3bun

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{{STRUCTURE_3bun| PDB=3bun | SCENE= }}
 
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===Crystal structure of c-Cbl-TKB domain complexed with its binding motif in Sprouty4===
 
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{{ABSTRACT_PUBMED_18273061}}
 
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==Disease==
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==Crystal structure of c-Cbl-TKB domain complexed with its binding motif in Sprouty4==
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[[http://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:[http://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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<StructureSection load='3bun' size='340' side='right'caption='[[3bun]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[3bun]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3BUN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3BUN 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">X-ray diffraction, [[Resolution|Resolution]] 2&#8491;</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=PTR:O-PHOSPHOTYROSINE'>PTR</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=3bun FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3bun OCA], [https://pdbe.org/3bun PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3bun RCSB], [https://www.ebi.ac.uk/pdbsum/3bun PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3bun ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/SPY4_HUMAN SPY4_HUMAN] Suppresses the insulin receptor and EGFR-transduced MAPK signaling pathway, but does not inhibit MAPK activation by a constitutively active mutant Ras. Probably impairs the formation of GTP-Ras. Inhibits Ras-independent, but not Ras-dependent, activation of RAF1.<ref>PMID:12717443</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/bu/3bun_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=3bun 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-Cbl tyrosine kinase binding domain (Cbl-TKB), essentially an 'embedded' SH2 domain, has a critical role in targeting proteins for ubiquitination. To address how this domain can bind to disparate recognition mofits and to determine whether this results in variations in substrate-binding affinity, we compared crystal structures of the Cbl-TKB domain complexed with phosphorylated peptides of Sprouty2, Sprouty4, epidermal growth factor receptor, Syk, and c-Met receptors and validated the binding with point-mutational analyses using full-length proteins. An obligatory, intrapeptidyl H-bond between the phosphotyrosine and the conserved asparagine or adjacent arginine is essential for binding and orients the peptide into a positively charged pocket on c-Cbl. Surprisingly, c-Met bound to Cbl in the reverse direction, which is unprecedented for SH2 domain binding. The necessity of this intrapeptidyl H-bond was confirmed with isothermal titration calorimetry experiments that also showed Sprouty2 to have the highest binding affinity to c-Cbl; this may enable the selective sequestration of c-Cbl from other target proteins.
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==Function==
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Structural basis for a novel intrapeptidyl H-bond and reverse binding of c-Cbl-TKB domain substrates.,Ng C, Jackson RA, Buschdorf JP, Sun Q, Guy GR, Sivaraman J EMBO J. 2008 Mar 5;27(5):804-16. Epub 2008 Feb 14. PMID:18273061<ref>PMID:18273061</ref>
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[[http://www.uniprot.org/uniprot/SPY4_HUMAN SPY4_HUMAN]] Suppresses the insulin receptor and EGFR-transduced MAPK signaling pathway, but does not inhibit MAPK activation by a constitutively active mutant Ras. Probably impairs the formation of GTP-Ras. Inhibits Ras-independent, but not Ras-dependent, activation of RAF1.<ref>PMID:12717443</ref> [[http://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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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[3bun]] 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=3BUN OCA].
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</div>
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<div class="pdbe-citations 3bun" style="background-color:#fffaf0;"></div>
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==Reference==
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==See Also==
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<ref group="xtra">PMID:018273061</ref><references group="xtra"/><references/>
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*[[Ubiquitin protein ligase 3D structures|Ubiquitin protein ligase 3D structures]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Buschdorf, J P.]]
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[[Category: Large Structures]]
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[[Category: Guy, G R.]]
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[[Category: Buschdorf JP]]
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[[Category: Jackson, R A.]]
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[[Category: Guy GR]]
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[[Category: Ng, C.]]
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[[Category: Jackson RA]]
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[[Category: Sivaraman, J.]]
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[[Category: Ng C]]
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[[Category: Sun, Q.]]
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[[Category: Sivaraman J]]
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[[Category: Cbl]]
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[[Category: Sun Q]]
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[[Category: Complex]]
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[[Category: Developmental protein]]
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[[Category: Ligase]]
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[[Category: Ligase-signaling protein complex]]
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[[Category: Membrane]]
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[[Category: Metal-binding]]
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[[Category: Phosphoprotein]]
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[[Category: Proto-oncogene]]
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[[Category: Sh2 domain]]
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[[Category: Signal transduction]]
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[[Category: Tkb]]
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[[Category: Ubl conjugation pathway]]
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[[Category: Zinc-finger]]
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Current revision

Crystal structure of c-Cbl-TKB domain complexed with its binding motif in Sprouty4

PDB ID 3bun

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