ArticleProceedings of the National Academy of Sciences of the United States of America2019
Site-specific phosphorylation of myosin binding protein-C coordinates thin and thick filament activation in cardiac muscle.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 56 papers, 1 of them a synthesis that pooled it.
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Who cites it
56 citing papers in PubMed, 1 synthesis or guideline pooled it, 84 citations in OpenAlex.
- Implications of S-glutathionylation of sarcomere proteins in cardiac disorders, therapies, and diagnosis.Frontiers in cardiovascular medicine · 2022Pooled it
- Evidence for a role of adverse sarcomere signaling in atrial fibrillation induction.Journal of molecular and cellular cardiology plus · 2026Review
- Fast skeletal myosin binding protein-C expression exacerbates dysfunction in heart failure.Basic research in cardiology · 2026Article
- Adipocyte fatty acid-binding protein 4 suppresses contraction of mouse ventricular myocytes via a calcium-independent pathway.Frontiers in physiology · 2026Article
- Cardiac myosin-binding protein-C acts as a tunable load sensor to regulate afterload dependence of ventricular function.American journal of physiology. Heart and circulatory physiology · 2025Article
- Myosin-binding protein C slows cardiac myofibril relaxation kinetics.The Journal of physiology · 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
- Myocardium From Patients With ATTR Amyloidosis Produces Less Force Secondary to Increased Fibrosis.JACC. Basic to translational science · 2025Article
- Research into the physiology of myosins - a personal odyssey.European journal of translational myology · 2025Article
- Myosin-actin crossbridge independent sarcomere length induced CaJournal of molecular and cellular cardiology · 2025Article
- Redox Regulation of cAMP-Dependent Protein Kinase and Its Role in Health and Disease.Life (Basel, Switzerland) · 2025Review
- Functional control of myosin motors in the cardiac cycle.Nature reviews. Cardiology · 2025Review
- An integrated picture of the structural pathways controlling the heart performance.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Structural changes in troponin during activation of skeletal and heart muscle determined in situ by polarised fluorescence.Biophysical reviews · 2024Review
- Early pathological mechanisms in a mouse model of heart failure with preserved ejection fraction.American journal of physiology. Heart and circulatory physiology · 2024Article
- Load-dependence of the activation of myosin filaments in heart muscle.The Journal of physiology · 2024Article
- Interacting myosin head dynamics and their modification by 2'-deoxy-ADP.Biophysical journal · 2024Article
- Alterations in cardiac contractile and regulatory proteins contribute to age-related cardiac dysfunction in male rats.Physiological reports · 2024Article
- Cardiac myosin binding protein-C phosphorylation as a function of multiple protein kinase and phosphatase activities.Nature communications · 2024Article
- Emerging Concepts of Mechanisms Controlling Cardiac Tension: Focus on Familial Dilated Cardiomyopathy (DCM) and Sarcomere-Directed Therapies.Biomedicines · 2024Review
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
The heart's response to varying demands of the body is regulated by signaling pathways that activate protein kinases which phosphorylate sarcomeric proteins. Although phosphorylation of cardiac myosin binding protein-C (cMyBP-C) has been recognized as a key regulator of myocardial contractility, little is known about its mechanism of action. Here, we used protein kinase A (PKA) and Cε (PKCε), as well as ribosomal S6 kinase II (RSK2), which have different specificities for cMyBP-C's multiple phosphorylation sites, to show that individual sites are not independent, and that phosphorylation of cMyBP-C is controlled by positive and negative regulatory coupling between those sites. PKA phosphorylation of cMyBP-C's N terminus on 3 conserved serine residues is hierarchical and antagonizes phosphorylation by PKCε, and vice versa. In contrast, RSK2 phosphorylation of cMyBP-C accelerates PKA phosphorylation. We used cMyBP-C's regulatory N-terminal domains in defined phosphorylation states for protein-protein interaction studies with isolated cardiac native thin filaments and the S2 domain of cardiac myosin to show that site-specific phosphorylation of this region of cMyBP-C controls its interaction with both the actin-containing thin and myosin-containing thick filaments. We also used fluorescence probes on the myosin-associated regulatory light chain in the thick filaments and on troponin C in the thin filaments to monitor structural changes in the myofilaments of intact heart muscle cells associated with activation of myocardial contraction by the N-terminal region of cMyBP-C in its different phosphorylation states. Our results suggest that cMyBP-C acts as a sarcomeric integrator of multiple signaling pathways that determines downstream physiological function.
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