2k4d

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[[Image:2k4d.png|left|200px]]
 
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{{STRUCTURE_2k4d| PDB=2k4d | SCENE= }}
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==E2-c-Cbl recognition is necessary but not sufficient for ubiquitination activity==
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<StructureSection load='2k4d' size='340' side='right'caption='[[2k4d]]' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2k4d]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2K4D OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2K4D FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR, 20 models</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2k4d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2k4d OCA], [https://pdbe.org/2k4d PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2k4d RCSB], [https://www.ebi.ac.uk/pdbsum/2k4d PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2k4d ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/CBL_HUMAN CBL_HUMAN] Defects in CBL are the cause of Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia (NSLL) [MIM:[https://omim.org/entry/613563 613563]. A syndrome characterized by a phenotype reminiscent of Noonan syndrome. Clinical features are highly variable, including facial dysmorphism, short neck, developmental delay, hyperextensible joints and thorax abnormalities with widely spaced nipples. The facial features consist of triangular face with hypertelorism, large low-set ears, ptosis, and flat nasal bridge. Some patients manifest cardiac defects.<ref>PMID:20619386</ref>
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== Function ==
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[https://www.uniprot.org/uniprot/CBL_HUMAN CBL_HUMAN] Adapter protein that functions as a negative regulator of many signaling pathways that are triggered by activation of cell surface receptors. Acts as an E3 ubiquitin-protein ligase, which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and then transfers it to substrates promoting their degradation by the proteasome. Recognizes activated receptor tyrosine kinases, including KIT, FLT1, FGFR1, FGFR2, PDGFRA, PDGFRB, EGFR, CSF1R, EPHA8 and KDR and terminates signaling. Recognizes membrane-bound HCK and other kinases of the SRC family and mediates their ubiquitination and degradation. Participates in signal transduction in hematopoietic cells. Plays an important role in the regulation of osteoblast differentiation and apoptosis. Essential for osteoclastic bone resorption. The Tyr-731 phosphorylated form induces the activation and recruitment of phosphatidylinositol 3-kinase to the cell membrane in a signaling pathway that is critical for osteoclast function.<ref>PMID:10514377</ref> <ref>PMID:11896602</ref> <ref>PMID:14739300</ref> <ref>PMID:15190072</ref> <ref>PMID:17509076</ref> <ref>PMID:18374639</ref> <ref>PMID:19689429</ref> <ref>PMID:21596750</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/k4/2k4d_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.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/main_output.php?pdb_ID=2k4d 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 E2 ubiquitin-conjugating enzymes UbcH7 and UbcH5B both show specific binding to the RING (really interesting new gene) domain of the E3 ubiquitin-protein ligase c-Cbl, but UbcH7 hardly supports ubiquitination of c-Cbl and substrate in a reconstituted system. Here, we found that neither structural changes nor subtle differences in the E2-E3 interaction surface are possible explanations for the functional specificity of UbcH5B and UbcH7 in their interaction with c-Cbl. The quick transfer of ubiquitin from the UbcH5B-Ub thioester to c-Cbl or other ubiquitin acceptors suggests that UbcH5B might functionally be a relatively pliable E2 enzyme. In contrast, the UbcH7-Ub thioester is too stable to transfer ubiquitin under our assay conditions, indicating that UbcH7 might be a more specific E2 enzyme. Our results imply that the interaction specificity between c-Cbl and E2 is required but not sufficient for transfer of ubiquitin to potential targets.
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===E2-c-Cbl recognition is necessary but not sufficient for ubiquitination activity===
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E2-c-Cbl recognition is necessary but not sufficient for ubiquitination activity.,Huang A, de Jong RN, Wienk H, Winkler GS, Timmers HT, Boelens R J Mol Biol. 2009 Jan 16;385(2):507-19. Epub 2008 Nov 1. PMID:18996392<ref>PMID:18996392</ref>
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{{ABSTRACT_PUBMED_18996392}}
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 2k4d" style="background-color:#fffaf0;"></div>
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==About this Structure==
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==See Also==
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[[2k4d]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2K4D OCA].
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*[[Ubiquitin protein ligase 3D structures|Ubiquitin protein ligase 3D structures]]
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== References ==
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==Reference==
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<references/>
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<ref group="xtra">PMID:018996392</ref><references group="xtra"/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Boelens, R.]]
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[[Category: Large Structures]]
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[[Category: Huang, A.]]
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[[Category: Boelens R]]
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[[Category: Jong, R N.De.]]
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[[Category: De Jong RN]]
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[[Category: Timmers, H T.M.]]
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[[Category: Huang A]]
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[[Category: Wienk, H.]]
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[[Category: Timmers HTM]]
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[[Category: Winkler, S G.]]
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[[Category: Wienk H]]
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[[Category: C-cbl]]
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[[Category: Winkler SG]]
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[[Category: Ligase]]
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[[Category: Metal-binding]]
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[[Category: Phosphoprotein]]
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[[Category: Protein]]
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[[Category: Proto-oncogene]]
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[[Category: Sh2 domain]]
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[[Category: Ubch5b]]
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[[Category: Ubch7]]
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[[Category: Ubiquitin]]
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[[Category: Ubl conjugation pathway]]
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[[Category: Zinc-finger]]
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Current revision

E2-c-Cbl recognition is necessary but not sufficient for ubiquitination activity

PDB ID 2k4d

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