Interplay between Mg2+ and Ca2+ at multiple sites of the ryanodine receptor
Year: 2024
Type: article
Abstract: RyR1 is an intracellular Ca 2+ channel important in excitable cells. Ca 2+ activates it at low concentrations and inhibits it at high concentrations. Mg 2+ is the main physiological RyR1 inhibitor, an effect that is overridden upon activation. Despite the significance of Mg 2+ -mediated inhibition, the molecular-level mechanisms remain unclear. We determined two cryo-EM structures of RyR1 with Mg 2+ up to 2.8 Å resolution, identifying multiple Mg 2+ binding sites. Mg 2+ inhibits at the known Ca 2+ 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, Mg 2+ inhibits RyR1 by interacting with the gating helices as validated by molecular dynamics. This structural insight enhances our understanding of how Mg 2+ inhibition is overcome during excitation.
Source: Nature Communications
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,790
Funders: Virginia Commonwealth University, Frederick National Laboratory for Cancer Research, Chulalongkorn University, Thailand Science Research and Innovation, National Institutes of Health, School of Medicine, Virginia Commonwealth University, National Institute of General Medical Sciences, National Institute of Arthritis and Musculoskeletal and Skin Diseases
OpenAlex ID: W4396919492