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

eLife

Beáta Töröcsik¹  László Csanády²  Csaba Mihályi² 

[1] MTA-SE Ion Channel Research Group, Semmelweis University, Budapest, Hungary;Department of Medical Biochemistry, Semmelweis University, Budapest, Hungary;

关键词: mutant cycle;    thermodynamic coupling;    ABC protein;    structure;    conformation;   

DOI  :  10.7554/eLife.18164

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown