1. Structural Biology and Molecular Biophysics
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A hydrophobic gate in the inner pore helix is the major determinant of inactivation in mechanosensitive Piezo channels

  1. Wang Zheng
  2. Elena O Gracheva
  3. Sviatoslav N Bagriantsev  Is a corresponding author
  1. Yale University School of Medicine, United States
Research Article
  • Cited 6
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Cite this article as: eLife 2019;8:e44003 doi: 10.7554/eLife.44003

Abstract

Piezo1 and Piezo2 belong to a family of mechanically-activated ion channels implicated in a wide range of physiological processes. Mechanical stimulation triggers Piezo channels to open, but their characteristic fast inactivation process results in rapid closure. Several disease-causing mutations in Piezo1 alter the rate of inactivation, highlighting the importance of inactivation to the normal function of this channel. However, despite the structural identification of two physical constrictions within the closed pore, the mechanism of inactivation remains unknown. Here we identify a functionally conserved inactivation gate in the pore-lining inner helix of mouse Piezo1 and Piezo2 that is distinct from the two constrictions. We show that this gate controls the majority of Piezo1 inactivation via a hydrophobic mechanism and that one of the physical constrictions acts as a secondary gate. Our results suggest that, unlike other rapidly inactivating ion channels, a hydrophobic barrier gives rise to fast inactivation in Piezo channels.

Article and author information

Author details

  1. Wang Zheng

    Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Elena O Gracheva

    Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Sviatoslav N Bagriantsev

    Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, United States
    For correspondence
    slav.bagriantsev@yale.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6661-3403

Funding

National Institutes of Health (1R01NS097547-01A1)

  • Sviatoslav N Bagriantsev

National Science Foundation (1453167)

  • Sviatoslav N Bagriantsev

National Institutes of Health (1R01NS091300-01A1)

  • Elena O Gracheva

James Hudson Brown-Alexander B Coxe Fellowship

  • Wang Zheng

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

Publication history

  1. Received: November 29, 2018
  2. Accepted: January 10, 2019
  3. Accepted Manuscript published: January 10, 2019 (version 1)
  4. Version of Record published: January 28, 2019 (version 2)

Copyright

© 2019, Zheng 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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