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

DOI: 10.1038/s41589-021-00844-0

Authors: Daniel Scholl (SFMB, Université Libre de Bruxelles) , Maud Sigoillot (SFMB, Université Libre de Bruxelles) , Marie Overtus (SFMB, Université Libre de Bruxelles) , Rafael Colomer Martinez (SFMB, Université Libre de Bruxelles) , Chloé Martens (SFMB, Université Libre de Bruxelles) , Yiting Wang (University of Bristol) , Els Pardon (VIB-VUB center for Structural Biology, VIB; Vrije Universiteit Brussel) , Toon Laeremans (VIB-VUB center for Structural Biology; Vrije Universiteit Brussel) , Abel Garcia-Pino (Université Libre de Bruxelles) , Jan Steyaert (VIB-VUB center for Structural Biology; Vrije Universiteit Brussel) , David N. Sheppard (University of Bristol) , Jelle Hendrix (Hasselt University; KU Leuven) , Cedric Govaerts (SFMB, Université Libre de Bruxelles)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Chemical Biology , VOL 245

State: Published (Approved)
Published: August 2021
Diamond Proposal Number(s): 12718 , 9426

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 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.

Journal Keywords: Ion channels; Protein folding; Single-molecule biophysics; X-ray crystallography

Diamond Keywords: Cystic Fibrosis

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I02-Macromolecular Crystallography , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Added On: 09/08/2021 11:04

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Biochemistry Genetics Chemistry Structural biology Biophysics Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)