1. Structural Biology and Molecular Biophysics
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Structure of a TRPM2 channel in complex with Ca2+ explains unique gating regulation

  1. Zhe Zhang  Is a corresponding author
  2. Balázs Tóth
  3. Andras Szollosi
  4. Jue Chen
  5. László Csanády  Is a corresponding author
  1. The Rockefeller University, United States
  2. Semmelweis University, Hungary
Research Article
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Cite this article as: eLife 2018;7:e36409 doi: 10.7554/eLife.36409

Abstract

Transient Receptor Potential Melastatin 2 (TRPM2) is a Ca2+-permeable cation channel required for immune cell activation, insulin secretion, and body heat control. TRPM2 is activated by cytosolic Ca2+, phosphatidyl-inositol-4,5-bisphosphate and ADP ribose. Here we present the ~3Å resolution electron cryo-microscopy structure of TRPM2 from Nematostella vectensis, 63% similar in sequence to human TRPM2, in the Ca2+-bound closed state. Compared to other TRPM channels, TRPM2 exhibits unique structural features that correlate with its function. The pore is larger and more negatively charged, consistent with its high Ca2+ selectivity and larger conductance. The intracellular Ca2+ binding sites are connected to the pore and cytosol, explaining the unusual dependence of TRPM2 activity on intra- and extracellular Ca2+. In addition, the absence of a post-filter motif is likely the cause of the rapid inactivation of human TRPM2. Together, our cryo-EM and electrophysiology studies provide a molecular understanding of the unique gating mechanism of TRPM2.

Data availability

Cryo-EM density map of nvTRPM2 has been deposited in the electron microscopy data bank (EMDB) under accession code EMD-7542. Atomic coordinates of nvTRPM2 have been deposited in the protein data bank (PDB) under accession code: 6CO7.

The following data sets were generated

Article and author information

Author details

  1. Zhe Zhang

    Laboratory of Membrane Biophysics and Biology, The Rockefeller University, New York, United States
    For correspondence
    zzhang01@mail.rockefeller.edu
    Competing interests
    No competing interests declared.
  2. Balázs Tóth

    Department of Medical Biochemistry, Semmelweis University, Budapest, Hungary
    Competing interests
    No competing interests declared.
  3. Andras Szollosi

    Department of Medical Biochemistry, Semmelweis University, Budapest, Hungary
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5570-4609
  4. Jue Chen

    Laboratory of Membrane Biophysics and Biology, The Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2075-4283
  5. László Csanády

    Department of Medical Biochemistry, Semmelweis University, Budapest, Hungary
    For correspondence
    csanady.laszlo@med.semmelweis-univ.hu
    Competing interests
    László Csanády, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6547-5889

Funding

Howard Hughes Medical Institute (International Early Career Scientist grant)

  • László Csanády

Magyar Tudományos Akadémia (Lendület grant LP2017-14/2017)

  • László Csanády

Charles H. Revson Foundation (Charles H. Revson fellowship in Biomedical Science)

  • Zhe Zhang

Ministry of Human Capacities of Hungary (ÚNKP-17-4 New National Excellence Program)

  • Balázs Tóth

Howard Hughes Medical Institute (HHMI Investigator)

  • Jue Chen

Magyar Tudományos Akadémia (János Bolyai Research Fellowship)

  • Andras Szollosi

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

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols of Semmelweis University (last approved 06-30-2016, expiration 06-30-2021).

Reviewing Editor

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

Publication history

  1. Received: March 5, 2018
  2. Accepted: May 9, 2018
  3. Accepted Manuscript published: May 10, 2018 (version 1)
  4. Version of Record published: May 30, 2018 (version 2)

Copyright

© 2018, Zhang 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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