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

Ashok R. Nayak, Warin Rangubpit, Alex H. Will, Yifan Hu, Pablo Castro-Hartmann, Joshua J. Lobo, Kelly Dryden, Graham D. Lamb, Pornthep Sompornpisut () and Montserrat Samsó ()
Additional contact information
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
Joshua J. Lobo: Virginia Commonwealth University
Kelly Dryden: University of Virginia
Graham D. Lamb: La Trobe University
Pornthep Sompornpisut: Chulalongkorn University
Montserrat Samsó: Virginia Commonwealth University

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
References: View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-48292-3 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48292-3

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-48292-3

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().