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| - | [[Image:2cbl.gif|left|200px]]<br /> | |
| - | <applet load="2cbl" size="450" color="white" frame="true" align="right" spinBox="true" | |
| - | caption="2cbl, resolution 2.1Å" /> | |
| - | '''N-TERMINAL DOMAIN OF CBL IN COMPLEX WITH ITS BINDING SITE ON ZAP-70'''<br /> | |
| | | | |
| - | ==Overview== | + | ==N-TERMINAL DOMAIN OF CBL IN COMPLEX WITH ITS BINDING SITE ON ZAP-70== |
| - | Cbl is an adaptor protein that functions as a negative regulator of many, signalling pathways that start from receptors at the cell surface. The, evolutionarily conserved amino-terminal region of Cbl (Cbl-N) binds to, phosphorylated tyrosine residues and has cell-transforming activity. Point, mutations in Cbl that disrupt its recognition of phosphotyrosine also, interfere with its negative regulatory function and, in the case of v-cbl, with its oncogenic potential. In T cells, Cbl-N binds to the, tyrosine-phosphorylated inhibitory site of the protein tyrosine kinase, ZAP-70. Here we describe the crystal structure of Cbl-N, both alone and in, complex with a phosphopeptide that represents its binding site in ZAP-70., The structures show that Cbl-N is composed of three interacting domains: a, four-helix bundle (4H), an EF-hand calcium-binding domain, and a divergent, SH2 domain that was not recognizable from the amino-acid sequence of the, protein. The calcium-bound EF hand wedges between the 4H and SH2 domains, and roughly determines their relative orientation. In the ligand-occupied, structure, the 4H domain packs against the SH2 domain and completes its, phosphotyrosine-recognition pocket. Disruption of this binding to ZAP-70, as a result of structure-based mutations in the 4H, EF-hand and SH2, domains confirms that the three domains together form an integrated, phosphoprotein-recognition module.
| + | <StructureSection load='2cbl' size='340' side='right'caption='[[2cbl]], [[Resolution|resolution]] 2.10Å' scene=''> |
| - | | + | == Structural highlights == |
| - | ==About this Structure== | + | <table><tr><td colspan='2'>[[2cbl]] 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=2CBL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2CBL FirstGlance]. <br> |
| - | 2CBL is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with CA as [http://en.wikipedia.org/wiki/ligand ligand]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2CBL OCA].
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.1Å</td></tr> |
| - | | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr> |
| - | ==Reference== | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2cbl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2cbl OCA], [https://pdbe.org/2cbl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2cbl RCSB], [https://www.ebi.ac.uk/pdbsum/2cbl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2cbl ProSAT]</span></td></tr> |
| - | Structure of the amino-terminal domain of Cbl complexed to its binding site on ZAP-70 kinase., Meng W, Sawasdikosol S, Burakoff SJ, Eck MJ, Nature. 1999 Mar 4;398(6722):84-90. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=10078535 10078535]
| + | </table> |
| | + | == Disease == |
| | + | [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> |
| | + | == Function == |
| | + | [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> |
| | + | == Evolutionary Conservation == |
| | + | [[Image:Consurf_key_small.gif|200px|right]] |
| | + | Check<jmol> |
| | + | <jmolCheckbox> |
| | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/cb/2cbl_consurf.spt"</scriptWhenChecked> |
| | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| | + | <text>to colour the structure by Evolutionary Conservation</text> |
| | + | </jmolCheckbox> |
| | + | </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=2cbl ConSurf]. |
| | + | <div style="clear:both"></div> |
| | + | == References == |
| | + | <references/> |
| | + | __TOC__ |
| | + | </StructureSection> |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Single protein]] | + | [[Category: Large Structures]] |
| - | [[Category: Burakoff, S.J.]] | + | [[Category: Burakoff SJ]] |
| - | [[Category: Eck, M.J.]] | + | [[Category: Eck MJ]] |
| - | [[Category: Meng, W.]] | + | [[Category: Meng W]] |
| - | [[Category: Sawasdikosol, S.]] | + | [[Category: Sawasdikosol S]] |
| - | [[Category: CA]]
| + | |
| - | [[Category: complex (proto-oncogene/peptide)]]
| + | |
| - | [[Category: phosphotyrosine binding]]
| + | |
| - | [[Category: proto-oncogene]]
| + | |
| - | [[Category: sh2]]
| + | |
| - | [[Category: signal transduction]]
| + | |
| - | | + | |
| - | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 21:13:45 2007''
| + | |
| Structural highlights
Disease
CBL_HUMAN Defects in CBL are the cause of Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia (NSLL) [MIM: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.[1]
Function
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.[2] [3] [4] [5] [6] [7] [8] [9]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
References
- ↑ Martinelli S, De Luca A, Stellacci E, Rossi C, Checquolo S, Lepri F, Caputo V, Silvano M, Buscherini F, Consoli F, Ferrara G, Digilio MC, Cavaliere ML, van Hagen JM, Zampino G, van der Burgt I, Ferrero GB, Mazzanti L, Screpanti I, Yntema HG, Nillesen WM, Savarirayan R, Zenker M, Dallapiccola B, Gelb BD, Tartaglia M. Heterozygous germline mutations in the CBL tumor-suppressor gene cause a Noonan syndrome-like phenotype. Am J Hum Genet. 2010 Aug 13;87(2):250-7. doi: 10.1016/j.ajhg.2010.06.015. Epub, 2010 Jul 8. PMID:20619386 doi:10.1016/j.ajhg.2010.06.015
- ↑ Joazeiro CA, Wing SS, Huang H, Leverson JD, Hunter T, Liu YC. The tyrosine kinase negative regulator c-Cbl as a RING-type, E2-dependent ubiquitin-protein ligase. Science. 1999 Oct 8;286(5438):309-12. PMID:10514377
- ↑ Howlett CJ, Robbins SM. Membrane-anchored Cbl suppresses Hck protein-tyrosine kinase mediated cellular transformation. Oncogene. 2002 Mar 7;21(11):1707-16. PMID:11896602 doi:10.1038/sj.onc.1205228
- ↑ Miyazaki T, Sanjay A, Neff L, Tanaka S, Horne WC, Baron R. Src kinase activity is essential for osteoclast function. J Biol Chem. 2004 Apr 23;279(17):17660-6. Epub 2004 Jan 22. PMID:14739300 doi:10.1074/jbc.M311032200
- ↑ Kaabeche K, Lemonnier J, Le Mee S, Caverzasio J, Marie PJ. Cbl-mediated degradation of Lyn and Fyn induced by constitutive fibroblast growth factor receptor-2 activation supports osteoblast differentiation. J Biol Chem. 2004 Aug 27;279(35):36259-67. Epub 2004 Jun 9. PMID:15190072 doi:10.1074/jbc.M402469200
- ↑ Bonaventure J, Horne WC, Baron R. The localization of FGFR3 mutations causing thanatophoric dysplasia type I differentially affects phosphorylation, processing and ubiquitylation of the receptor. FEBS J. 2007 Jun;274(12):3078-93. Epub 2007 May 17. PMID:17509076 doi:10.1111/j.1742-4658.2007.05835.x
- ↑ Dufour C, Guenou H, Kaabeche K, Bouvard D, Sanjay A, Marie PJ. FGFR2-Cbl interaction in lipid rafts triggers attenuation of PI3K/Akt signaling and osteoblast survival. Bone. 2008 Jun;42(6):1032-9. doi: 10.1016/j.bone.2008.02.009. Epub 2008 Feb 29. PMID:18374639 doi:10.1016/j.bone.2008.02.009
- ↑ Wehrle C, Van Slyke P, Dumont DJ. Angiopoietin-1-induced ubiquitylation of Tie2 by c-Cbl is required for internalization and degradation. Biochem J. 2009 Oct 12;423(3):375-80. doi: 10.1042/BJ20091010. PMID:19689429 doi:10.1042/BJ20091010
- ↑ Severe N, Miraoui H, Marie PJ. The Casitas B lineage lymphoma (Cbl) mutant G306E enhances osteogenic differentiation in human mesenchymal stromal cells in part by decreased Cbl-mediated platelet-derived growth factor receptor alpha and fibroblast growth factor receptor 2 ubiquitination. J Biol Chem. 2011 Jul 8;286(27):24443-50. doi: 10.1074/jbc.M110.197525. Epub 2011, May 19. PMID:21596750 doi:10.1074/jbc.M110.197525
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