ArticleJournal of molecular and cellular cardiology2018
Hypertrophic cardiomyopathy mutation R58Q in the myosin regulatory light chain perturbs thick filament-based regulation in cardiac muscle.
Article in Journal of molecular and cellular cardiology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 29 citations in OpenAlex.
- Transcriptomic and Meat Quality Differences in Longissimus Dorsi Muscle of Surgically Castrated Three-Year-Old Kazakh Horses.Biology · 2026Article
- Modulation of striated-muscle contractility by a high-affinity myosin-targeting peptide.Biophysical journal · 2025Article
- Dynamics of β-cardiac myosin between the super-relaxed and disordered-relaxed states.The Journal of biological chemistry · 2025Article
- The structural and functional effects of myosin regulatory light chain phosphorylation are amplified by increases in sarcomere length and [CaThe Journal of physiology · 2024Article
- Cryo-EM structure of the folded-back state of human β-cardiac myosin.Nature communications · 2023Article
- Muscle Mechanics and Thick Filament Activation: An Emerging Two-Way Interaction for the Vertebrate Striated Muscle Fine Regulation.International journal of molecular sciences · 2023Review
- In situ FRET-based localization of the N terminus of myosin binding protein-C in heart muscle cells.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Functional comparison of phosphomimetic S15D and T160D mutants of myosin regulatory light chain exchanged in cardiac muscle preparations of HCM and WT mice.Frontiers in cardiovascular medicine · 2022Article
- The regulatory light chain mediates inactivation of myosin motors during active shortening of cardiac muscle.Nature communications · 2021Article
- Impact of regulatory light chain mutation K104E on the ATPase and motor properties of cardiac myosin.The Journal of general physiology · 2021Article
- Molecular Diagnosis of Inherited Cardiac Diseases in the Era of Next-Generation Sequencing: A Single Center's Experience Over 5 Years.Molecular diagnosis & therapy · 2021Article
- Regulatory Light Chains in Cardiac Development and Disease.International journal of molecular sciences · 2021Review
- Stress-dependent activation of myosin in the heart requires thin filament activation and thick filament mechanosensing.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Ablation of the N terminus of cardiac essential light chain promotes the super-relaxed state of myosin and counteracts hypercontractility in hypertrophic cardiomyopathy mutant mice.The FEBS journal · 2020Article
- Novel frameshift variant in MYL2 reveals molecular differences between dominant and recessive forms of hypertrophic cardiomyopathy.PLoS genetics · 2020Article
- Slow-twitch skeletal muscle defects accompany cardiac dysfunction in transgenic mice with a mutation in the myosin regulatory light chain.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2019Article
- Proposed mechanism for the length dependence of the force developed in maximally activated muscles.Scientific reports · 2019Article
- Phosphomimetic-mediated in vitro rescue of hypertrophic cardiomyopathy linked to R58Q mutation in myosin regulatory light chain.The FEBS journal · 2019Article
- Structural and functional effects of myosin-binding protein-C phosphorylation in heart muscle are not mimicked by serine-to-aspartate substitutions.The Journal of biological chemistry · 2018Article
- Mavacamten stabilizes an autoinhibited state of two-headed cardiac myosin.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
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3 authors at 2 institutions in 1 country.
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Abstract
Hypertrophic cardiomyopathy (HCM) is frequently linked to mutations in the protein components of the myosin-containing thick filaments leading to contractile dysfunction and ultimately heart failure. However, the molecular structure-function relationships that underlie these pathological effects remain largely obscure. Here we chose an example mutation (R58Q) in the myosin regulatory light chain (RLC) that is associated with a severe HCM phenotype and combined the results from a wide range of in vitro and in situ structural and functional studies on isolated protein components, myofibrils and ventricular trabeculae to create an extensive map of structure-function relationships. The results can be understood in terms of a unifying hypothesis that illuminates both the effects of the mutation and physiological signaling pathways. R58Q promotes an OFF state of the thick filaments that reduces the number of myosin head domains that are available for actin interaction and ATP utilization. Moreover this mutation uncouples two aspects of length-dependent activation (LDA), the cellular basis of the Frank-Starling relation that couples cardiac output to venous return; R58Q reduces maximum calcium-activated force with no significant effect on myofilament calcium sensitivity. Finally, phosphorylation of R58Q-RLC to levels that may be relevant both physiologically and pathologically restores the regulatory state of the thick filament and the effect of sarcomere length on maximum calcium-activated force and thick filament structure, as well as increasing calcium sensitivity. We conclude that perturbation of thick filament-based regulation may be a common mechanism in the etiology of missense mutation-associated HCM, and that this signaling pathway offers a promising target for the development of novel therapeutics.
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