ArticleThe Biochemical journal2007
Malignant hyperthermia mutation sites in the Leu2442-Pro2477 (DP4) region of RyR1 (ryanodine receptor 1) are clustered in a structurally and functionally definable area.
Article in The Biochemical journal, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 22 citations in OpenAlex.
- Correlation of phenotype with genotype and protein structure in RYR1-related disorders.Journal of neurology · 2018Trial
- Effects ofAnimals : an open access journal from MDPI · 2025Article
- Mitochondrial Calcium Overload Plays a Causal Role in Oxidative Stress in the Failing Heart.Biomolecules · 2023Review
- FKBP12 binds to the cardiac ryanodine receptor with negative cooperativity: implications for heart muscle physiology in health and disease.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2023Article
- Recent advances in understanding the ryanodine receptor calcium release channels and their role in calcium signalling.F1000Research · 2018Review
- Review of RyR1 pathway and associated pathomechanisms.Acta neuropathologica communications · 2016Review
- Structures of the colossal RyR1 calcium release channel.Current opinion in structural biology · 2016Review
- Effects of conformational peptide probe DP4 on bidirectional signaling between DHPR and RyR1 calcium channels in voltage-clamped skeletal muscle fibers.Biophysical journal · 2011Article
- Ryanodine receptor-mediated arrhythmias and sudden cardiac death.Pharmacology & therapeutics · 2009Review
- Alternative splicing of RyR1 alters the efficacy of skeletal EC coupling.Cell calcium · 2009Article
- Postulated role of interdomain interaction between regions 1 and 2 within type 1 ryanodine receptor in the pathogenesis of porcine malignant hyperthermia.The Biochemical journal · 2007Article
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
Abstract
To explain the mechanism of pathogenesis of channel disorder in MH (malignant hyperthermia), we have proposed a model in which tight interactions between the N-terminal and central domains of RyR1 (ryanodine receptor 1) stabilize the closed state of the channel, but mutation in these domains weakens the interdomain interaction and destabilizes the channel. DP4 (domain peptide 4), a peptide corresponding to residues Leu2442-Pro2477 of the central domain, also weakens the domain interaction and produces MH-like channel destabilization, whereas an MH mutation (R2458C) in DP4 abolishes these effects. Thus DP4 and its mutants serve as excellent tools for structure-function studies. Other MH mutations have been reported in the literature involving three other amino acid residues in the DP4 region (Arg2452, Ile2453 and Arg2454). In the present paper we investigated the activity of several mutants of DP4 at these three residues. The ability to activate ryanodine binding or to effect Ca2+ release was severely diminished for each of the MH mutants. Other substitutions were less effective. Structural studies, using NMR analysis, revealed that the peptide has two a-helical regions. It is apparent that the MH mutations are clustered at the C-terminal end of the first helix. The data in the present paper indicates that mutation of residues in this region disrupts the interdomain interactions that stabilize the closed state of the channel.
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