Cryo-EM investigation of ryanodine receptor type 3

Yu Seby Chen, Maricela Garcia-Castañeda, Maria Charalambous, Daniela Rossi, Vincenzo Sorrentino and Filip Van Petegem ()
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Yu Seby Chen: University of British Columbia
Maricela Garcia-Castañeda: University of British Columbia
Maria Charalambous: University of British Columbia
Daniela Rossi: University of Siena
Vincenzo Sorrentino: University of Siena
Filip Van Petegem: University of British Columbia

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract Ryanodine Receptor isoform 3 (RyR3) is a large ion channel found in the endoplasmic reticulum membrane of many different cell types. Within the hippocampal region of the brain, it is found in dendritic spines and regulates synaptic plasticity. It controls myogenic tone in arteries and is upregulated in skeletal muscle in early development. RyR3 has a unique functional profile with a very high sensitivity to activating ligands, enabling high gain in Ca2+-induced Ca2+ release. Here we solve high-resolution cryo-EM structures of RyR3 in non-activating and activating conditions, revealing structural transitions that occur during channel opening. Addition of activating ligands yields only open channels, indicating an intrinsically high open probability under these conditions. RyR3 has reduced binding affinity to the auxiliary protein FKBP12.6 due to several sequence variations in the binding interface. We map disease-associated sequence variants and binding sites for known pharmacological agents. The N-terminal region contains ligand binding sites for a putative chloride anion and ATP, both of which are targeted by sequence variants linked to epileptic encephalopathy.

Date: 2024
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DOI: 10.1038/s41467-024-52998-9

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