ArticleProceedings of the National Academy of Sciences of the United States of America2024
Structure of mavacamten-free human cardiac thick filaments within the sarcomere by cryoelectron tomography.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2024. 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.
- Subsarcomeric regulation of thin and thick filaments in skeletal muscle myofibrils.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Dynamics of the β-cardiac myosin auto-inhibited state explain cardiomyopathy pathogenesis.Nature communications · 2026Article
- Mavacamten inhibits myosin activity by stabilizing the myosin interacting-heads motif and stalling motor force generation.Science advances · 2026Article
- Smooth muscle contractile cytoskeleton in health and disease.Journal of muscle research and cell motility · 2026Review
- Myosin Filaments of Vertebrate Skeletal and Cardiac Muscle are Highly Similar, but not Identical.bioRxiv : the preprint server for biology · 2026Article
- Advantages and Limitations of AlphaFold in Structural Biology: Insights from Recent Studies.The protein journal · 2026Review
- Comparing cryo-EM structures of the vertebrate cardiac muscle thick filament.Biophysical reviews · 2026Article
- 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
- Strategies for studying discrete heterogeneity in situ using cryo-electron tomography.Current opinion in structural biology · 2025Review
- Milestone for the interpretation of muscle x-ray diffraction patterns.Biophysical journal · 2025Article
- Annotating the x-ray diffraction pattern of vertebrate striated muscle.Biophysical journal · 2025Article
- Spatially resolving how cMyBP-C phosphorylation and haploinsufficiency in porcine and human myofibrils affect β-cardiac myosin activity.The Journal of general physiology · 2025Article
- Heterogeneous Dysregulation of Myosin Super-Relaxation and Energetics in Hypertrophic Cardiomyopathy.Circulation. Heart failure · 2025Article
- ATP directly modulates thick filament structure and function in porcine myocardium.Biophysical journal · 2025Article
- 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
- Article
- Thick-Filament-Based Regulation and the Determinants of Force Generation.Biomedicines · 2025Article
- Functional role of myosin-binding protein H in thick filaments of developing vertebrate fast-twitch skeletal muscle.The Journal of general physiology · 2024Article
- Post-translational modifications of vertebrate striated muscle myosin heavy chains.Cytoskeleton (Hoboken, N.J.) · 2024Review
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Authors and funding
6 authors.
Funding
Abstract
Heart muscle has the unique property that it can never rest; all cardiomyocytes contract with each heartbeat which requires a complex control mechanism to regulate cardiac output to physiological requirements. Changes in calcium concentration regulate the thin filament activation. A separate but linked mechanism regulates the thick filament activation, which frees sufficient myosin heads to bind the thin filament, thereby producing the required force. Thick filaments contain additional nonmyosin proteins, myosin-binding protein C and titin, the latter being the protein that transmits applied tension to the thick filament. How these three proteins interact to control thick filament activation is poorly understood. Here, we show using 3-D image reconstruction of frozen-hydrated human cardiac muscle myofibrils lacking exogenous drugs that the thick filament is structured to provide three levels of myosin activation corresponding to the three crowns of myosin heads in each 429Å repeat. In one crown, the myosin heads are almost completely activated and disordered. In another crown, many myosin heads are inactive, ordered into a structure called the interacting heads motif. At the third crown, the myosin heads are ordered into the interacting heads motif, but the stability of that motif is affected by myosin-binding protein C. We think that this hierarchy of control explains many of the effects of length-dependent activation as well as stretch activation in cardiac muscle control.
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