Macrocycle-stabilization of its interaction with 14-3-3 increases plasma membrane localization and activity of CFTR

Impaired activity of the chloride channel CFTR is the cause of cystic fibrosis. 14-3-3 proteins have been shown to stabilize CFTR and increase its biogenesis and activity. Here, we report the identification and mechanism of action of a macrocycle stabilizing the 14-3-3/CFTR complex. This molecule re...

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Autores principales: Stevers, Loes M., Wolter, Madita, Carlile, Graeme W., Macdonald, Dwight, Richard, Luc, Gielkens, Frank, Hanrahan, John W., Thomas, David Y., Chakka, Sai Kumar, Peterson, Mark L., Thomas, Helmut, Brunsveld, Luc, Ottmann, Christian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
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Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9226124/
https://www.ncbi.nlm.nih.gov/pubmed/35739107
http://dx.doi.org/10.1038/s41467-022-31206-6
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author Stevers, Loes M.
Wolter, Madita
Carlile, Graeme W.
Macdonald, Dwight
Richard, Luc
Gielkens, Frank
Hanrahan, John W.
Thomas, David Y.
Chakka, Sai Kumar
Peterson, Mark L.
Thomas, Helmut
Brunsveld, Luc
Ottmann, Christian
author_facet Stevers, Loes M.
Wolter, Madita
Carlile, Graeme W.
Macdonald, Dwight
Richard, Luc
Gielkens, Frank
Hanrahan, John W.
Thomas, David Y.
Chakka, Sai Kumar
Peterson, Mark L.
Thomas, Helmut
Brunsveld, Luc
Ottmann, Christian
author_sort Stevers, Loes M.
collection PubMed
description Impaired activity of the chloride channel CFTR is the cause of cystic fibrosis. 14-3-3 proteins have been shown to stabilize CFTR and increase its biogenesis and activity. Here, we report the identification and mechanism of action of a macrocycle stabilizing the 14-3-3/CFTR complex. This molecule rescues plasma membrane localization and chloride transport of F508del-CFTR and works additively with the CFTR pharmacological chaperone corrector lumacaftor (VX-809) and the triple combination Trikafta®. This macrocycle is a useful tool to study the CFTR/14-3-3 interaction and the potential of molecular glues in cystic fibrosis therapeutics.
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spelling pubmed-92261242022-06-25 Macrocycle-stabilization of its interaction with 14-3-3 increases plasma membrane localization and activity of CFTR Stevers, Loes M. Wolter, Madita Carlile, Graeme W. Macdonald, Dwight Richard, Luc Gielkens, Frank Hanrahan, John W. Thomas, David Y. Chakka, Sai Kumar Peterson, Mark L. Thomas, Helmut Brunsveld, Luc Ottmann, Christian Nat Commun Article Impaired activity of the chloride channel CFTR is the cause of cystic fibrosis. 14-3-3 proteins have been shown to stabilize CFTR and increase its biogenesis and activity. Here, we report the identification and mechanism of action of a macrocycle stabilizing the 14-3-3/CFTR complex. This molecule rescues plasma membrane localization and chloride transport of F508del-CFTR and works additively with the CFTR pharmacological chaperone corrector lumacaftor (VX-809) and the triple combination Trikafta®. This macrocycle is a useful tool to study the CFTR/14-3-3 interaction and the potential of molecular glues in cystic fibrosis therapeutics. Nature Publishing Group UK 2022-06-23 /pmc/articles/PMC9226124/ /pubmed/35739107 http://dx.doi.org/10.1038/s41467-022-31206-6 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Stevers, Loes M.
Wolter, Madita
Carlile, Graeme W.
Macdonald, Dwight
Richard, Luc
Gielkens, Frank
Hanrahan, John W.
Thomas, David Y.
Chakka, Sai Kumar
Peterson, Mark L.
Thomas, Helmut
Brunsveld, Luc
Ottmann, Christian
Macrocycle-stabilization of its interaction with 14-3-3 increases plasma membrane localization and activity of CFTR
title Macrocycle-stabilization of its interaction with 14-3-3 increases plasma membrane localization and activity of CFTR
title_full Macrocycle-stabilization of its interaction with 14-3-3 increases plasma membrane localization and activity of CFTR
title_fullStr Macrocycle-stabilization of its interaction with 14-3-3 increases plasma membrane localization and activity of CFTR
title_full_unstemmed Macrocycle-stabilization of its interaction with 14-3-3 increases plasma membrane localization and activity of CFTR
title_short Macrocycle-stabilization of its interaction with 14-3-3 increases plasma membrane localization and activity of CFTR
title_sort macrocycle-stabilization of its interaction with 14-3-3 increases plasma membrane localization and activity of cftr
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9226124/
https://www.ncbi.nlm.nih.gov/pubmed/35739107
http://dx.doi.org/10.1038/s41467-022-31206-6
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