1. Structural Biology and Molecular Biophysics
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Electron cryo-microscopy structure of the canonical TRPC4 ion channel

  1. Deivanayagabarathy Vinayagam
  2. Thomas Mager
  3. Amir Apelbaum
  4. Arne Bothe
  5. Felipe Merino
  6. Oliver Hofnagel
  7. Christos Gatsogiannis
  8. Stefan Raunser  Is a corresponding author
  1. Max Planck Institute of Molecular Physiology, Germany
  2. Max Planck Institute of Biophysics, Germany
Research Article
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Cite this article as: eLife 2018;7:e36615 doi: 10.7554/eLife.36615

Abstract

Canonical transient receptor channels (TRPC) are non-selective cation channels. They are involved in receptor-operated Ca2+ signaling and have been proposed to act as store-operated channels (SOC). Their malfunction is related to cardiomyopathies and their modulation by small molecules has been shown to be effective against renal cancer cells. The molecular mechanism underlying the complex activation and regulation is poorly understood. Here, we report the electron cryo-microscopy structure of zebrafish TRPC4 in its unliganded (apo), closed state at an overall resolution of 3.6 Å. The structure reveals the molecular architecture of the cation conducting pore, including the selectivity filter and lower gate. The cytoplasmic domain contains two key hubs that have been shown to interact with modulating proteins. Structural comparisons with other TRP channels give novel insights into the general architecture and domain organization of this superfamily of channels and help to understand their function and pharmacology.

Data availability

The atomic coordinates and cryo-EM maps for TRPC4DR are available at the Protein Data Bank (PDB)/Electron Microscopy Data Bank (EMDB) databases. The accession numbers are 6G1K/EMD-4339. The raw data sets generated in the current study (motion corrected and dose weighted mrc files and box files; 215 GB) are available from the corresponding author upon request.

The following data sets were generated

Article and author information

Author details

  1. Deivanayagabarathy Vinayagam

    Department of Structural Biochemistry, Max Planck Institute of Molecular Physiology, Dortmund, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Thomas Mager

    Department of Biophysical Chemistry, Max Planck Institute of Biophysics, Frankfurt am Main, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Amir Apelbaum

    Department of Structural Biochemistry, Max Planck Institute of Molecular Physiology, Dortmund, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Arne Bothe

    Department of Structural Biochemistry, Max Planck Institute of Molecular Physiology, Dortmund, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Felipe Merino

    Department of Structural Biochemistry, Max Planck Institute of Molecular Physiology, Dortmund, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4166-8747
  6. Oliver Hofnagel

    Department of Structural Biochemistry, Max Planck Institute of Molecular Physiology, Dortmund, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Christos Gatsogiannis

    Department of Structural Biochemistry, Max Planck Institute of Molecular Physiology, Dortmund, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Stefan Raunser

    Department of Structural Biochemistry, Max Planck Institute of Molecular Physiology, Dortmund, Germany
    For correspondence
    stefan.raunser@mpi-dortmund.mpg.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9373-3016

Funding

Max-Planck-Gesellschaft (Open-access funding)

  • Stefan Raunser

European Commission (615984)

  • Stefan Raunser

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

Reviewing Editor

  1. Kenton J Swartz, National Institute of Neurological Disorders and Stroke, National Institutes of Health, United States

Publication history

  1. Received: March 12, 2018
  2. Accepted: April 30, 2018
  3. Accepted Manuscript published: May 2, 2018 (version 1)
  4. Version of Record published: May 14, 2018 (version 2)

Copyright

© 2018, Vinayagam 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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