ArticleProceedings of the National Academy of Sciences of the United States of America2016
Phosphorylation and calcium antagonistically tune myosin-binding protein C's structure and function.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 68 papers.
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Who cites it
68 citing papers in PubMed, 103 citations in OpenAlex.
- From bedside to bench: A multimodal approach uncovering the molecular basis of theProceedings of the National Academy of Sciences of the United States of America · 2026Article
- Spatially resolving how cMyBP-C phosphorylation and haploinsufficiency in porcine and human myofibrils affect β-cardiac myosin activity.The Journal of general physiology · 2025Article
- Modeling the effects of thin filament near-neighbor cooperative interactions in mammalian myocardium.The Journal of general physiology · 2025Article
- Autoinhibition of cMyBP-C by its middle domains.Journal of molecular and cellular cardiology · 2025Article
- cMyBP-C in hypertrophic cardiomyopathy: gene therapy and small-molecule innovations.Frontiers in cardiovascular medicine · 2025Review
- Myosin-binding protein-H: Not just filler.The Journal of general physiology · 2024Review
- The D75N and P161S Mutations in the C0-C2 Fragment of cMyBP-C Associated with Hypertrophic Cardiomyopathy Disturb the Thin Filament Activation, Nucleotide Exchange in Myosin, and Actin-Myosin Interaction.International journal of molecular sciences · 2024Article
- Sex-specific cardiovascular remodeling leads to a divergent sex-dependent development of heart failure in aged hypertensive rats.GeroScience · 2024Article
- Cardiac myosin binding protein-C phosphorylation as a function of multiple protein kinase and phosphatase activities.Nature communications · 2024Article
- Assessing Cardiac Contractility From Single Molecules to Whole Hearts.JACC. Basic to translational science · 2024Review
- Mechanism-based myofilament manipulation to treat diastolic dysfunction in HFpEF.Frontiers in physiology · 2024Review
- Design Principles and Benefits of Spatially Explicit Models of Myofilament Function.Methods in molecular biology (Clifton, N.J.) · 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
- Myosin-binding protein H-like regulates myosin-binding protein distribution and function in atrial cardiomyocytes.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
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- cMyBP-C ablation in human engineered cardiac tissue causes progressive Ca2+-handling abnormalities.The Journal of general physiology · 2023Article
- RLC phosphorylation amplifies Ca2+ sensitivity of force in myocardium from cMyBP-C knockout mice.The Journal of general physiology · 2023Article
- 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
- Etiology of genetic muscle disorders induced by mutations in fast and slow skeletal MyBP-C paralogs.Experimental & molecular medicine · 2023Review
8 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
During each heartbeat, cardiac contractility results from calcium-activated sliding of actin thin filaments toward the centers of myosin thick filaments to shorten cellular length. Cardiac myosin-binding protein C (cMyBP-C) is a component of the thick filament that appears to tune these mechanochemical interactions by its N-terminal domains transiently interacting with actin and/or the myosin S2 domain, sensitizing thin filaments to calcium and governing maximal sliding velocity. Both functional mechanisms are potentially further tunable by phosphorylation of an intrinsically disordered, extensible region of cMyBP-C's N terminus, the M-domain. Using atomic force spectroscopy, electron microscopy, and mutant protein expression, we demonstrate that phosphorylation reduced the M-domain's extensibility and shifted the conformation of the N-terminal domain from an extended structure to a compact configuration. In combination with motility assay data, these structural effects of M-domain phosphorylation suggest a mechanism for diminishing the functional potency of individual cMyBP-C molecules. Interestingly, we found that calcium levels necessary to maximally activate the thin filament mitigated the structural effects of phosphorylation by increasing M-domain extensibility and shifting the phosphorylated N-terminal fragments back to the extended state, as if unphosphorylated. Functionally, the addition of calcium to the motility assays ablated the impact of phosphorylation on maximal sliding velocities, fully restoring cMyBP-C's inhibitory capacity. We conclude that M-domain phosphorylation may have its greatest effect on tuning cMyBP-C's calcium-sensitization of thin filaments at the low calcium levels between contractions. Importantly, calcium levels at the peak of contraction would allow cMyBP-C to remain a potent contractile modulator, regardless of cMyBP-C's phosphorylation state.
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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.