Divergent Cl-and H+ pathways underlie transport coupling and gating in CLC exchangers and channels

  1. Lilia Leisle
  2. Yanyan Xu
  3. Eva Fortea
  4. Sangyun Lee
  5. Jason D Galpin
  6. Malvin Vien
  7. Christopher A Ahern
  8. Alessio Accardi  Is a corresponding author
  9. Simon Bernèche  Is a corresponding author
  1. Weill Cornell Medical College, United States
  2. University of Basel, Switzerland
  3. University of Iowa Carver College of Medicine, United States

Abstract

The CLC family comprises H+-coupled exchangers and Cl- channels, and mutations causing their dysfunction lead to genetic disorders. The CLC exchangers, unlike canonical 'ping-pong' antiporters, simultaneously bind and translocate substrates through partially congruent pathways. How ions of opposite charge bypass each other while moving through a shared pathway remains unknown. Here, we use MD simulations, biochemical and electrophysiological measurements to identify two conserved phenylalanine residues that form an aromatic pathway whose dynamic rearrangements enable H+ movement outside the Cl- pore. These residues are important for H+ transport and voltage-dependent gating in the CLC exchangers. The aromatic pathway residues are evolutionarily conserved in CLC channels where their electrostatic properties and conformational flexibility determine gating. We propose that Cl- and H+ move through physically distinct and evolutionarily conserved routes through the CLC channels and transporters and suggest a unifying mechanism that describes the gating mechanism of both CLC subtypes.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Lilia Leisle

    Department of Anesthesiology, Weill Cornell Medical College, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Yanyan Xu

    Biozentrum, University of Basel, Basel, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  3. Eva Fortea

    Department of Physiology and Biophysics, Weill Cornell Medical College, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Sangyun Lee

    Department of Anesthesiology, Weill Cornell Medical College, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Jason D Galpin

    Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Malvin Vien

    Department of Anesthesiology, Weill Cornell Medical College, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Christopher A Ahern

    Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7975-2744
  8. Alessio Accardi

    Department of Anesthesiology, Weill Cornell Medical College, New York, United States
    For correspondence
    ala2022@med.cornell.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6584-0102
  9. Simon Bernèche

    Biozentrum, University of Basel, Basel, Switzerland
    For correspondence
    simon.berneche@me.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6274-4094

Funding

National Institutes of Health (GM128420)

  • Alessio Accardi

National Institutes of Health (NS104617)

  • Christopher A Ahern

SNF (No PP00P3_139205)

  • Simon Bernèche

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Leon D Islas, Universidad Nacional Autónoma de México, Mexico

Version history

  1. Received: August 20, 2019
  2. Accepted: April 28, 2020
  3. Accepted Manuscript published: April 28, 2020 (version 1)
  4. Version of Record published: June 5, 2020 (version 2)

Copyright

© 2020, Leisle 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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  1. Lilia Leisle
  2. Yanyan Xu
  3. Eva Fortea
  4. Sangyun Lee
  5. Jason D Galpin
  6. Malvin Vien
  7. Christopher A Ahern
  8. Alessio Accardi
  9. Simon Bernèche
(2020)
Divergent Cl-and H+ pathways underlie transport coupling and gating in CLC exchangers and channels
eLife 9:e51224.
https://doi.org/10.7554/eLife.51224

Share this article

https://doi.org/10.7554/eLife.51224

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    This work was supported by the Weizmann Krenter Foundation and the Weizmann – Ichilov (Tel Aviv Sourasky Medical Center) Collaborative Grant in Biomedical Research, by the Minerva Foundation, by the ISF KillCorona grant 3777/19.