ArticleThe Journal of biological chemistry
Synthetic thick filaments: A new avenue for better understanding the myosin super-relaxed state in healthy, diseased, and mavacamten-treated cardiac systems.
Article in The Journal of biological chemistry. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 58 citations in OpenAlex.
- Kinetic modeling of mant-ATP turnover to interpret the biochemically defined myosin SRX state.Biophysical journal · 2026Article
- Assaying the myosin super-relaxed state across muscle types, cells and proteins for understanding muscle biology and use in drug discovery.Nature protocols · 2026Review
- Pharmacological Inhibition of β Myosin II Disrupts Sarcomere Assembly in Human iPSC-Derived Cardiac Myocytes.Cytoskeleton (Hoboken, N.J.) · 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
- Resolving zone-specific regulation of cardiac myosin.The Journal of general physiology · 2025Article
- Myosin-binding protein C slows cardiac myofibril relaxation kinetics.The Journal of physiology · 2025Article
- Early-Stage Alcoholic Cardiomyopathy Highlighted by Metabolic Remodeling, Oxidative Stress, and Cardiac Myosin Dysfunction in Male Rats.International journal of molecular sciences · 2025Article
- Various challenges in understanding the thick filaments, within and outside skeletal and cardiac muscles.Biophysical reviews · 2025Article
- Mechanistic basis for rescuing hypertrophic cardiomyopathy with myosin regulatory light chain phosphorylation.Cytoskeleton (Hoboken, N.J.) · 2024Article
- Tail length and E525K dilated cardiomyopathy mutant alter human β-cardiac myosin super-relaxed state.The Journal of general physiology · 2024Article
- Myosin-Catalyzed ATP Hydrolysis in the Presence of Disease-Causing Mutations: Mavacamten as a Way to Repair Mechanism.The journal of physical chemistry. B · 2024Article
- Myosin in autoinhibitedProceedings of the National Academy of Sciences of the United States of America · 2024Article
- The biochemically defined super relaxed state of myosin-A paradox.The Journal of biological chemistry · 2024Article
- Bringing into focus the central domains C3-C6 of myosin binding protein C.Frontiers in physiology · 2024Review
- Cardiac myosin-binding protein C N-terminal interactions with myosin and actin filaments: Opposite effects of phosphorylation and M-domain mutations.Journal of molecular and cellular cardiology · 2024Article
- Tail Length and E525K Dilated Cardiomyopathy Mutant Alter Human β-Cardiac Myosin Super-Relaxed State.bioRxiv : the preprint server for biology · 2023Article
- Mavacamten, a precision medicine for hypertrophic cardiomyopathy: From a motor protein to patients.Science advances · 2023Review
- HTS driven by fluorescence lifetime detection of FRET identifies activators and inhibitors of cardiac myosin.SLAS discovery : advancing life sciences R & D · 2023Article
- Myosin-binding protein C stabilizes, but is not the sole determinant of SRX myosin in cardiac muscle.The Journal of general physiology · 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
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
A hallmark feature of myosin-II is that it can spontaneously self-assemble into bipolar synthetic thick filaments (STFs) in low-ionic-strength buffers, thereby serving as a reconstituted in vitro model for muscle thick filaments. Although these STFs have been extensively used for structural characterization, their functional evaluation has been limited. In this report, we show that myosins in STFs mirror the more electrostatic and cooperative interactions that underlie the energy-sparing super-relaxed (SRX) state, which are not seen using shorter myosin subfragments, heavy meromyosin (HMM) and myosin subfragment 1 (S1). Using these STFs, we show several pathophysiological insults in hypertrophic cardiomyopathy, including the R403Q myosin mutation, phosphorylation of myosin light chains, and an increased ADP:ATP ratio, destabilize the SRX population. Furthermore, WT myosin containing STFs, but not S1, HMM, or STFs-containing R403Q myosin, recapitulated the ADP-induced destabilization of the SRX state. Studies involving a clinical-stage small-molecule inhibitor, mavacamten, showed that it is more effective in not only increasing myosin SRX population in STFs than in S1 or HMM but also in increasing myosin SRX population equally well in STFs made of healthy and disease-causing R403Q myosin. Importantly, we also found that pathophysiological perturbations such as elevated ADP concentration weakens mavacamten's ability to increase the myosin SRX population, suggesting that mavacamten-bound myosin heads are not permanently protected in the SRX state but can be recruited into action. These findings collectively emphasize that STFs serve as a valuable tool to provide novel insights into the myosin SRX state in healthy, diseased, and therapeutic conditions.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.