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Instruments / Technical Area	Publication Details	Published	Actions
I02-Macromolecular Crystallography I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	A topological switch in CFTR modulates channel activity and sensitivity to unfolding Daniel Scholl , Maud Sigoillot , Marie Overtus , Rafael Colomer Martinez , Chloé Martens , Yiting Wang , Els Pardon , Toon Laeremans , Abel Garcia-Pino , Jan Steyaert , David N. Sheppard , Jelle Hendrix , Cedric Govaerts Nature Chemical Biology 245 DOI: 10.1038/s41589-021-00844-0 Diamond Proposal Number(s): [12718, 9426] Show Abstract ▼ 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.	Aug 2021

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I02-Macromolecular Crystallography
I04-Macromolecular Crystallography
I24-Microfocus Macromolecular Crystallography

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