1. Biochemistry and Chemical Biology
  2. Structural Biology and Molecular Biophysics
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Obligate coupling of CFTR pore opening to tight nucleotide-binding domain dimerization

  1. Csaba Mihályi
  2. Beáta Töröcsik
  3. László Csanády  Is a corresponding author
  1. Semmelweis University, Hungary
Research Article
  • Cited 16
  • Annotations
Cite this article as: eLife 2016;5:e18164 doi: 10.7554/eLife.18164

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.

Article and author information

Author details

  1. Csaba Mihályi

    Department of Medical Biochemistry, Semmelweis University, Budapest, Hungary
    Competing interests
    The authors declare that no competing interests exist.
  2. Beáta Töröcsik

    Department of Medical Biochemistry, Semmelweis University, Budapest, Hungary
    Competing interests
    The authors declare that no competing interests exist.
  3. László Csanády

    Department of Medical Biochemistry, Semmelweis University, Budapest, Hungary
    For correspondence
    csanady.laszlo@med.semmelweis-univ.hu
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols of Semmelweis University (22.1/1935/3/2011).

Reviewing Editor

  1. Kenton J Swartz, National Institutes of Health, United States

Publication history

  1. Received: May 24, 2016
  2. Accepted: June 20, 2016
  3. Accepted Manuscript published: June 21, 2016 (version 1)
  4. Version of Record published: July 14, 2016 (version 2)
  5. Version of Record updated: August 5, 2016 (version 3)

Copyright

© 2016, Mihályi et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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