The cochaperone CHIP marks Hsp70- and Hsp90-bound substrates for degradation through a very flexible mechanism

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  • dc.contributor.author Quintana-Gallardo, Lucía
  • dc.contributor.author Martín-Benito, Jaime
  • dc.contributor.author Marcilla, Miguel
  • dc.contributor.author Espadas, Guadalupe
  • dc.contributor.author Sabidó Aguadé, Eduard, 1981-
  • dc.contributor.author Valpuesta, José M.
  • dc.date.accessioned 2019-05-21T07:49:29Z
  • dc.date.available 2019-05-21T07:49:29Z
  • dc.date.issued 2019
  • dc.description.abstract Some molecular chaperones are involved not only in assisting the folding of proteins but also, given appropriate conditions, in their degradation. This is the case for Hsp70 and Hsp90 which, in concert with the cochaperone CHIP, direct their bound substrate to degradation through ubiquitination. We generated complexes between the chaperones (Hsp70 or Hsp90), the cochaperone CHIP and, as substrate, a p53 variant containing the GST protein (p53-TMGST). Both ternary complexes (Hsp70:p53-TMGST:CHIP and Hsp90:p53-TMGST:CHIP) ubiquitinated the substrate at a higher efficiency than in the absence of the chaperones. The 3D structures of the two complexes, obtained using a combination of cryoelectron microscopy and crosslinking mass spectrometry, showed the substrate located between the chaperone and the cochaperone, suggesting a ubiquitination mechanism in which the chaperone-bound substrate is presented to CHIP. These complexes are inherently flexible, which is important for the ubiquitination process.
  • dc.description.sponsorship This research was supported by the grant BFU2016-75984 (AEI/FEDER, EU) to JMV. We thank Diamond Light Source for access to beamline EM16943 and EM15997 that contributed to the results presented here. The CRG/UPF Proteomics Unit is a member of Proteored, PRB3 and is supported by grant PT17/0019, of the PE I + D + i 2013–2016, funded by ISCIII and ERDF. We acknowledge support from the Spanish Ministry of Economy and Competitiveness, “Centro de Excelencia Severo Ochoa 2013–2017”, SEV-2012–0208, and “Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya” (2017SGR595).
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Quintana-Gallardo L, Martín-Benito J, Marcilla M, Espadas G, Sabidó E, Valpuesta JM. The cochaperone CHIP marks Hsp70- and Hsp90-bound substrates for degradation through a very flexible mechanism. Sci Rep. 2019; 9(1):5102. DOI 10.1038/s41598-019-41060-0
  • dc.identifier.doi http://dx.doi.org/10.1038/s41598-019-41060-0
  • dc.identifier.issn 2045-2322
  • dc.identifier.uri http://hdl.handle.net/10230/37250
  • dc.language.iso eng
  • dc.publisher Nature Research
  • dc.relation.ispartof Sci Rep. 2019; 9(1):5102
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2016-75984
  • dc.rights © The Author(s) 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.subject.keyword Chaperones
  • dc.subject.keyword Cryoelectron microscopy
  • dc.title The cochaperone CHIP marks Hsp70- and Hsp90-bound substrates for degradation through a very flexible mechanism
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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