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Updated: Nov 18, 2025
Crystal Structure of the N-terminal Domain of Ryanodine Receptor from Plutella xylostella
Published on: November 30, 2018
Pathological conformations of disease mutant Ryanodine Receptors revealed by cryo-EM
Kellie A Woll1, Omid Haji-Ghassemi1, Filip Van Petegem2
1University of British Columbia, Department of Biochemistry and Molecular Biology, Life Sciences Centre, Vancouver, BC, Canada.
Abstract:
Ryanodine Receptors (RyRs) are massive channels that release Ca2+ from the endoplasmic and sarcoplasmic reticulum. Hundreds of mutations are linked to malignant hyperthermia (MH), myopathies, and arrhythmias. Here, we explore the first MH mutation identified in humans by providing cryo-EM snapshots of the pig homolog, R615C, showing that it affects an interface between three solenoid regions. We also show the impact of apo-calmodulin (apoCaM) and how it can induce opening by bending of the bridging solenoid, mediated by its N-terminal lobe. For R615C RyR1, apoCaM binding abolishes a pathological 'intermediate' conformation, distributing the population to a mixture of open and closed channels, both different from the structure without apoCaM. Comparisons show that the mutation primarily affects the closed state, inducing partial movements linked to channel activation. This shows that disease mutations can cause distinct pathological conformations of the RyR and facilitate channel opening by disrupting interactions between different solenoid regions.
Insights
Malignant hyperthermia mutations in Ryanodine Receptors (RyRs) disrupt channel function. Apo-calmodulin binding to the R615C RyR1 mutation normalizes channel opening by altering pathological conformations.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- Ryanodine Receptors (RyRs) are critical Ca2+ release channels.
- Mutations in RyRs are associated with severe conditions like malignant hyperthermia (MH), myopathies, and arrhythmias.
Purpose of the Study:
- To investigate the structural and functional impact of the first identified human MH mutation in RyRs.
- To elucidate the role of apo-calmodulin (apoCaM) in modulating RyR channel activity.
Main Methods:
- Cryo-electron microscopy (cryo-EM) to capture structural snapshots of the pig RyR homolog (R615C).
- Structural analysis of apoCaM binding and its effect on RyR conformations.
Main Results:
- The R615C mutation affects an interface between RyR solenoid regions, primarily impacting the closed state.
- ApoCaM binding induces channel opening by bending a bridging solenoid via its N-terminal lobe.
- ApoCaM binding to R615C RyR1 abolishes a pathological intermediate conformation, leading to a mix of open and closed states.
Conclusions:
- Disease-causing mutations can induce unique pathological conformations in RyRs.
- Disruption of inter-solenoid interactions by mutations facilitates channel opening.
- ApoCaM binding can restore normal channel gating by mitigating mutation-induced pathological states.
