1. Structural Biology and Molecular Biophysics
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Cryo-EM structure of the mechanically activated ion channel OSCA1.2

  1. Sebastian Jojoa Cruz
  2. Kei Saotome
  3. Swetha E Murthy
  4. Che Chun (Alex) Tsui
  5. Mark SP Sansom
  6. Ardem Patapoutian  Is a corresponding author
  7. Andrew B Ward  Is a corresponding author
  1. The Scripps Research Institute, United States
  2. University of Oxford, United Kingdom
Research Article
  • Cited 42
  • Views 5,542
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Cite this article as: eLife 2018;7:e41845 doi: 10.7554/eLife.41845

Abstract

Mechanically activated ion channels underlie touch, hearing, shear-stress sensing, and response to turgor pressure. OSCA/TMEM63s are a newly-identified family of eukaryotic mechanically activated ion channels opened by membrane tension. The structural underpinnings of OSCA/TMEM63 function are not explored. Here, we elucidate high resolution cryo-electron microscopy structures of OSCA1.2, revealing a dimeric architecture containing eleven transmembrane helices per subunit and surprising topological similarities to TMEM16 proteins. We locate the ion permeation pathway within each subunit by demonstrating that a conserved acidic residue is a determinant of channel conductance. Molecular dynamics simulations reveal membrane interactions, suggesting the role of lipids in OSCA1.2 gating. These results lay a foundation to decipher how the structural organization of OSCA/TMEM63 is suited for their roles as MA ion channels.

Data availability

Cryo-EM maps of OSCA1.2 in nanodiscs and LMNG have been deposited to the Electron Microscopy Data Bank under accession codes 9112 and 9113. Atomic coordinates of OSCA1.2 in nanodiscs and LMNG have been deposited to the PDB under IDs 6MGV and 6MGW. Due to their large size (300Gb+), the raw data files are available upon request to the corresponding author(s).

The following data sets were generated

Article and author information

Author details

  1. Sebastian Jojoa Cruz

    Department of Neuroscience, The Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4392-3898
  2. Kei Saotome

    Department of Neuroscience, The Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Swetha E Murthy

    Department of Neuroscience, The Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9580-3380
  4. Che Chun (Alex) Tsui

    Department of Biochemistry, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4886-9824
  5. Mark SP Sansom

    Department of Biochemistry, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6360-7959
  6. Ardem Patapoutian

    Department of Neuroscience, The Scripps Research Institute, La Jolla, United States
    For correspondence
    ardem@scripps.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0726-7034
  7. Andrew B Ward

    Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, United States
    For correspondence
    andrew@scripps.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7153-3769

Funding

Howard Hughes Medical Institute

  • Ardem Patapoutian

Croucher Foundation

  • Che Chun (Alex) Tsui

National Institute of Neurological Disorders and Stroke (1R35NS105067)

  • Ardem Patapoutian

Ray Thomas Edwards Foundation

  • Andrew B Ward

Wellcome (208361/Z/17/Z)

  • Mark SP Sansom

Biotechnology and Biological Sciences Research Council (BB/N000145/1)

  • Mark SP Sansom

Biotechnology and Biological Sciences Research Council (BB/R00126X/1)

  • Mark SP Sansom

Engineering and Physical Sciences Research Council (EP/R004722/1)

  • Mark SP Sansom

Jane Coffin Childs Memorial Fund for Medical Research

  • Kei Saotome

Skaggs-Oxford Scholarship

  • Che Chun (Alex) Tsui

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

Reviewing Editor

  1. Baron Chanda, University of Wisconsin-Madison, United States

Publication history

  1. Received: September 8, 2018
  2. Accepted: October 11, 2018
  3. Accepted Manuscript published: November 1, 2018 (version 1)
  4. Version of Record published: November 14, 2018 (version 2)

Copyright

© 2018, Jojoa Cruz 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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