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Interplay between Mg2+ and Ca2+ at multiple sites of the ryanodine receptor

Author

Listed:
  • Ashok R. Nayak

    (Virginia Commonwealth University)

  • Warin Rangubpit

    (Chulalongkorn University)

  • Alex H. Will

    (Virginia Commonwealth University)

  • Yifan Hu

    (Virginia Commonwealth University)

  • Pablo Castro-Hartmann

    (Virginia Commonwealth University
    ThermoFisher Scientific)

  • Joshua J. Lobo

    (Virginia Commonwealth University)

  • Kelly Dryden

    (University of Virginia
    UC Santa Barbara)

  • Graham D. Lamb

    (La Trobe University)

  • Pornthep Sompornpisut

    (Chulalongkorn University)

  • Montserrat Samsó

    (Virginia Commonwealth University)

Abstract

RyR1 is an intracellular Ca2+ channel important in excitable cells such as neurons and muscle fibers. Ca2+ activates it at low concentrations and inhibits it at high concentrations. Mg2+ is the main physiological RyR1 inhibitor, an effect that is overridden upon activation. Despite the significance of Mg2+-mediated inhibition, the molecular-level mechanisms remain unclear. In this work we determined two cryo-EM structures of RyR1 with Mg2+ up to 2.8 Å resolution, identifying multiple Mg2+ binding sites. Mg2+ inhibits at the known Ca2+ activating site and we propose that the EF hand domain is an inhibitory divalent cation sensor. Both divalent cations bind to ATP within a crevice, contributing to the precise transmission of allosteric changes within the enormous channel protein. Notably, Mg2+ inhibits RyR1 by interacting with the gating helices as validated by molecular dynamics. This structural insight enhances our understanding of how Mg2+ inhibition is overcome during excitation.

Suggested Citation

  • Ashok R. Nayak & Warin Rangubpit & Alex H. Will & Yifan Hu & Pablo Castro-Hartmann & Joshua J. Lobo & Kelly Dryden & Graham D. Lamb & Pornthep Sompornpisut & Montserrat Samsó, 2024. "Interplay between Mg2+ and Ca2+ at multiple sites of the ryanodine receptor," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48292-3
    DOI: 10.1038/s41467-024-48292-3
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