ArticleThe Journal of biological chemistry2013
Transgenic mouse α- and β-cardiac myosins containing the R403Q mutation show isoform-dependent transient kinetic differences.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed.
- Mutation-induced free-energy remodeling of recovery stroke and ATP hydrolysis in human cardiac β-myosin.Biophysical journal · 2026Article
- Molecular mechanisms of altered contraction with the β-myosin R403Q mutation in porcine ventricular muscle and a human stem cell-derived cardiomyocyte model.Journal of molecular and cellular cardiology · 2025Article
- Homologous mutations in human β, embryonic, and perinatal muscle myosins have divergent effects on molecular power generation.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- EMQN: Recommendations for genetic testing in inherited cardiomyopathies and arrhythmias.European journal of human genetics : EJHG · 2023Review
- Critical Evaluation of Current Hypotheses for the Pathogenesis of Hypertrophic Cardiomyopathy.International journal of molecular sciences · 2022Review
- Cardiac myosin contraction and mechanotransduction in health and disease.The Journal of biological chemistry · 2021Review
- Impact of regulatory light chain mutation K104E on the ATPase and motor properties of cardiac myosin.The Journal of general physiology · 2021Article
- Beyond genomics-technological advances improving the molecular characterization and precision treatment of heart failure.Heart failure reviews · 2021Review
- Complexity in genetic cardiomyopathies and new approaches for mechanism-based precision medicine.The Journal of general physiology · 2021Article
- Human-induced pluripotent stem cells for modelling metabolic perturbations and impaired bioenergetics underlying cardiomyopathies.Cardiovascular research · 2021Review
- Disrupted mechanobiology links the molecular and cellular phenotypes in familial dilated cardiomyopathy.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- INDUCED PLURIPOTENT STEM CELLS FOR MODELLING ENERGETIC ALTERATIONS IN HYPERTROPHIC CARDIOMYOPATHY.Conditioning medicine · 2019Article
- Disease modelling and drug discovery for hypertrophic cardiomyopathy using pluripotent stem cells: how far have we come?European heart journal · 2018Article
- Hypertrophic cardiomyopathy R403Q mutation in rabbit β-myosin reduces contractile function at the molecular and myofibrillar levels.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Absence of the Drosophila jump muscle actin Act79B is compensated by up-regulation of Act88F.Developmental dynamics : an official publication of the American Association of Anatomists · 2018Article
- Functional Assays to Screen and Dissect Genomic Hits: Doubling Down on the National Investment in Genomic Research.Circulation. Genomic and precision medicine · 2018Review
- Genetic and Tissue Engineering Approaches to Modeling the Mechanics of Human Heart Failure for Drug Discovery.Frontiers in cardiovascular medicine · 2018Review
- Contractility parameters of human β-cardiac myosin with the hypertrophic cardiomyopathy mutation R403Q show loss of motor function.Science advances · 2015Article
- Effect of a myosin regulatory light chain mutation K104E on actin-myosin interactions.American journal of physiology. Heart and circulatory physiology · 2015Article
- Research priorities in sarcomeric cardiomyopathies.Cardiovascular research · 2015Review
Corrections and comments
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Authors and funding
5 authors.
Funding
Abstract
Familial hypertrophic cardiomyopathy (FHC) is a major cause of sudden cardiac death in young athletes. The discovery in 1990 that a point mutation at residue 403 (R403Q) in the β-myosin heavy chain (MHC) caused a severe form of FHC was the first of many demonstrations linking FHC to mutations in muscle proteins. A mouse model for FHC has been widely used to study the mechanochemical properties of mutated cardiac myosin, but mouse hearts express α-MHC, whereas the ventricles of larger mammals express predominantly β-MHC. To address the role of the isoform backbone on function, we generated a transgenic mouse in which the endogenous α-MHC was partially replaced with transgenically encoded β-MHC or α-MHC. A His6 tag was cloned at the N terminus, along with R403Q, to facilitate isolation of myosin subfragment 1 (S1). Stopped flow kinetics were used to measure the equilibrium constants and rates of nucleotide binding and release for the mouse S1 isoforms bound to actin. For the wild-type isoforms, we found that the affinity of MgADP for α-S1 (100 μM) is ~ 4-fold weaker than for β-S1 (25 μM). Correspondingly, the MgADP release rate for α-S1 (350 s(-1)) is ~3-fold greater than for β-S1 (120 s(-1)). Introducing the R403Q mutation caused only a minor reduction in kinetics for β-S1, but R403Q in α-S1 caused the ADP release rate to increase by 20% (430 s(-1)). These transient kinetic studies on mouse cardiac myosins provide strong evidence that the functional impact of an FHC mutation on myosin depends on the isoform backbone.
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