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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Bibliographic Details
Published in:Nature communications Vol. 13; no. 1; pp. 3586 - 9
Main Authors: 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
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 23.06.2022
Nature Publishing Group
Nature Portfolio
Subjects:
101/47
13/109
14-3-3 protein
631/45/269/1147
631/535/1266
631/80/86/2372
631/92/96
82/1
82/47
82/80
Binding sites
Biology
Chloride ions
Chloride transport
Crystal structure
Cystic fibrosis
Evolution
Glues
Humanities and Social Sciences
Ion channels
Ion transport
Libraries
Localization
Membranes
multidisciplinary
Mutation
Peptides
Plasma
Proteins
Science
Science (multidisciplinary)
ISSN:2041-1723, 2041-1723
Online Access:Get full text
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Summary: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. Mutations in the chloride channel CFTR that impair plasma membrane insertion and ion transport are the cause of cystic fibrosis. Here, the authors identify a macrocycle that stabilizes the interaction of mutant CFTR with the chaperone-like protein 14-3-3 and rescues its biological function.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-022-31206-6