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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Substitution
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Animals
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Apoproteins / chemistry*
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Apoproteins / genetics
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Apoproteins / metabolism
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Arginine / chemistry
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Arginine / metabolism
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Calcium / chemistry*
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Calcium / metabolism
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Calmodulin / chemistry*
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Calmodulin / genetics
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Calmodulin / metabolism
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Cryoelectron Microscopy
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Cysteine / chemistry
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Cysteine / metabolism
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Gene Expression
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Humans
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Ion Transport
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Malignant Hyperthermia / genetics
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Malignant Hyperthermia / metabolism*
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Malignant Hyperthermia / pathology
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Models, Molecular
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Muscle, Skeletal / chemistry
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Muscle, Skeletal / metabolism
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Mutation
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Protein Binding
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Protein Conformation, alpha-Helical
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Protein Conformation, beta-Strand
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Protein Interaction Domains and Motifs
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Ryanodine Receptor Calcium Release Channel / chemistry*
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Ryanodine Receptor Calcium Release Channel / genetics
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Ryanodine Receptor Calcium Release Channel / metabolism
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Sarcoplasmic Reticulum / chemistry
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Sarcoplasmic Reticulum / metabolism
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Sequence Homology, Amino Acid
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Substrate Specificity
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Swine
Substances
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Apoproteins
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Calmodulin
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Recombinant Proteins
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Ryanodine Receptor Calcium Release Channel
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Arginine
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Cysteine
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Calcium