1. Structural Biology and Molecular Biophysics
Download icon

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 11
  • Views 2,476
  • Annotations
Cite this article as: eLife 2019;8:e44003 doi: 10.7554/eLife.44003


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
    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


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)


© 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.


  • 2,476
    Page views
  • 389
  • 11

Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Structural Biology and Molecular Biophysics
    Julia Steiner, Leonid Sazanov
    Research Article

    Multiple resistance and pH adaptation (Mrp) antiporters are multi-subunit Na+ (or K+)/H+ exchangers representing an ancestor of many essential redox-driven proton pumps, such as respiratory complex I. The mechanism of coupling between ion or electron transfer and proton translocation in this large protein family is unknown. Here, we present the structure of the Mrp complex from Anoxybacillus flavithermus solved by cryo-EM at 3.0 Å resolution. It is a dimer of seven-subunit protomers with 50 trans-membrane helices each. Surface charge distribution within each monomer is remarkably asymmetric, revealing probable proton and sodium translocation pathways. On the basis of the structure we propose a mechanism where the coupling between sodium and proton translocation is facilitated by a series of electrostatic interactions between a cation and key charged residues. This mechanism is likely to be applicable to the entire family of redox proton pumps, where electron transfer to substrates replaces cation movements.

    1. Structural Biology and Molecular Biophysics
    Tone Bengtsen et al.
    Research Article

    Nanodiscs are membrane mimetics that consist of a protein belt surrounding a lipid bilayer, and are broadly used for characterization of membrane proteins. Here, we investigate the structure, dynamics and biophysical properties of two small nanodiscs, MSP1D1ΔH5 and ΔH4H5. We combine our SAXS and SANS experiments with molecular dynamics simulations and previously obtained NMR and EPR data to derive and validate a conformational ensemble that represents the structure and dynamics of the nanodisc. We find that it displays conformational heterogeneity with various elliptical shapes, and with substantial differences in lipid ordering in the centre and rim of the discs. Together, our results reconcile previous apparently conflicting observations about the shape of nanodiscs, and paves the way for future integrative studies of larger complex systems such as membrane proteins embedded in nanodiscs.