ArticleeLife2022
Dilated cardiomyopathy mutation E525K in human beta-cardiac myosin stabilizes the interacting-heads motif and super-relaxed state of myosin.
Article in eLife, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 36 citations in OpenAlex.
- Evidence for a role of adverse sarcomere signaling in atrial fibrillation induction.Journal of molecular and cellular cardiology plus · 2026Review
- The E525K β-Myosin Mutation Causes Hypocontractility in Cardiomyocytes Without Altering Loaded Crossbridge Cycling.bioRxiv : the preprint server for biology · 2026Article
- Dynamics of the β-cardiac myosin auto-inhibited state explain cardiomyopathy pathogenesis.Nature communications · 2026Article
- Impact of salt concentration and free magnesium on human beta-cardiac myosin reveal important details about the conserved mechanochemical mechanism.The Journal of biological chemistry · 2026Article
- The thin line between biochemistry and structure where myosin super relaxed state lies.Biophysical reviews · 2026Review
- Assaying the myosin super-relaxed state across muscle types, cells and proteins for understanding muscle biology and use in drug discovery.Nature protocols · 2026Review
- "QuickStainer": a rapid negative staining device for improved preservation of molecular structure.Journal of structural biology · 2026Article
- Cryo-EM reveals how cardiomyopathy therapeutic drugs modulate the myosin motors of the heart.Science advances · 2026Article
- MYBPC3 (c.194 C > T) mutation-mediated RyR2 dysfunction contributes to pathogenic phenotypes of DCM revealed by HiPSC modeling.Cellular and molecular life sciences : CMLS · 2026Article
- Comparing cryo-EM structures of the vertebrate cardiac muscle thick filament.Biophysical reviews · 2026Article
- A myosin hypertrophic cardiomyopathy mutation disrupts the super-relaxed state and boosts contractility by enhanced actin attachment.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Direct measurement of mavacamten and deoxyATP perturbation of the SRX/DRX ratio in porcine cardiac myofibrils using a simple, accessible and multiplexed approach.Journal of muscle research and cell motility · 2025Article
- Cryo-EM Reveals How Cardiomyopathy Therapeutic Drugs Modulate the Myosin Motors of the Heart.bioRxiv : the preprint server for biology · 2025Article
- Hypertrophic cardiomyopathy mutations Y115H and E497D disrupt the folded-back state of human β-cardiac myosin allosterically.Nature communications · 2025Article
- Cardiology's best friend: Using naturally occurring disease in dogs to understand heart disease in humans.Journal of molecular and cellular cardiology plus · 2025Review
- A FRET assay to monitor different structural states of human β-cardiac myosin including the interacting-heads motif.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Early-Stage Alcoholic Cardiomyopathy Highlighted by Metabolic Remodeling, Oxidative Stress, and Cardiac Myosin Dysfunction in Male Rats.International journal of molecular sciences · 2025Article
- A FRET assay to quantitate levels of the human β-cardiac myosin interacting heads motif based on its near-atomic resolution structure.bioRxiv : the preprint server for biology · 2024Article
- Reassessing the unifying hypothesis for hypercontractility caused by myosin mutations in hypertrophic cardiomyopathy.The EMBO journal · 2024Review
- Dilated cardiomyopathy mutation in beta-cardiac myosin enhances actin activation of the power stroke and phosphate release.PNAS nexus · 2024Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
The auto-inhibited, super-relaxed (SRX) state of cardiac myosin is thought to be crucial for regulating contraction, relaxation, and energy conservation in the heart. We used single ATP turnover experiments to demonstrate that a dilated cardiomyopathy (DCM) mutation (E525K) in human beta-cardiac myosin increases the fraction of myosin heads in the SRX state (with slow ATP turnover), especially in physiological ionic strength conditions. We also utilized FRET between a C-terminal GFP tag on the myosin tail and Cy3ATP bound to the active site of the motor domain to estimate the fraction of heads in the closed, interacting-heads motif (IHM); we found a strong correlation between the IHM and SRX state. Negative stain electron microscopy and 2D class averaging of the construct demonstrated that the E525K mutation increased the fraction of molecules adopting the IHM. Overall, our results demonstrate that the E525K DCM mutation may reduce muscle force and power by stabilizing the auto-inhibited SRX state. Our studies also provide direct evidence for a correlation between the SRX biochemical state and the IHM structural state in cardiac muscle myosin. Furthermore, the E525 residue may be implicated in crucial electrostatic interactions that modulate this conserved, auto-inhibited conformation of myosin.
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