ArticleNature communications2025
Hypertrophic cardiomyopathy mutations Y115H and E497D disrupt the folded-back state of human β-cardiac myosin allosterically.
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14 citing papers in PubMed.
- Thick filament molecular interfaces play a critical role in the pathogenesis of hypertrophic cardiomyopathy.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- The hypertrophic cardiomyopathy mutation G768R makes cardiac myosin a high duty ratio motor.bioRxiv : the preprint server for biology · 2026Article
- Dynamics of the β-cardiac myosin auto-inhibited state explain cardiomyopathy pathogenesis.Nature communications · 2026Article
- Cryo-EM reveals how cardiomyopathy therapeutic drugs modulate the myosin motors of the heart.Science advances · 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
- Cryo-EM Reveals How Cardiomyopathy Therapeutic Drugs Modulate the Myosin Motors of the Heart.bioRxiv : the preprint server for biology · 2025Article
- Understanding hypertrophic cardiomyopathy and its regulation by myosin drugs.Protein science : a publication of the Protein Society · 2025Article
- Unraveling Mutation-Induced Protein Communication Pathways in the Actomyosin Complex: Insights from Comprehensive Metadynamics Simulations.The journal of physical chemistry. B · 2025Article
- 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
- Dynamics of β-cardiac myosin between the super-relaxed and disordered-relaxed states.The Journal of biological chemistry · 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
- Dynamics of the Pre-Powerstroke Myosin Lever Arm and the Effects of Omecamtiv Mecarbil.International journal of molecular sciences · 2024Article
- Dilated cardiomyopathy mutation in beta-cardiac myosin enhances actin activation of the power stroke and phosphate release.PNAS nexus · 2024Article
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Abstract
At the molecular level, clinical hypercontractility associated with many hypertrophic cardiomyopathy (HCM)-causing mutations in β-cardiac myosin appears to be driven by their disruptive effect on the energy-conserving, folded-back 'OFF'-state of myosin, which results in increased number of heads free to interact with actin and produce force. While many characterized mutations likely act by directly perturbing intramolecular interfaces stabilizing the OFF-state, others may function allosterically by altering conformational states of the myosin motor. We investigate two such allosteric HCM mutations, Y115H (Transducer) and E497D (Relay helix), which do not directly contact OFF-state interfaces. Biochemical analyses and high-resolution crystallography reveal that both mutations increase active myosin head availability likely by destabilizing the pre-powerstroke conformation required for OFF-state formation. We propose that destabilization of the folded-back state of myosin, either directly or allosterically, represents a common molecular mechanism underlying hypercontractility in HCM across a broader spectrum of pathogenic mutations than previously recognized.
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