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Chaperones rescue the energetic landscape of mutant CFTR at single molecule and in cell
Molecular chaperones are pivotal in folding and degradation of the cellular proteome but their impact on the conformational dynamics of near-native membrane proteins with disease relevance remains unknown. Here we report the effect of chaperone activity on the functional conformation of the temperat...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5577305/ https://www.ncbi.nlm.nih.gov/pubmed/28855508 http://dx.doi.org/10.1038/s41467-017-00444-4 |
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author | Bagdany, Miklos Veit, Guido Fukuda, Ryosuke Avramescu, Radu G. Okiyoneda, Tsukasa Baaklini, Imad Singh, Jay Sovak, Guy Xu, Haijin Apaja, Pirjo M. Sattin, Sara Beitel, Lenore K. Roldan, Ariel Colombo, Giorgio Balch, William Young, Jason C. Lukacs, Gergely L. |
author_facet | Bagdany, Miklos Veit, Guido Fukuda, Ryosuke Avramescu, Radu G. Okiyoneda, Tsukasa Baaklini, Imad Singh, Jay Sovak, Guy Xu, Haijin Apaja, Pirjo M. Sattin, Sara Beitel, Lenore K. Roldan, Ariel Colombo, Giorgio Balch, William Young, Jason C. Lukacs, Gergely L. |
author_sort | Bagdany, Miklos |
collection | PubMed |
description | Molecular chaperones are pivotal in folding and degradation of the cellular proteome but their impact on the conformational dynamics of near-native membrane proteins with disease relevance remains unknown. Here we report the effect of chaperone activity on the functional conformation of the temperature-sensitive mutant cystic fibrosis channel (∆F508-CFTR) at the plasma membrane and after reconstitution into phospholipid bilayer. Thermally induced unfolding at 37 °C and concomitant functional inactivation of ∆F508-CFTR are partially suppressed by constitutive activity of Hsc70 and Hsp90 chaperone/co-chaperone at the plasma membrane and post-endoplasmic reticulum compartments in vivo, and at single-molecule level in vitro, indicated by kinetic and thermodynamic remodeling of the mutant gating energetics toward its wild-type counterpart. Thus, molecular chaperones can contribute to functional maintenance of ∆F508-CFTR by reshaping the conformational energetics of its final fold, a mechanism with implication in the regulation of metastable ABC transporters and other plasma membrane proteins activity in health and diseases. |
format | Online Article Text |
id | pubmed-5577305 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-55773052017-09-01 Chaperones rescue the energetic landscape of mutant CFTR at single molecule and in cell Bagdany, Miklos Veit, Guido Fukuda, Ryosuke Avramescu, Radu G. Okiyoneda, Tsukasa Baaklini, Imad Singh, Jay Sovak, Guy Xu, Haijin Apaja, Pirjo M. Sattin, Sara Beitel, Lenore K. Roldan, Ariel Colombo, Giorgio Balch, William Young, Jason C. Lukacs, Gergely L. Nat Commun Article Molecular chaperones are pivotal in folding and degradation of the cellular proteome but their impact on the conformational dynamics of near-native membrane proteins with disease relevance remains unknown. Here we report the effect of chaperone activity on the functional conformation of the temperature-sensitive mutant cystic fibrosis channel (∆F508-CFTR) at the plasma membrane and after reconstitution into phospholipid bilayer. Thermally induced unfolding at 37 °C and concomitant functional inactivation of ∆F508-CFTR are partially suppressed by constitutive activity of Hsc70 and Hsp90 chaperone/co-chaperone at the plasma membrane and post-endoplasmic reticulum compartments in vivo, and at single-molecule level in vitro, indicated by kinetic and thermodynamic remodeling of the mutant gating energetics toward its wild-type counterpart. Thus, molecular chaperones can contribute to functional maintenance of ∆F508-CFTR by reshaping the conformational energetics of its final fold, a mechanism with implication in the regulation of metastable ABC transporters and other plasma membrane proteins activity in health and diseases. Nature Publishing Group UK 2017-08-30 /pmc/articles/PMC5577305/ /pubmed/28855508 http://dx.doi.org/10.1038/s41467-017-00444-4 Text en © The Author(s) 2017 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/. |
spellingShingle | Article Bagdany, Miklos Veit, Guido Fukuda, Ryosuke Avramescu, Radu G. Okiyoneda, Tsukasa Baaklini, Imad Singh, Jay Sovak, Guy Xu, Haijin Apaja, Pirjo M. Sattin, Sara Beitel, Lenore K. Roldan, Ariel Colombo, Giorgio Balch, William Young, Jason C. Lukacs, Gergely L. Chaperones rescue the energetic landscape of mutant CFTR at single molecule and in cell |
title | Chaperones rescue the energetic landscape of mutant CFTR at single molecule and in cell |
title_full | Chaperones rescue the energetic landscape of mutant CFTR at single molecule and in cell |
title_fullStr | Chaperones rescue the energetic landscape of mutant CFTR at single molecule and in cell |
title_full_unstemmed | Chaperones rescue the energetic landscape of mutant CFTR at single molecule and in cell |
title_short | Chaperones rescue the energetic landscape of mutant CFTR at single molecule and in cell |
title_sort | chaperones rescue the energetic landscape of mutant cftr at single molecule and in cell |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5577305/ https://www.ncbi.nlm.nih.gov/pubmed/28855508 http://dx.doi.org/10.1038/s41467-017-00444-4 |
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