ArticleThe Journal of biological chemistry2013
A gain-of-function mutation in the M-domain of cardiac myosin-binding protein-C increases binding to actin.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 47 citations in OpenAlex.
- Scaled Multidimensional Assays of Variant Effect Identify Sequence-Function Relationships in Hypertrophic Cardiomyopathy.Circulation · 2026Article
- Myosin-binding protein C slows cardiac myofibril relaxation kinetics.The Journal of physiology · 2025Article
- The L348P point mutation in cardiac myosin binding protein-C alters transient responses to stretch, slows cardiac relaxation, and is embryonic lethal in homozygous CRISPR gene-edited mice.Journal of molecular and cellular cardiology · 2025Article
- Myosin binding protein-C modulates loaded sarcomere shortening in rodent permeabilized cardiac myocytes.The Journal of general physiology · 2025Article
- Disparate Molecular Properties of Two Hypertrophic Cardiomyopathy-Associated cMyBP-C Mutants Reveal Distinct Pathogenic Mechanisms Beyond Haploinsufficiency.Biomedicines · 2025Article
- The N-Terminal Mutations of cMyBP-C Affect Calcium Regulation, Kinetics, and Force of Muscle Contraction.International journal of molecular sciences · 2024Article
- 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 N-terminal interactions with myosin and actin filaments: Opposite effects of phosphorylation and M-domain mutations.Journal of molecular and cellular cardiology · 2024Article
- cMyBP-C ablation in human engineered cardiac tissue causes progressive Ca2+-handling abnormalities.The Journal of general physiology · 2023Article
- Cryo-Electron Microscopy Reveals Cardiac Myosin Binding Protein-C M-Domain Interactions with the Thin Filament.Journal of molecular biology · 2022Article
- Nanosurfer assay dissects β-cardiac myosin and cardiac myosin-binding protein C interactions.Biophysical journal · 2022Article
- Assessment of the Contribution of a Thermodynamic and Mechanical Destabilization of Myosin-Binding Protein C Domain C2 to the Pathomechanism of Hypertrophic Cardiomyopathy-Causing Double MutationInternational journal of molecular sciences · 2021Article
- Interaction of the C2 Ig-like Domain of Cardiac Myosin Binding Protein-C with F-actin.Journal of molecular biology · 2021Article
- Protein haploinsufficiency drivers identify MYBPC3 variants that cause hypertrophic cardiomyopathy.The Journal of biological chemistry · 2021Article
- Making waves: A proposed new role for myosin-binding protein C in regulating oscillatory contractions in vertebrate striated muscle.The Journal of general physiology · 2021Article
- A high-throughput fluorescence lifetime-based assay to detect binding of myosin-binding protein C to F-actin.The Journal of general physiology · 2021Article
- cMyBP-C phosphorylation modulates the time-dependent slowing of unloaded shortening in murine skinned myocardium.The Journal of general physiology · 2021Article
- A Novel "Cut and Paste" Method for In Situ Replacement of cMyBP-C Reveals a New Role for cMyBP-C in the Regulation of Contractile Oscillations.Circulation research · 2020Article
- Single-Molecule Force Spectroscopy on the N2A Element of Titin: Effects of Phosphorylation and CARP.Frontiers in physiology · 2020Article
- Human cardiac myosin-binding protein C restricts actin structural dynamics in a cooperative and phosphorylation-sensitive manner.The Journal of biological chemistry · 2019Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
The M-domain is the major regulatory subunit of cardiac myosin-binding protein-C (cMyBP-C) that modulates actin and myosin interactions to influence muscle contraction. However, the precise mechanism(s) and the specific residues involved in mediating the functional effects of the M-domain are not fully understood. Positively charged residues adjacent to phosphorylation sites in the M-domain are thought to be critical for effects of cMyBP-C on cross-bridge interactions by mediating electrostatic binding with myosin S2 and/or actin. However, recent structural studies revealed that highly conserved sequences downstream of the phosphorylation sites form a compact tri-helix bundle. Here we used site-directed mutagenesis to probe the functional significance of charged residues adjacent to the phosphorylation sites and conserved residues within the tri-helix bundle. Results confirm that charged residues adjacent to phosphorylation sites and residues within the tri-helix bundle are important for mediating effects of the M-domain on contraction. In addition, four missense variants within the tri-helix bundle that are associated with human hypertrophic cardiomyopathy caused either loss-of-function or gain-of-function effects on force. Importantly, the effects of the gain-of-function variant, L348P, increased the affinity of the M-domain for actin. Together, results demonstrate that functional effects of the M-domain are not due solely to interactions with charged residues near phosphorylatable serines and provide the first demonstration that the tri-helix bundle contributes to the functional effects of the M-domain, most likely by binding to actin.
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