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- Title
Obligate coupling of CFTR pore opening to tight nucleotide-binding domain dimerization.
- Authors
Mihályi, Csaba; Töröcsik, Beáta; Csanády, László
- 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.
- Subjects
CYSTIC fibrosis transmembrane conductance regulator; DNA-binding proteins; DIMERIZATION; HYDROLYSIS; PROTEIN conformation
- Publication
eLife, 2016, p1
- ISSN
2050-084X
- Publication type
Article
- DOI
10.7554/eLife.18164