CFTR function, pathology and pharmacology at single-molecule resolution

Jesper Levring, Daniel S. Terry, Zeliha Kilic, Gabriel Fitzgerald, Scott C. Blanchard () and Jue Chen ()
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Jesper Levring: The Rockefeller University
Daniel S. Terry: St. Jude Children’s Research Hospital
Zeliha Kilic: St. Jude Children’s Research Hospital
Gabriel Fitzgerald: Weill Cornell Medicine
Scott C. Blanchard: St. Jude Children’s Research Hospital
Jue Chen: The Rockefeller University

Nature, 2023, vol. 616, issue 7957, 606-614

Abstract: Abstract The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel that regulates salt and fluid homeostasis across epithelial membranes1. Alterations in CFTR cause cystic fibrosis, a fatal disease without a cure2,3. Electrophysiological properties of CFTR have been analysed for decades4–6. The structure of CFTR, determined in two globally distinct conformations, underscores its evolutionary relationship with other ATP-binding cassette transporters. However, direct correlations between the essential functions of CFTR and extant structures are lacking at present. Here we combine ensemble functional measurements, single-molecule fluorescence resonance energy transfer, electrophysiology and kinetic simulations to show that the two nucleotide-binding domains (NBDs) of human CFTR dimerize before channel opening. CFTR exhibits an allosteric gating mechanism in which conformational changes within the NBD-dimerized channel, governed by ATP hydrolysis, regulate chloride conductance. The potentiators ivacaftor and GLPG1837 enhance channel activity by increasing pore opening while NBDs are dimerized. Disease-causing substitutions proximal (G551D) or distal (L927P) to the ATPase site both reduce the efficiency of NBD dimerization. These findings collectively enable the framing of a gating mechanism that informs on the search for more efficacious clinical therapies.

Date: 2023
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DOI: 10.1038/s41586-023-05854-7

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