Work

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

Year: 2016

Type: article

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.

Source: eLife

DOI: 10.7554/elife.18164

Authors: Csaba Mihályi, Beáta Töröcsik, László Csanády

Institutions: Semmelweis University, Hungarian Academy of Sciences

Language: English

Topic: Cystic Fibrosis Research Advances

Subfield: Pulmonary and Respiratory Medicine

Field: Medicine

Domain: Health Sciences

Open Access status: gold

Estimated APC paid: $2,500

Funders: Howard Hughes Medical Institute, Cystic Fibrosis Foundation, Magyar Tudományos Akadémia