (SH2) domain found in suppressor of cytokine signaling (SOCS) proteins; SH2 domain found in SOCS proteins. SOCS was first recognized as a group of cytokine-inducible SH2 (CIS) domain proteins comprising eight family members in human (CIS and SOCS1-SOCS7). In addition to the SH2 domain, SOCS proteins have a variable N-terminal domain and a conserved SOCS box in the C-terminal domain. SOCS proteins bind to a substrate via their SH2 domain. The prototypical members, CIS and SOCS1-SOCS3, have been shown to regulate growth hormone signaling in vitro and in a classic negative feedback response compete for binding at phosphotyrosine sites in JAK kinase and receptor pathways to displace effector proteins and target bound receptors for proteasomal degradation. Loss of SOCS activity results in excessive cytokine signaling associated with a variety of hematopoietic, autoimmune, and inflammatory diseases and certain cancers. Members (SOCS4-SOCS7) were identified by their conserved SOCS box, an adapter motif of 3 helices that associates substrate binding domains, such as the SOCS SH2 domain, ankryin, and WD40 with ubiquitin ligase components. These show limited cytokine induction. 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 1158943420 421 NPQWYVGQVTRGQAEGCLRQVNmDGAFLVRDSSKRSSIqpYTLMVLYQDKVYNIQIRCEQNEFLLGTGLKVS---ETYPM 497
Cdd:cd10383     6 QTGWYWGSMTVNEAKEKLQDAP-EGTFLVRDSSHSDYL--LTISVKTSAGPTNLRIEYQDGKFRLDSIICVKsklKQFDS 82

                          90
                  ....*....|
gi 1158943420 498 VAHIIAHYRQ 507
Cdd:cd10383    83 VVHLIEYYVQ 92

DNA polymerase III subunits gamma and tau; Validated

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1158943420  85 RTAAPKYEPAMPQEDQPWGPDEFDEGSDEDYENPDAEEDDGSGGDYESPTEDVGLEDSDNGYESPPSEAPEEIPHQLRAA 164
Cdd:PRK07764  614 RPAAPAAPAAPAAPAPAGAAAAPAEASAAPAPGVAAPEHHPKHVAVPDASDGGDGWPAKAGGAAPAAPPPAPAPAAPAAP 693

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1158943420 165 KPLADGEYIDSTPHRNTARSHPPPTTQRPGAGPPIPSASHPSLLQPPPPRREQSPQHPGRITGKLPATSSNAAPAPPVDR 244
Cdd:PRK07764  694 AGAAPAQPAPAPAATPPAGQADDPAAQPPQAAQGASAPSPAADDPVPLPPEPDDPPDPAGAPAQPPPPPAPAPAAAPAAA 773

                         170
                  ....*....|....*....
gi 1158943420 245 RRKPTKLDRTRLAESPIPA 263
Cdd:PRK07764  774 PPPSPPSEEEEMAEDDAPS 792

hypothetical protein; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1158943420  96 PQEDQPWGPDEFDEGSDEDYENPDAEEDDGSGGDYESPTEDVGLEDSDNGYESPPSEAPEEIPHQLRA-----AKPLADG 170
Cdd:PHA03169  128 PESPASHSPPPSPPSHPGPHEPAPPESHNPSPNQQPSSFLQPSHEDSPEEPEPPTSEPEPDSPGPPQSetptsSPPPQSP 207

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1158943420 171 EYIDSTPHRNTARSHPPPTTQRPGAgppipSASHPSLLQPPPPRREQSPQHPGRITGKLPATSSNAAPAPPVDRRRKPTK 250
Cdd:PHA03169  208 PDEPGEPQSPTPQQAPSPNTQQAVE-----HEDEPTEPEREGPPFPGHRSHSYTVVGWKPSTRPGGVPKLCLRCTSHPSH 282

                  ...
gi 1158943420 251 LDR 253
Cdd:PHA03169  283 RSR 285

DNA polymerase III subunit gamma/tau;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1158943420 144 NGYESPPSEAPEEIPHQLRAAKPLADgeyidSTPHRNTARSHPPPTTqrPGAGPPIPSASHPSLLQPPPPRREQSPQHPG 223
Cdd:PRK12323  369 GGGAGPATAAAAPVAQPAPAAAAPAA-----AAPAPAAPPAAPAAAP--AAAAAARAVAAAPARRSPAPEALAAARQASA 441