4a49

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{{STRUCTURE_4a49| PDB=4a49 | SCENE= }}
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==Structure of phosphoTyr371-c-Cbl-UbcH5B complex==
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===Structure of phosphoTyr371-c-Cbl-UbcH5B complex===
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<StructureSection load='4a49' size='340' side='right' caption='[[4a49]], [[Resolution|resolution]] 2.21&Aring;' scene=''>
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{{ABSTRACT_PUBMED_22266821}}
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== Structural highlights ==
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<table><tr><td colspan='2'>[[4a49]] 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=4A49 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4A49 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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<tr id='NonStdRes'><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 id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2cbl|2cbl]], [[2y1n|2y1n]], [[1w4u|1w4u]], [[4a4b|4a4b]], [[2esq|2esq]], [[2c4o|2c4o]], [[4a4c|4a4c]], [[2esk|2esk]], [[1ur6|1ur6]], [[2y1m|2y1m]], [[1b47|1b47]], [[1fbv|1fbv]], [[2eso|2eso]], [[1yvh|1yvh]], [[2esp|2esp]], [[2clw|2clw]]</td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Ubiquitin--protein_ligase Ubiquitin--protein ligase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=6.3.2.19 6.3.2.19] </span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4a49 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4a49 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4a49 RCSB], [http://www.ebi.ac.uk/pdbsum/4a49 PDBsum]</span></td></tr>
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</table>
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== Disease ==
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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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== Function ==
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[[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> [[http://www.uniprot.org/uniprot/UB2D2_HUMAN UB2D2_HUMAN]] Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. In vitro catalyzes 'Lys-48'-linked polyubiquitination. Mediates the selective degradation of short-lived and abnormal proteins. Functions in the E6/E6-AP-induced ubiquitination of p53/TP53. Mediates ubiquitination of PEX5 and autoubiquitination of STUB1 and TRAF6. Involved in the signal-induced conjugation and subsequent degradation of NFKBIA, FBXW2-mediated GCM1 ubiquitination and degradation, MDM2-dependent degradation of p53/TP53 and the activation of MAVS in the mitochondria by DDX58/RIG-I in response to viral infection. Essential for viral activation of IRF3.<ref>PMID:10329681</ref> <ref>PMID:15280377</ref> <ref>PMID:18042044</ref> <ref>PMID:18703417</ref> <ref>PMID:18359941</ref> <ref>PMID:19854139</ref> <ref>PMID:20403326</ref> <ref>PMID:20061386</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Cbls are RING ubiquitin ligases that attenuate receptor tyrosine kinase (RTK) signal transduction. Cbl ubiquitination activity is stimulated by phosphorylation of a linker helix region (LHR) tyrosine residue. To elucidate the mechanism of activation, we determined the structures of human CBL, a CBL-substrate peptide complex and a phosphorylated-Tyr371-CBL-E2-substrate peptide complex, and we compared them with the known structure of a CBL-E2-substrate peptide complex. Structural and biochemical analyses show that CBL adopts an autoinhibited RING conformation, where the RING's E2-binding surface associates with CBL to reduce E2 affinity. Tyr371 phosphorylation activates CBL by inducing LHR conformational changes that eliminate autoinhibition, flip the RING domain and E2 into proximity of the substrate-binding site and transform the RING domain into an enhanced E2-binding module. This activation is required for RTK ubiquitination. Our results present a mechanism for regulation of c-Cbl's activity by autoinhibition and phosphorylation-induced activation.
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==Disease==
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Structural basis for autoinhibition and phosphorylation-dependent activation of c-Cbl.,Dou H, Buetow L, Hock A, Sibbet GJ, Vousden KH, Huang DT Nat Struct Mol Biol. 2012 Jan 22;19(2):184-92. doi: 10.1038/nsmb.2231. PMID:22266821<ref>PMID:22266821</ref>
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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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==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/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> [[http://www.uniprot.org/uniprot/UB2D2_HUMAN UB2D2_HUMAN]] Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. In vitro catalyzes 'Lys-48'-linked polyubiquitination. Mediates the selective degradation of short-lived and abnormal proteins. Functions in the E6/E6-AP-induced ubiquitination of p53/TP53. Mediates ubiquitination of PEX5 and autoubiquitination of STUB1 and TRAF6. Involved in the signal-induced conjugation and subsequent degradation of NFKBIA, FBXW2-mediated GCM1 ubiquitination and degradation, MDM2-dependent degradation of p53/TP53 and the activation of MAVS in the mitochondria by DDX58/RIG-I in response to viral infection. Essential for viral activation of IRF3.<ref>PMID:10329681</ref><ref>PMID:15280377</ref><ref>PMID:18042044</ref><ref>PMID:18703417</ref><ref>PMID:18359941</ref><ref>PMID:19854139</ref><ref>PMID:20403326</ref><ref>PMID:20061386</ref>
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</div>
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==About this Structure==
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==See Also==
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[[4a49]] 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=4A49 OCA].
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*[[Ubiquitin conjugating enzyme|Ubiquitin conjugating enzyme]]
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*[[Ubiquitin protein ligase|Ubiquitin protein ligase]]
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==Reference==
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== References ==
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<ref group="xtra">PMID:022266821</ref><references group="xtra"/><references/>
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<references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Ubiquitin--protein ligase]]
[[Category: Ubiquitin--protein ligase]]
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[[Category: Buetow, L.]]
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[[Category: Buetow, L]]
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[[Category: Dou, H.]]
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[[Category: Dou, H]]
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[[Category: Hock, A.]]
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[[Category: Hock, A]]
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[[Category: Huang, D T.]]
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[[Category: Huang, D T]]
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[[Category: Sibbet, G J.]]
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[[Category: Sibbet, G J]]
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[[Category: Vousden, K H.]]
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[[Category: Vousden, K H]]
[[Category: Ligase]]
[[Category: Ligase]]

Revision as of 10:37, 4 January 2015

Structure of phosphoTyr371-c-Cbl-UbcH5B complex

4a49, resolution 2.21Å

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