Obligate coupling of CFTR pore opening to tight nucleotide-binding domain dimerization

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

In CFTR, the chloride channel mutated in cystic fibrosis (CF) patients, ATP-binding- induced dimerization of two cytosolic nucleotide binding domains (NBDs) opens the pore, and dimer disruption following ATP hydrolysis closes it. Spontaneous openings without ATP are rare in wild-type CFTR, but in certain CF mutants constitute the only gating mechanism, stimulated by ivacaftor, a clinically approved CFTR potentiator. The molecular motions underlying spontaneous gating are unclear. Here we correlate energetic coupling between residues across the dimer interface with spontaneous pore opening/closure in single CFTR channels. We show that spontaneous openings are also strictly coupled to NBD dimerization, which may therefore occur even without ATP. Coordinated NBD/pore movements are therefore intrinsic to CFTR: ATP alters the stability, but not the fundamental structural architecture, of open- and closed-pore conformations. This explains correlated effects of phosphorylation, mutations, and drugs on ATP- driven and spontaneous activity, providing insights for understanding CF mutation and drug mechanisms.

Original languageEnglish
Article numbere18164
JournaleLife
Volume5
Issue numberJUN2016
DOIs
Publication statusPublished - Jun 21 2016

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'Obligate coupling of CFTR pore opening to tight nucleotide-binding domain dimerization'. Together they form a unique fingerprint.

  • Cite this