ArticleJournal of molecular and cellular cardiology2016
The cMyBP-C HCM variant L348P enhances thin filament activation through an increased shift in tropomyosin position.
Article in Journal of molecular and cellular cardiology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 26 citations in OpenAlex.
- 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
- Autoinhibition of cMyBP-C by its middle domains.Journal of molecular and cellular cardiology · 2025Article
- 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
- Aficamten is a small-molecule cardiac myosin inhibitor designed to treat hypertrophic cardiomyopathy.Nature cardiovascular research · 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
- Human cardiac myosin-binding protein C phosphorylation- and mutation-dependent structural dynamics monitored by time-resolved FRET.Journal of molecular and cellular cardiology · 2022Article
- Gender- and age-related differences in distinct phenotypes of hypertrophic cardiomyopathy-associated mutation MYBPC3-E334K.Heart and vessels · 2021Article
- Cardiac MyBP-C phosphorylation regulates the Frank-Starling relationship in murine hearts.The Journal of general physiology · 2021Article
- Nanomechanical Phenotypes in Cardiac Myosin-Binding Protein C Mutants That Cause Hypertrophic Cardiomyopathy.ACS nano · 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
- 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
- The HCM-causing Y235S cMyBPC mutation accelerates contractile function by altering C1 domain structure.Biochimica et biophysica acta. Molecular basis of disease · 2019Article
- N-Terminal Domains of Cardiac Myosin Binding Protein C Cooperatively Activate the Thin Filament.Structure (London, England : 1993) · 2018Article
- Force-Dependent Recruitment from the Myosin Off State Contributes to Length-Dependent Activation.Biophysical journal · 2018Article
- Point mutations in the tri-helix bundle of the M-domain of cardiac myosin binding protein-C influence systolic duration and delay cardiac relaxation.Journal of molecular and cellular cardiology · 2018Article
- Skeletal myosin binding protein-C isoforms regulate thin filament activity in a CaScientific reports · 2018Article
- Phosphorylation of cardiac myosin binding protein C releases myosin heads from the surface of cardiac thick filaments.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
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Authors and funding
4 authors at 3 institutions in 2 countries.
Funding
Abstract
Mutations in cardiac myosin binding protein C (cMyBP-C), a thick filament protein that modulates contraction of the heart, are a leading cause of hypertrophic cardiomyopathy (HCM). Electron microscopy and 3D reconstruction of thin filaments decorated with cMyBP-C N-terminal fragments suggest that one mechanism of this modulation involves the interaction of cMyBP-C's N-terminal domains with thin filaments to enhance their Ca(2+)-sensitivity by displacement of tropomyosin from its blocked (low Ca(2+)) to its closed (high Ca(2+)) position. The extent of this tropomyosin shift is reduced when cMyBP-C N-terminal domains are phosphorylated. In the current study, we have examined L348P, a sequence variant of cMyBP-C first identified in a screen of patients with HCM. In L348P, leucine 348 is replaced by proline in cMyBP-C's regulatory M-domain, resulting in an increase in cMyBP-C's ability to enhance thin filament Ca(2+)-sensitization. Our goal here was to determine the structural basis for this enhancement by carrying out 3D reconstruction of thin filaments decorated with L348P-mutant cMyBP-C. When thin filaments were decorated with wild type N-terminal domains at low Ca(2+), tropomyosin moved from the blocked to the closed position, as found previously. In contrast, the L348P mutant caused a significantly larger tropomyosin shift, to approximately the open position, consistent with its enhancement of Ca(2+)-sensitization. Phosphorylated wild type fragments showed a smaller shift than unphosphorylated fragments, whereas the shift induced by the L348P mutant was not affected by phosphorylation. We conclude that the L348P mutation causes a gain of function by enhancing tropomyosin displacement on the thin filament in a phosphorylation-independent way.
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