ArticleProceedings of the National Academy of Sciences of the United States of America2016
Site-directed spectroscopy of cardiac myosin-binding protein C reveals effects of phosphorylation on protein structural dynamics.
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 37 papers.
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Who cites it
37 citing papers in PubMed, 56 citations in OpenAlex.
- ERK-METTL3 axis acts as a novel regulator of antiviral innate immunity combating pseudorabies virus infection.PLoS pathogens · 2025Article
- Development of bifunctional fluorescent probes and their application to α-helix labelling.Organic & biomolecular chemistry · 2025Article
- cMyBP-C in hypertrophic cardiomyopathy: gene therapy and small-molecule innovations.Frontiers in cardiovascular medicine · 2025Review
- 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
- Cardiac myosin binding protein-C phosphorylation as a function of multiple protein kinase and phosphatase activities.Nature communications · 2024Article
- Structural Dynamics of Protein Interactions Using Site-Directed Spin Labeling of Cysteines to Measure Distances and Rotational Dynamics with EPR Spectroscopy.Applied magnetic resonance · 2024Article
- 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
- Bringing into focus the central domains C3-C6 of myosin binding protein C.Frontiers in physiology · 2024Review
- 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
- Myofilament-associated proteins with intrinsic disorder (MAPIDs) and their resolution by computational modeling.Quarterly reviews of biophysics · 2023Review
- Cryo-Electron Microscopy Reveals Cardiac Myosin Binding Protein-C M-Domain Interactions with the Thin Filament.Journal of molecular biology · 2022Article
- Molecular characterization of linker and loop-mediated structural modulation and hinge motion in the C4-C5 domains of cMyBPC.Journal of structural biology · 2022Article
- Human cardiac myosin-binding protein C phosphorylation- and mutation-dependent structural dynamics monitored by time-resolved FRET.Journal of molecular and cellular cardiology · 2022Article
- Article
- Myofilament glycation in diabetes reduces contractility by inhibiting tropomyosin movement, is rescued by cMyBPC domains.Journal of molecular and cellular cardiology · 2022Article
- Actomyosin Complex.Sub-cellular biochemistry · 2022Article
- Interaction of the C2 Ig-like Domain of Cardiac Myosin Binding Protein-C with F-actin.Journal of molecular biology · 2021Article
- The N terminus of myosin-binding protein C extends toward actin filaments in intact cardiac muscle.The Journal of general physiology · 2021Article
- AAV9 gene transfer of cMyBPC N-terminal domains ameliorates cardiomyopathy in cMyBPC-deficient mice.JCI insight · 2020Article
- Phosphomimetic cardiac myosin-binding protein C partially rescues a cardiomyopathy phenotype in murine engineered heart tissue.Scientific reports · 2019Article
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4 authors at 1 institution in 1 country.
Funding
Abstract
We have used the site-directed spectroscopies of time-resolved fluorescence resonance energy transfer (TR-FRET) and double electron-electron resonance (DEER), combined with complementary molecular dynamics (MD) simulations, to resolve the structure and dynamics of cardiac myosin-binding protein C (cMyBP-C), focusing on the N-terminal region. The results have implications for the role of this protein in myocardial contraction, with particular relevance to β-adrenergic signaling, heart failure, and hypertrophic cardiomyopathy. N-terminal cMyBP-C domains C0-C2 (C0C2) contain binding regions for potential interactions with both thick and thin filaments. Phosphorylation by PKA in the MyBP-C motif regulates these binding interactions. Our spectroscopic assays detect distances between pairs of site-directed probes on cMyBP-C. We engineered intramolecular pairs of labeling sites within cMyBP-C to measure, with high resolution, the distance and disorder in the protein's flexible regions using TR-FRET and DEER. Phosphorylation reduced the level of molecular disorder and the distribution of C0C2 intramolecular distances became more compact, with probes flanking either the motif between C1 and C2 or the Pro/Ala-rich linker (PAL) between C0 and C1. Further insight was obtained from microsecond MD simulations, which revealed a large structural change in the disordered motif region in which phosphorylation unmasks the surface of a series of residues on a stable α-helix within the motif with high potential as a protein-protein interaction site. These experimental and computational findings elucidate structural transitions in the flexible and dynamic portions of cMyBP-C, providing previously unidentified molecular insight into the modulatory role of this protein in cardiac muscle contractility.
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