Ligand recognition and gating mechanism through three ligand-binding sites of human TRPM2 channel

  1. Yihe Huang
  2. Becca Roth
  3. Wei Lu  Is a corresponding author
  4. Juan Du  Is a corresponding author
  1. Van Andel Institute, United States

Abstract

TRPM2 is critically involved in diverse physiological processes including core temperature sensing, apoptosis, and immune response. TRPM2's activation by Ca2+ and ADP ribose (ADPR), an NAD+-metabolite produced under oxidative stress and neurodegenerative conditions, suggests a role in neurological disorders. We provide a central concept between triple-site ligand binding and the channel gating of human TRPM2. We show consecutive structural rearrangements and channel activation of TRPM2 induced by binding of ADPR in two indispensable locations, and the binding of Ca2+ in the transmembrane domain. The 8-Br-cADPR-an antagonist of cADPR-binds only to the MHR1/2 domain and inhibits TRPM2 by stabilizing the channel in an apo-like conformation. We conclude that MHR1/2 acts as a orthostatic ligand-binding site for TRPM2. The NUDT9-H domain binds to a second ADPR to assist channel activation in vertebrates, but not necessary in invertebrates. Our work provides insights into the gating mechanism of human TRPM2 and its pharmacology.

Data availability

All the cryo-EM data generated in this study will be deposited to PDB and EMDB databank.

The following data sets were generated

Article and author information

Author details

  1. Yihe Huang

    Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Becca Roth

    Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Wei Lu

    Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, United States
    For correspondence
    wei.lu@vai.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3009-1025
  4. Juan Du

    Center for Cancer and Cell Biology, Van Andel Institute, Grand Rapids, United States
    For correspondence
    juan.du@vai.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1467-1203

Funding

Esther A. and Joseph Klingenstein Fund (2019 class)

  • Juan Du

McKnight Endowment Fund for Neuroscience (2019 class)

  • Juan Du

National Institutes of Health (R01NS111031)

  • Juan Du

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: July 12, 2019
  2. Accepted: September 11, 2019
  3. Accepted Manuscript published: September 12, 2019 (version 1)
  4. Version of Record published: September 24, 2019 (version 2)

Copyright

© 2019, Huang 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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  1. Yihe Huang
  2. Becca Roth
  3. Wei Lu
  4. Juan Du
(2019)
Ligand recognition and gating mechanism through three ligand-binding sites of human TRPM2 channel
eLife 8:e50175.
https://doi.org/10.7554/eLife.50175

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