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 355691834 410 PAEEENSLNE-EWYVSYITRPEAEAALRKINQDGTFLVRDSSKKTITNPYVLMVLYKDKVYNIQIRYQKESQVYLLGTGL 488
Cdd:cd09929    1 SAEEEADLLPkEWYAGNIDRKEAEEALRRSNKDGTFLVRDSSGKDSSQPYTLMVLYNDKVYNIQIRFLENTRQYALGTGL 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|..
gi 355691834 489 RGKEDFLSVSDIIGYFRKMPLLLIDGKNRGSRYQCTLtHAAG 530
Cdd:cd09929   81 RGEETFSSVAEIIEHHQKTPLLLIDGKDNTKDSTCLL-YAAG 121

large tegument protein UL36; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 355691834  137 APVEDDADYEPPPSNDEEAlQNSILPAKPFPNSNSMYIGKGPFLDF-PAPAVPSQAPHCCTEDRcpslpvqplpppqtnh 215
Cdd:PHA03247 2693 GSLTSLADPPPPPPTPEPA-PHALVSATPLPPGPAAARQASPALPAaPAPPAVPAGPATPGGPA---------------- 2755

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 355691834  216 eEPSRSRNHKTAKLPAPSIDRSTKPPLDRSLAPFDREPFTLGKKPPFSDKPSIPAG-RPLGEHLPKVQKP--PLPPTTER 292
Cdd:PHA03247 2756 -RPARPPTTAGPPAPAPPAAPAAGPPRRLTRPAVASLSESRESLPSPWDPADPPAAvLAPAAALPPAASPagPLPPPTSA 2834

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 355691834  293 HERSSPLPGK--KPPVPKHGWGADrrenvSTKLHQRPLPQPALlpmssnTFPSRSAKPsPMNSLPSShmhgAFSESNSSF 370
Cdd:PHA03247 2835 QPTAPPPPPGppPPSLPLGGSVAP-----GGDVRRRPPSRSPA------AKPAAPARP-PVRRLARP----AVSRSTESF 2898

                         250       260       270       280
                  ....*....|....*....|....*....|....*....|.
gi 355691834  371 PQSASLPPYFSQGPSNRPPI-RAEGRNFPLPLPNKPRPPSP 410
Cdd:PHA03247 2899 ALPPDQPERPPQPQAPPPPQpQPQPPPPPQPQPPPPPPPRP 2939

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 355691834 410 PAEEENSLNE-EWYVSYITRPEAEAALRKINQDGTFLVRDSSKKTITNPYVLMVLYKDKVYNIQIRYQKESQVYLLGTGL 488
Cdd:cd09929    1 SAEEEADLLPkEWYAGNIDRKEAEEALRRSNKDGTFLVRDSSGKDSSQPYTLMVLYNDKVYNIQIRFLENTRQYALGTGL 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|..
gi 355691834 489 RGKEDFLSVSDIIGYFRKMPLLLIDGKNRGSRYQCTLtHAAG 530
Cdd:cd09929   81 RGEETFSSVAEIIEHHQKTPLLLIDGKDNTKDSTCLL-YAAG 121

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 355691834   419 EEWYVSYITRPEAEAALRKiNQDGTFLVRDSSKKtiTNPYVLMVLYKDKVYNIQIRYQKESQVYLLgtglrGKEDFLSVS 498
Cdd:smart00252   1 QPWYHGFISREEAEKLLKN-EGDGDFLVRDSESS--PGDYVLSVRVKGKVKHYRIRRNEDGKFYLE-----GGRKFPSLV 72

                           90
                   ....*....|.
gi 355691834   499 DIIGYFRKMPL 509
Cdd:smart00252  73 ELVEHYQKNSL 83

SAM domain (Sterile alpha motif);

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 355691834   12 VLGWDPDSLADYFKKLNYKDCEKAVKKYHIDGARFL-NLTENDIQKFPKLRVPILSKLSQEINKNE 76
Cdd:pfam07647   1 VESWSLESVADWLRSIGLEQYTDNFRDQGITGAELLlRLTLEDLKRLGITSVGHRRKILKKIQELK 66

Sterile alpha motif; Widespread domain in signalling and nuclear proteins. In EPH-related tyrosine kinases, appears to mediate cell-cell initiated signal transduction via the binding of SH2-containing proteins to a conserved tyrosine that is phosphorylated. In many cases mediates homodimerisation.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 355691834    12 VLGWDPDSLADYFKKLNYKDCEKAVKKYHIDGARFLNLT-ENDIQKFPKLRVPILSKLSQEINK 74
Cdd:smart00454   1 VSQWSPESVADWLESIGLEQYADNFRKNGIDGALLLLLTsEEDLKELGITKLGHRKKILKAIQK 64

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 355691834 410 PAEEENSLNE-EWYVSYITRPEAEAALRKINQDGTFLVRDSSKKTITNPYVLMVLYKDKVYNIQIRYQKESQVYLLGTGL 488
Cdd:cd09929    1 SAEEEADLLPkEWYAGNIDRKEAEEALRRSNKDGTFLVRDSSGKDSSQPYTLMVLYNDKVYNIQIRFLENTRQYALGTGL 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|..
gi 355691834 489 RGKEDFLSVSDIIGYFRKMPLLLIDGKNRGSRYQCTLtHAAG 530
Cdd:cd09929   81 RGEETFSSVAEIIEHHQKTPLLLIDGKDNTKDSTCLL-YAAG 121

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 355691834   419 EEWYVSYITRPEAEAALRKiNQDGTFLVRDSSKKtiTNPYVLMVLYKDKVYNIQIRYQKESQVYLLgtglrGKEDFLSVS 498
Cdd:smart00252   1 QPWYHGFISREEAEKLLKN-EGDGDFLVRDSESS--PGDYVLSVRVKGKVKHYRIRRNEDGKFYLE-----GGRKFPSLV 72

                           90
                   ....*....|.
gi 355691834   499 DIIGYFRKMPL 509
Cdd:smart00252  73 ELVEHYQKNSL 83

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 355691834 420 EWYVSYITRPEAEAALRKiNQDGTFLVRDSSkkTITNPYVLMVLYK-DKVYNIQIRYQKESQVYLLGTGLRgkedFLSVS 498
Cdd:cd00173    1 PWFHGSISREEAERLLRG-KPDGTFLVRESS--SEPGDYVLSVRSGdGKVKHYLIERNEGGYYLLGGSGRT----FPSLP 73

                 ....*.
gi 355691834 499 DIIGYF 504
Cdd:cd00173   74 ELVEHY 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 355691834 417 LNEEWYVSYITRPEAEAALRKINQDGTFLVRDSSKKtiTNPYVLMVLYKDKVYNIQIryQKESQVYLLGTglrgkEDFLS 496
Cdd:cd09932    2 ESKEWFHANLTREQAEEMLMRVPRDGAFLVRPSETD--PNSFAISFRAEGKIKHCRI--KQEGRLFVIGT-----SQFES 72

                         90
                 ....*....|...
gi 355691834 497 VSDIIGYFRKMPL 509
Cdd:cd09932   73 LVELVSYYEKHPL 85

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 355691834 419 EEWYVSYITRPEAEAALRKI-NQDGTFLVRDSskKTITNPYVLMVLYKDKVYNIQIRYQKESQVYLLGTGLRGKEDFLSV 497
Cdd:cd10365    3 EEWYFGKITRRESERLLLNAeNPRGTFLVRES--ETTKGAYCLSVSDFDNAKGLNVKHYKIRKLDSGGFYITSRTQFNSL 80

                 ....*....
gi 355691834 498 SDIIGYFRK 506
Cdd:cd10365   81 QQLVAYYSK 89

Src homology 2 (SH2) domain found in Tec-like proteins; The Tec protein tyrosine kinase is the founding member of a family that includes Btk, Itk, Bmx, and Txk. The members have a PH domain, a zinc-binding motif, a SH3 domain, a SH2 domain, and a protein kinase catalytic domain. Btk is involved in B-cell receptor signaling with mutations in Btk responsible for X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (xid) in mice. Itk is involved in T-cell receptor signaling. Tec is expressed in both T and B cells, and is thought to function in activated and effector T lymphocytes to induce the expression of genes regulated by NFAT transcription factors. 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 355691834 420 EWYVSYITRPEAEAALRKINQDGTFLVRDSSKKTItnpYVLMVLYK----DKVYNIQIRYQKESQVYllgtgLRGKEDFL 495
Cdd:cd09934    7 EWYVGDMSRQRAESLLKQEDKEGCFVVRNSSTKGL---YTVSLFTKvpgsPHVKHYHIKQNARSEFY-----LAEKHCFE 78

                         90
                 ....*....|
gi 355691834 496 SVSDIIGYFR 505
Cdd:cd09934   79 TIPELINYHQ 88

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 355691834 419 EEWYVSYITRPEAEAALRKINQDGTFLVRDSSkktiTNPYVLMVLYKDKVYNIQIRYQKESQVYLLGTglrgkEDFLSVS 498
Cdd:cd09943    1 QPWYYGRITRHQAETLLNEHGHEGDFLIRDSE----SNPGDYSVSLKAPGRNKHFKVQVVDNVYCIGQ-----RKFHTMD 71

                         90
                 ....*....|.
gi 355691834 499 DIIGYFRKMPL 509
Cdd:cd09943   72 ELVEHYKKAPI 82

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 355691834 420 EWYVSYITRPEAEAALRKINQDGTFLVRDSSkktiTNPYVLMVLYKDKVYNIQIRYQKESQVYLLgtglrGKEDFLSVSD 499
Cdd:cd10408    2 PWYYGKVTRHQAEMALNERGNEGDFLIRDSE----SSPNDFSVSLKAQGKNKHFKVQLKECVYCI-----GQRKFSSMEE 72

                         90
                 ....*....|.
gi 355691834 500 IIGYFRKMPLL 510
Cdd:cd10408   73 LVEHYKKAPIF 83

large tegument protein UL36; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 355691834  137 APVEDDADYEPPPSNDEEAlQNSILPAKPFPNSNSMYIGKGPFLDF-PAPAVPSQAPHCCTEDRcpslpvqplpppqtnh 215
Cdd:PHA03247 2693 GSLTSLADPPPPPPTPEPA-PHALVSATPLPPGPAAARQASPALPAaPAPPAVPAGPATPGGPA---------------- 2755

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 355691834  216 eEPSRSRNHKTAKLPAPSIDRSTKPPLDRSLAPFDREPFTLGKKPPFSDKPSIPAG-RPLGEHLPKVQKP--PLPPTTER 292
Cdd:PHA03247 2756 -RPARPPTTAGPPAPAPPAAPAAGPPRRLTRPAVASLSESRESLPSPWDPADPPAAvLAPAAALPPAASPagPLPPPTSA 2834

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 355691834  293 HERSSPLPGK--KPPVPKHGWGADrrenvSTKLHQRPLPQPALlpmssnTFPSRSAKPsPMNSLPSShmhgAFSESNSSF 370
Cdd:PHA03247 2835 QPTAPPPPPGppPPSLPLGGSVAP-----GGDVRRRPPSRSPA------AKPAAPARP-PVRRLARP----AVSRSTESF 2898

                         250       260       270       280
                  ....*....|....*....|....*....|....*....|.
gi 355691834  371 PQSASLPPYFSQGPSNRPPI-RAEGRNFPLPLPNKPRPPSP 410
Cdd:PHA03247 2899 ALPPDQPERPPQPQAPPPPQpQPQPPPPPQPQPPPPPPPRP 2939

Sterile alpha motif; Widespread domain in signalling and nuclear proteins. In EPH-related tyrosine kinases, appears to mediate cell-cell initiated signal transduction via the binding of SH2-containing proteins to a conserved tyrosine that is phosphorylated. In many cases mediates homodimerisation.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 355691834    12 VLGWDPDSLADYFKKLNYKDCEKAVKKYHIDGARFLNLT-ENDIQKFPKLRVPILSKLSQEINK 74
Cdd:smart00454   1 VSQWSPESVADWLESIGLEQYADNFRKNGIDGALLLLLTsEEDLKELGITKLGHRKKILKAIQK 64

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 355691834 421 WYVSYITRPEAEAALRKINQDGTFLVRDSSKKtiTNPYVLMVLYKDKVYNIQIRYQKESQVYllgtglrGKEDFLSVSDI 500
Cdd:cd10355    8 WYHGNLTRHAAEALLLSNGVDGSYLLRNSNEG--TGLFSLSVRAKDSVKHFHVEYTGYSFKF-------GFNEFSSLQDF 78

                         90
                 ....*....|
gi 355691834 501 IGYFRKMPLL 510
Cdd:cd10355   79 VKHFANQPLI 88

N-terminal Src homology 2 (nSH2) domain found in p85; Phosphoinositide 3-kinases (PI3Ks) are essential for cell growth, migration, and survival. p110, the catalytic subunit, is composed of an adaptor-binding domain, a Ras-binding domain, a C2 domain, a helical domain, and a kinase domain. The regulatory unit is called p85 and is composed of an SH3 domain, a RhoGap domain, a N-terminal SH2 (nSH2) domain, an internal SH2 (iSH2) domain, and C-terminal (cSH2) domain. There are 2 inhibitory interactions between p110alpha and p85 of P13K: (1) p85 nSH2 domain with the C2, helical, and kinase domains of p110alpha and (2) p85 iSH2 domain with C2 domain of p110alpha. There are 3 inhibitory interactions between p110beta and p85 of P13K: (1) p85 nSH2 domain with the C2, helical, and kinase domains of p110beta, (2) p85 iSH2 domain with C2 domain of p110alpha, and (3) p85 cSH2 domain with the kinase domain of p110alpha. It is interesting to note that p110beta is oncogenic as a wild type protein while p110alpha lacks this ability. One explanation is the idea that the regulation of p110beta by p85 is unique because of the addition of inhibitory contacts from the cSH2 domain and the loss of contacts in the iSH2 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 355691834 418 NEEWYVSYITRPEAEAALRKiNQDGTFLVRDSSkkTITNPYVLMVLYKDKVYNIQIrYQKESQVyllgtGLRGKEDFLSV 497
Cdd:cd09942    6 EAEWYWGDISREEVNEKMRD-TPDGTFLVRDAS--TMKGDYTLTLRKGGNNKLIKI-FHRDGKY-----GFSDPLTFNSV 76

                         90
                 ....*....|..
gi 355691834 498 SDIIGYFRKMPL 509
Cdd:cd09942   77 VELINYYRNNSL 88

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 355691834 419 EEWYVSYIT--RPEAEAALRKINQ--DGTFLVRDSSkkTITNPYVLMVLYKDKVYNIQIRYQKE--SQVYLlgtgLRGKE 492
Cdd:cd10341    4 EPWFHGKLGdgRDEAEKLLLEYCEggDGTFLVRESE--TFVGDYTLSFWRNGKVQHCRIRSRQEngEKKYY----LTDNL 77

                         90
                 ....*....|....*..
gi 355691834 493 DFLSVSDIIGYFRKMPL 509
Cdd:cd10341   78 VFDSLYELIDYYRQNPL 94

large tegument protein UL36; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 355691834  183 PAPAVPSQAPHcCTEDRCPSLPVQPLPPPQTNHEEPSRSRNHKTAKLPAPSIDRSTKP--PLDRSLAPfDREPFTLGKKP 260
Cdd:PHA03247 2624 PDPPPPSPSPA-ANEPDPHPPPTVPPPERPRDDPAPGRVSRPRRARRLGRAAQASSPPqrPRRRAARP-TVGSLTSLADP 2701

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 355691834  261 PfsDKPSIPAGRPlgehLPKVQKPPLPPTTERHERSSPLPGKKPPVPkhgwgadrrenvstklhqrPLPQPALLPMSSNT 340
Cdd:PHA03247 2702 P--PPPPTPEPAP----HALVSATPLPPGPAAARQASPALPAAPAPP-------------------AVPAGPATPGGPAR 2756

                         170       180       190       200       210       220       230
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 355691834  341 FPSRSAKPSPMNSLPSSHMHGAfSESNSSFPQSASLPPYFSQGPSNR----PPIRAEGRNFPLPLPNKPRPPSP 410
Cdd:PHA03247 2757 PARPPTTAGPPAPAPPAAPAAG-PPRRLTRPAVASLSESRESLPSPWdpadPPAAVLAPAAALPPAASPAGPLP 2829

SAM domain of Polycomb group; SAM (sterile alpha motif) domain of Polycomb group is a protein-protein interaction domain. The Polycomb group includes transcriptional repressors which are involved in the regulation of some key regulatory genes during development in many organisms. They are best known for silencing Hox (Homeobox) genes. Polycomb proteins work together in large multimeric and chromatin-associated complexes. They organize chromatin of the target genes and maintain repressed states during many cell divisions. Polycomb proteins are classified based on their common function, but not on conserved domains and/or motifs; however many Polycomb proteins (members of PRC1 class complex) contain SAM domains which are more similar to each other inside of the Polycomb group than to SAM domains outside of it. Most information about structure and function of Polycomb SAM domains comes from studies of Ph (Polyhomeotic) and Scm (Sex comb on midleg) proteins. Polycomb SAM domains usually can be found at the C-terminus of the proteins. Some members of this group contain, in addition to the SAM domain, MTB repeats, Zn finger, and/or DUF3588 domains. Polycomb SAM domains can form homo- and/or heterooligomers through ML and EH surfaces. SAM/SAM oligomers apparently play a role in transcriptional repression through polymerization along the chromosome. Polycomb proteins are known to be highly expressed in some cells years before their cancer pathology; thus they are attractive markers for early cancer therapy.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 355691834  12 VLGWDPDSLADYFKKLN-YKDCEKAVKKYHIDGARFLNLTENDIQKFPKLRV-PILsKLSQEINK 74
Cdd:cd09509    1 PSKWSVDDVAQFIKSLDgCAEYAEVFREQEIDGQALLLLTEDDLLKGMGLKLgPAL-KIYNHIVK 64

C-terminal Src homology 2 (cSH2) domain found in p85; Phosphoinositide 3-kinases (PI3Ks) are essential for cell growth, migration, and survival. p110, the catalytic subunit, is composed of an adaptor-binding domain, a Ras-binding domain, a C2 domain, a helical domain, and a kinase domain. The regulatory unit is called p85 and is composed of an SH3 domain, a RhoGap domain, a N-terminal SH2 (nSH2) domain, a inter SH2 (iSH2) domain, and C-terminal (cSH2) domain. There are 2 inhibitory interactions between p110alpha and p85 of P13K: 1) p85 nSH2 domain with the C2, helical, and kinase domains of p110alpha and 2) p85 iSH2 domain with C2 domain of p110alpha. There are 3 inhibitory interactions between p110beta and p85 of P13K: 1) p85 nSH2 domain with the C2, helical, and kinase domains of p110beta, 2) p85 iSH2 domain with C2 domain of p110alpha, and 3) p85 cSH2 domain with the kinase domain of p110alpha. It is interesting to note that p110beta is oncogenic as a wild type protein while p110alpha lacks this ability. One explanation is the idea that the regulation of p110beta by p85 is unique because of the addition of inhibitory contacts from the cSH2 domain and the loss of contacts in the iSH2 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
                 ....*....|....*....|....*....|....*....|....*....|....
gi 355691834 421 WYVSYITRPEAEAALRKiNQDGTFLVRDSSKKtitNPYVLMVLYKDKVYNIQIR 474
Cdd:cd09930    8 WLVGDINRTQAEELLRG-KPDGTFLIRESSTQ---GCYACSVVCNGEVKHCVIY 57

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 355691834 421 WYVSYITRPEAEAALRK-INqdGTFLVRDSskKTITNPYVLMVLYKDKVYNIQIRYQKESQVYllgtgLRGKEDFLSVSD 499
Cdd:cd09935    5 WYHGPISRNAAEYLLSSgIN--GSFLVRES--ESSPGQYSISLRYDGRVYHYRISEDSDGKVY-----VTQEHRFNTLAE 75

                 ....*....
gi 355691834 500 IIGYFRKMP 508
Cdd:cd09935   76 LVHHHSKNA 84

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
                 ....*....|....*....|....*....|....*....|....*...
gi 355691834 422 YVSYITRPEAEAALRKINQDGTFLVRDSskKTITNPYVLMVLYKDKVY 469
Cdd:cd10400    6 YHGKISRETGEKLLLAAGLDGSYLLRDS--ESVPGVYCLCVLYKGYVY 51

N-terminal Src homology 2 (N-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): [IVL]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 355691834 421 WYVSYITRPEAEAALRKINQDGTFLVRDSSKktitNP--YVLMVLYKDKVYNIQIryQKESQVYLLGTGlrgkEDFLSVS 498
Cdd:cd10340    2 WFHPVISGIEAENLLKTRGVDGSFLARPSKS----NPgdFTLSVRRGDEVTHIKI--QNTGDYYDLYGG----EKFATLS 71

                         90
                 ....*....|...
gi 355691834 499 DIIGYFRKMPLLL 511
Cdd:cd10340   72 ELVQYYMEQHGQL 84

Src homology 2 domain found in SH2 domain-containing adapter protein F (SHF); SHF is thought to play a role in PDGF-receptor signaling and regulation of apoptosis. SHF is mainly expressed in skeletal muscle, brain, liver, prostate, testis, ovary, small intestine, and colon. 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 355691834 421 WYVSYITRPEAEAALRkINQDGTFLVRDSskKTITNPYVLMVLYKDKVYNIQIRYQKESQvYLLGtglRGKEDFLSVSDI 500
Cdd:cd10392    3 WYHGAISRTDAENLLR-LCKEASYLVRNS--ETSKNDFSLSLKSSQGFMHMKLSRTKEHK-YVLG---QNSPPFSSVPEI 75

                         90
                 ....*....|.
gi 355691834 501 IGYF--RKMPL 509
Cdd:cd10392   76 IHHYasRKLPI 86

SAM domain of Scm-like-3MBT3,4 proteins of Polycomb group; SAM (sterile alpha motif) domain of Scm-like-3MBT3,4 (Sex comb on midleg, Malignant brain tumor) subfamily proteins (also known as L3mbtl3,4 proteins) is a putative protein-protein interaction domain. Proteins of this subfamily are predicted transcriptional regulators belonging to Polycomb group. The majority of them are multidomain proteins: in addition to the C-terminal SAM domain, they contain three MBT repeats and Zn finger domain. Murine L3mbtl3 protein of this subfamily is essential for maturation of myeloid progenitor cells during differentiation. Human L3mbtl4 is a potential tumor suppressor gene in breast cancer, while deregulation of L3MBTL3 is associated with neuroblastoma.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|..
gi 355691834  12 VLGWDPDSLADYFKKL-NYKDCEKAVKKYHIDGARFLNLTENDIQKFPKLRV 62
Cdd:cd09582    1 VLRWSVDEVAEFVQSLpGCEEHAKVFRDEQIDGEAFLLLTQSDLVKILGIKL 52

Src homology 2 domain found in cancer-related signaling adaptor protein CRK; SH2 domain in the CRK proteins. CRKI (SH2-SH3) and CRKII (SH2-SH3-SH3) are splicing isoforms of the oncoprotein CRK. CRKs regulate transcription and cytoskeletal reorganization for cell growth and motility by linking tyrosine kinases to small G proteins. The SH2 domain of CRK associates with tyrosine-phosphorylated receptors or components of focal adhesions, such as p130Cas and paxillin. CRK transmits signals to small G proteins through effectors that bind its SH3 domain, such as C3G, the guanine-nucleotide exchange factor (GEF) for Rap1 and R-Ras, and DOCK180, the GEF for Rac6. The binding of p130Cas to the CRK-C3G complex activates Rap1, leading to regulation of cell adhesion, and activates R-Ras, leading to JNK-mediated activation of cell proliferation, whereas the binding of CRK DOCK180 induces Rac1-mediated activation of cellular migration. The activity of the different splicing isoforms varies greatly with CRKI displaying substantial transforming activity, CRKII less so, and phosphorylated CRKII with no biological activity whatsoever. CRKII has a linker region with a phosphorylated Tyr and an additional C-terminal SH3 domain. The phosphorylated Tyr creates a binding site for its SH2 domain which disrupts the association between CRK and its SH2 target proteins. 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 355691834 421 WYVSYITRPEAEAALRKiNQDGTFLVRDSSkkTITNPYVLMVLYKDKV--YNIQ 472
Cdd:cd09926    9 WYFGPMSRQEAQELLQG-QRHGVFLVRDSS--TIPGDYVLSVSENSRVshYIIN 59

Src homology 2 (SH2) domain found in Tec protein, IL2-inducible T-cell kinase (Itk); A member of the Tec protein tyrosine kinase Itk is expressed thymus, spleen, lymph node, T lymphocytes, NK and mast cells. It plays a role in T-cell proliferation and differentiation, analogous to Tec family kinases Txk. Itk has been shown to interact with Fyn, Wiskott-Aldrich syndrome protein, KHDRBS1, PLCG1, Lymphocyte cytosolic protein 2, Linker of activated T cells, Karyopherin alpha 2, Grb2, and Peptidylprolyl isomerase A. 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 and it's lack of presence in Txk 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
                 ....*....|....*....|....*....|..
gi 355691834 420 EWYVSYITRPEAEAALRKINQDGTFLVRDSSK 451
Cdd:cd10396    7 EWYNKNINRSKAEKLLRDEGKEGGFMVRDSSQ 38

Src homology 2 (SH2) domain in the Breast Cancer Anti-estrogen Resistance protein 3; BCAR3 is part of a growing family of guanine nucleotide exchange factors is responsible for activation of Ras-family GTPases, including Sos1 and 2, GRF1 and 2, CalDAG-GEF/GRP1-4, C3G, cAMP-GEF/Epac 1 and 2, PDZ-GEFs, MR-GEF, RalGDS family members, RalGPS, RasGEF, Smg GDS, and phospholipase C(epsilon). 12102558 21262352 BCAR3 binds to the carboxy-terminus of BCAR1/p130Cas, a focal adhesion adapter protein. Over expression of BCAR1 (p130Cas) and BCAR3 induces estrogen independent growth in normally estrogen-dependent cell lines. They have been linked to resistance to anti-estrogens in breast cancer, Rac activation, and cell motility, though the BCAR3/p130Cas complex is not required for this activity in BCAR3. Many BCAR3-mediated signaling events in epithelial and mesenchymal cells are independent of p130Cas association. Structurally these proteins contain a single SH2 domain upstream of their RasGEF domain, which is responsible for the ability of BCAR3 to enhance p130Cas over-expression-induced migration. 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 355691834 421 WYVSYITRPEAEAALRkinQDGTFLVRDSSkkTITNPYVLMVLYKDKVYNIQIR--YQKESQVYLLGTGLRGKEDFLSVS 498
Cdd:cd10337    8 WYHGRIPRQVAESLVQ---REGDFLVRDSL--SSPGDYVLTCRWKGQPLHFKINrvVLRPSEAYTRVQYQFEDEQFDSIP 82

                 ....*.
gi 355691834 499 DIIGYF 504
Cdd:cd10337   83 ALVHFY 88

C-terminal Src homology 2 (SH2) domain found in Ras GTPase-activating protein 1 (GAP); RasGAP is part of the GAP1 family of GTPase-activating proteins. The protein is located in the cytoplasm and stimulates the GTPase activity of normal RAS p21, but not its oncogenic counterpart. Acting as a suppressor of RAS function, the protein enhances the weak intrinsic GTPase activity of RAS proteins resulting in RAS inactivation, thereby allowing control of cellular proliferation and differentiation. Mutations leading to changes in the binding sites of either protein are associated with basal cell carcinomas. Alternative splicing results in two isoforms. The shorter isoform which lacks the N-terminal hydrophobic region, has the same activity, and is expressed in placental tissues. In general longer isoform contains 2 SH2 domains, a SH3 domain, a pleckstrin homology (PH) domain, and a calcium-dependent phospholipid-binding C2 domain. The C-terminus contains the catalytic domain of RasGap which catalyzes the activation of Ras by hydrolyzing GTP-bound active Ras into an inactive GDP-bound form of Ras. This model contains the C-terminal 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 355691834 420 EWYVSYITRPEAEAALRKINQDGTFLVRDSskktITNP--YVLMVLYKDKVYNIQIRYQKESQvYLLGtGLRgkedFLSV 497
Cdd:cd10354    1 IWFHGKISREEAYNMLVKVGGPGSFLVRES----DNTPgdYSLSFRVNEGIKHFKIIPTGNNQ-FMMG-GRY----FSSL 70

                 ....*..
gi 355691834 498 SDIIGYF 504
Cdd:cd10354   71 DDVIDRY 77

transcriptional regulator ICP4; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 355691834  130 SPNEEEEAPVEDDADYEPPPSNDEEALQNSILPAKPFPNSNSMYIGKGPFLDFPAPAVP-----SQAPHCCTEDRCPSLP 204
Cdd:PHA03307   65 FEPPTGPPPGPGTEAPANESRSTPTWSLSTLAPASPAREGSPTPPGPSSPDPPPPTPPPaspppSPAPDLSEMLRPVGSP 144

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 355691834  205 VQPLPPPQ-----TNHEEPSRSRNHKTAKLPAPSIDRST------KPPLDRSLAPFDREPFTLGKKPPFSDKPSIPAGRP 273
Cdd:PHA03307  145 GPPPAASPpaagaSPAAVASDAASSRQAALPLSSPEETArapsspPAEPPPSTPPAAASPRPPRRSSPISASASSPAPAP 224