2vif

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{{STRUCTURE_2vif| PDB=2vif | SCENE= }}
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==CRYSTAL STRUCTURE OF SOCS6 SH2 DOMAIN IN COMPLEX WITH A C-KIT PHOSPHOPEPTIDE==
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===CRYSTAL STRUCTURE OF SOCS6 SH2 DOMAIN IN COMPLEX WITH A C-KIT PHOSPHOPEPTIDE===
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<StructureSection load='2vif' size='340' side='right' caption='[[2vif]], [[Resolution|resolution]] 1.45&Aring;' scene=''>
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{{ABSTRACT_PUBMED_21030588}}
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2vif]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VIF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2VIF FirstGlance]. <br>
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</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene><br>
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<tr><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr>
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<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1qzj|1qzj]], [[1t45|1t45]], [[1pkg|1pkg]], [[1qzk|1qzk]], [[1r01|1r01]], [[1t46|1t46]]</td></tr>
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<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2vif FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2vif OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2vif RCSB], [http://www.ebi.ac.uk/pdbsum/2vif PDBsum]</span></td></tr>
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<table>
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== Disease ==
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[[http://www.uniprot.org/uniprot/KIT_HUMAN KIT_HUMAN]] Defects in KIT are a cause of piebald trait (PBT) [MIM:[http://omim.org/entry/172800 172800]]; also known as piebaldism. PBT is an autosomal dominant genetic developmental abnormality of pigmentation characterized by congenital patches of white skin and hair that lack melanocytes.<ref>PMID:1376329</ref> <ref>PMID:1370874</ref> <ref>PMID:1717985</ref> <ref>PMID:7687267</ref> <ref>PMID:8680409</ref> <ref>PMID:9029028</ref> <ref>PMID:9450866</ref> <ref>PMID:9699740</ref> <ref>PMID:11074500</ref> Defects in KIT are a cause of gastrointestinal stromal tumor (GIST) [MIM:[http://omim.org/entry/606764 606764]].<ref>PMID:9029028</ref> <ref>PMID:9697690</ref> <ref>PMID:9438854</ref> <ref>PMID:11505412</ref> <ref>PMID:15824741</ref> Defects in KIT have been associated with testicular germ cell tumor (TGCT) [MIM:[http://omim.org/entry/273300 273300]]. A common solid malignancy in males. Germ cell tumors of the testis constitute 95% of all testicular neoplasms.<ref>PMID:9029028</ref> Defects in KIT are a cause of acute myelogenous leukemia (AML) [MIM:[http://omim.org/entry/601626 601626]]. AML is a malignant disease in which hematopoietic precursors are arrested in an early stage of development. Note=Somatic mutations that lead to constitutive activation of KIT are detected in AML patients. These mutations fall into two classes, the most common being in-frame internal tandem duplications of variable length in the juxtamembrane region that disrupt the normal regulation of the kinase activity. Likewise, point mutations in the kinase domain can result in a constitutively activated kinase.<ref>PMID:9029028</ref>
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== Function ==
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[[http://www.uniprot.org/uniprot/SOCS6_HUMAN SOCS6_HUMAN]] SOCS family proteins form part of a classical negative feedback system that regulates cytokine signal transduction. May be a substrate recognition component of a SCF-like ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins (By similarity). Regulates KIT degradation by ubiquitination of the tyrosine-phosphorylated receptor. [[http://www.uniprot.org/uniprot/KIT_HUMAN KIT_HUMAN]] Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine KITLG/SCF and plays an essential role in the regulation of cell survival and proliferation, hematopoiesis, stem cell maintenance, gametogenesis, mast cell development, migration and function, and in melanogenesis. In response to KITLG/SCF binding, KIT can activate several signaling pathways. Phosphorylates PIK3R1, PLCG1, SH2B2/APS and CBL. Activates the AKT1 signaling pathway by phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase. Activated KIT also transmits signals via GRB2 and activation of RAS, RAF1 and the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1. Promotes activation of STAT family members STAT1, STAT3, STAT5A and STAT5B. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. KIT signaling is modulated by protein phosphatases, and by rapid internalization and degradation of the receptor. Activated KIT promotes phosphorylation of the protein phosphatases PTPN6/SHP-1 and PTPRU, and of the transcription factors STAT1, STAT3, STAT5A and STAT5B. Promotes phosphorylation of PIK3R1, CBL, CRK (isoform Crk-II), LYN, MAPK1/ERK2 and/or MAPK3/ERK1, PLCG1, SRC and SHC1.<ref>PMID:7520444</ref> <ref>PMID:9528781</ref> <ref>PMID:10397721</ref> <ref>PMID:12444928</ref> <ref>PMID:12878163</ref> <ref>PMID:12511554</ref> <ref>PMID:17904548</ref> <ref>PMID:19265199</ref> <ref>PMID:21640708</ref> <ref>PMID:21135090</ref>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/vi/2vif_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The c-KIT receptor tyrosine kinase mediates the cellular response to stem cell factor (SCF). While c-KIT activity is important for the proliferation of hematopoietic cells, melanocytes and germ cells, uncontrolled c-KIT activity contributes to the growth of diverse human tumors. Suppressor of cytokine signaling 6 (SOCS6) is a member of the SOCS family of E3 ubiquitin ligases that can interact with c-KIT and suppress c-KIT-dependent pathways. Here, we analyzed the molecular mechanisms that determine SOCS6 substrate recognition. Our results show that the SH2 domain of SOCS6 is essential for its interaction with c-KIT pY568. The 1.45 A crystal structure of SOCS6 SH2 domain bound to the c-KIT substrate peptide (c-KIT residues 564-574) revealed a highly complementary and specific interface giving rise to a high affinity interaction (Kd = 0.3 muM). Interestingly, the SH2 binding pocket extends to substrate residue position pY+6 and envelopes the c-KIT phosphopeptide with a large BG loop insertion that contributes significantly to substrate interaction. We demonstrate that SOCS6 has ubiquitin ligase activity towards c-KIT and regulates c-KIT protein turnover in cells. Our data support a role of SOCS6 as a feedback inhibitor of SCF-dependent signaling and provides molecular data to account for target specificity within the SOCS family of ubiquitin ligases.
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==Disease==
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Structural basis for c-KIT inhibition by the suppressor of cytokine signaling 6 (SOCS6) ubiquitin ligase.,Zadjali F, Pike AC, Vesterlund M, Sun J, Wu C, Li SS, Ronnstrand L, Knapp S, Bullock AN, Flores-Morales A J Biol Chem. 2010 Oct 28. PMID:21030588<ref>PMID:21030588</ref>
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[[http://www.uniprot.org/uniprot/KIT_HUMAN KIT_HUMAN]] Defects in KIT are a cause of piebald trait (PBT) [MIM:[http://omim.org/entry/172800 172800]]; also known as piebaldism. PBT is an autosomal dominant genetic developmental abnormality of pigmentation characterized by congenital patches of white skin and hair that lack melanocytes.<ref>PMID:1376329</ref><ref>PMID:1370874</ref><ref>PMID:1717985</ref><ref>PMID:7687267</ref><ref>PMID:8680409</ref><ref>PMID:9029028</ref><ref>PMID:9450866</ref><ref>PMID:9699740</ref><ref>PMID:11074500</ref> Defects in KIT are a cause of gastrointestinal stromal tumor (GIST) [MIM:[http://omim.org/entry/606764 606764]].<ref>PMID:9029028</ref><ref>PMID:9697690</ref><ref>PMID:9438854</ref><ref>PMID:11505412</ref><ref>PMID:15824741</ref> Defects in KIT have been associated with testicular germ cell tumor (TGCT) [MIM:[http://omim.org/entry/273300 273300]]. A common solid malignancy in males. Germ cell tumors of the testis constitute 95% of all testicular neoplasms.<ref>PMID:9029028</ref> Defects in KIT are a cause of acute myelogenous leukemia (AML) [MIM:[http://omim.org/entry/601626 601626]]. AML is a malignant disease in which hematopoietic precursors are arrested in an early stage of development. Note=Somatic mutations that lead to constitutive activation of KIT are detected in AML patients. These mutations fall into two classes, the most common being in-frame internal tandem duplications of variable length in the juxtamembrane region that disrupt the normal regulation of the kinase activity. Likewise, point mutations in the kinase domain can result in a constitutively activated kinase.<ref>PMID:9029028</ref>
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==Function==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[http://www.uniprot.org/uniprot/SOCS6_HUMAN SOCS6_HUMAN]] SOCS family proteins form part of a classical negative feedback system that regulates cytokine signal transduction. May be a substrate recognition component of a SCF-like ECS (Elongin BC-CUL2/5-SOCS-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins (By similarity). Regulates KIT degradation by ubiquitination of the tyrosine-phosphorylated receptor. [[http://www.uniprot.org/uniprot/KIT_HUMAN KIT_HUMAN]] Tyrosine-protein kinase that acts as cell-surface receptor for the cytokine KITLG/SCF and plays an essential role in the regulation of cell survival and proliferation, hematopoiesis, stem cell maintenance, gametogenesis, mast cell development, migration and function, and in melanogenesis. In response to KITLG/SCF binding, KIT can activate several signaling pathways. Phosphorylates PIK3R1, PLCG1, SH2B2/APS and CBL. Activates the AKT1 signaling pathway by phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase. Activated KIT also transmits signals via GRB2 and activation of RAS, RAF1 and the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1. Promotes activation of STAT family members STAT1, STAT3, STAT5A and STAT5B. Activation of PLCG1 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate. KIT signaling is modulated by protein phosphatases, and by rapid internalization and degradation of the receptor. Activated KIT promotes phosphorylation of the protein phosphatases PTPN6/SHP-1 and PTPRU, and of the transcription factors STAT1, STAT3, STAT5A and STAT5B. Promotes phosphorylation of PIK3R1, CBL, CRK (isoform Crk-II), LYN, MAPK1/ERK2 and/or MAPK3/ERK1, PLCG1, SRC and SHC1.<ref>PMID:7520444</ref><ref>PMID:9528781</ref><ref>PMID:10397721</ref><ref>PMID:12444928</ref><ref>PMID:12878163</ref><ref>PMID:12511554</ref><ref>PMID:17904548</ref><ref>PMID:19265199</ref><ref>PMID:21640708</ref><ref>PMID:21135090</ref>
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</div>
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== References ==
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==About this Structure==
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<references/>
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[[2vif]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VIF OCA].
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__TOC__
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</StructureSection>
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==Reference==
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<ref group="xtra">PMID:021030588</ref><references group="xtra"/><references/>
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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Arrowsmith, C H.]]
[[Category: Arrowsmith, C H.]]

Revision as of 01:49, 1 October 2014

CRYSTAL STRUCTURE OF SOCS6 SH2 DOMAIN IN COMPLEX WITH A C-KIT PHOSPHOPEPTIDE

2vif, resolution 1.45Å

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