Please use this identifier to cite or link to this item:
http://hdl.handle.net/1942/34721
Title: | A topological switch in CFTR modulates channel activity and sensitivity to unfolding | Authors: | Scholl, Daniel Sigoillot, Maud Overtus, Marie Martinez, Rafael Colomer Martens, Chloe Wang, Yiting Pardon, Els Laeremans, Toon Garcia-Pino, Abel Steyaert, Jan Sheppard, David N. HENDRIX, Jelle Govaerts, Cedric |
Issue Date: | 2021 | Publisher: | NATURE PORTFOLIO | Source: | Nature chemical biology, 17 (9) , p. 989-997 | Abstract: | 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 beta-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. | Notes: | Govaerts, C (corresponding author), Univ Libre Bruxelles, SFMB, Brussels, Belgium. Cedric.Govaerts@ulb.ac.be |
Document URI: | http://hdl.handle.net/1942/34721 | ISSN: | 1552-4450 | e-ISSN: | 1552-4469 | DOI: | 10.1038/s41589-021-00844-0 | ISI #: | WOS:000680383200003 | Rights: | The Author(s), under exclusive licence to Springer Nature America, Inc. 2021 | Category: | A1 | Type: | Journal Contribution | Validations: | ecoom 2022 |
Appears in Collections: | Research publications |
Files in This Item:
File | Description | Size | Format | |
---|---|---|---|---|
s41589-021-00844-0.pdf Restricted Access | Published version | 9.9 MB | Adobe PDF | View/Open Request a copy |
Scholl_et_al_Nat_Chem_Biol_2021_accepted_text_figures.pdf | Peer-reviewed author version | 63.65 MB | Adobe PDF | View/Open |
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.