A topological switch in CFTR modulates channel activity and sensitivity to unfolding.

Autor: Scholl D; SFMB, Université Libre de Bruxelles, Brussels, Belgium., Sigoillot M; SFMB, Université Libre de Bruxelles, Brussels, Belgium., Overtus M; SFMB, Université Libre de Bruxelles, Brussels, Belgium., Martinez RC; SFMB, Université Libre de Bruxelles, Brussels, Belgium., Martens C; SFMB, Université Libre de Bruxelles, Brussels, Belgium., Wang Y; School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK., Pardon E; VIB-VUB center for Structural Biology, VIB, Brussels, Belgium.; Structural Biology Brussels, Vrije Universiteit Brussel, Brussels, Belgium., Laeremans T; VIB-VUB center for Structural Biology, VIB, Brussels, Belgium.; Structural Biology Brussels, Vrije Universiteit Brussel, Brussels, Belgium., Garcia-Pino A; Cellular and Molecular Microbiology, Université Libre de Bruxelles, Gosselies, Belgium., Steyaert J; VIB-VUB center for Structural Biology, VIB, Brussels, Belgium.; Structural Biology Brussels, Vrije Universiteit Brussel, Brussels, Belgium., Sheppard DN; School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, UK., Hendrix J; Dynamic Bioimaging Lab, Advanced Optical Microscopy Centre and Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium.; Molecular Imaging and Photonics, Chemistry Department, KU Leuven, Leuven, Belgium., Govaerts C; SFMB, Université Libre de Bruxelles, Brussels, Belgium. Cedric.Govaerts@ulb.ac.be.
Jazyk: angličtina
Zdroj: Nature chemical biology [Nat Chem Biol] 2021 Sep; Vol. 17 (9), pp. 989-997. Date of Electronic Publication: 2021 Aug 02.
DOI: 10.1038/s41589-021-00844-0
Abstrakt: The cystic fibrosis transmembrane conductance regulator (CFTR) anion channel is essential to maintain fluid homeostasis in key organs. Functional impairment of CFTR due to mutations in the cftr gene leads to cystic fibrosis. Here, we show that the first nucleotide-binding domain (NBD1) of CFTR can spontaneously adopt an alternate conformation that departs from the canonical NBD fold previously observed. Crystallography reveals that this conformation involves a topological reorganization of NBD1. Single-molecule fluorescence resonance energy transfer microscopy shows that the equilibrium between the conformations is regulated by adenosine triphosphate binding. However, under destabilizing conditions, such as the disease-causing mutation F508del, this conformational flexibility enables unfolding of the β-subdomain. Our data indicate that, in wild-type CFTR, this conformational transition of NBD1 regulates channel function, but, in the presence of the F508del mutation, it allows domain misfolding and subsequent protein degradation. Our work provides a framework to design conformation-specific therapeutics to prevent noxious transitions.
(© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE
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