ArticleJournal of molecular and cellular cardiology2018
N-terminal extension in cardiac myosin-binding protein C regulates myofilament binding.
Article in Journal of molecular and cellular cardiology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 23 citations in OpenAlex.
- Early fibrotic gene activation precedes structural remodeling in the heart of cardiac myosin binding protein-C knockout mice.Physiological genomics · 2026Article
- N-Terminal Actin-Binding Site of Lmod2 Promotes Controlled Pointed End Elongation.Circulation research · 2026Article
- 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
- RLC phosphorylation amplifies Ca2+ sensitivity of force in myocardium from cMyBP-C knockout mice.The Journal of general physiology · 2023Article
- Fluorescence lifetime-based assay reports structural changes in cardiac muscle mediated by effectors of contractile regulation.The Journal of general physiology · 2023Article
- Evaluation of the DBA/2J mouse as a potential background strain for genetic models of cardiomyopathy.Journal of molecular and cellular cardiology plus · 2022Article
- Structure and Dynamics of the Flexible Cardiac Troponin T Linker Domain in a Fully Reconstituted Thin Filament.Biochemistry · 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
- A high-throughput fluorescence lifetime-based assay to detect binding of myosin-binding protein C to F-actin.The Journal of general physiology · 2021Article
- Purification and Enzymatic Properties of a Difunctional Glycoside Hydrolase fromIndian journal of microbiology · 2020Article
- AAV9 gene transfer of cMyBPC N-terminal domains ameliorates cardiomyopathy in cMyBPC-deficient mice.JCI insight · 2020Article
- Cardiac myosin regulatory light chain kinase modulates cardiac contractility by phosphorylating both myosin regulatory light chain and troponin I.The Journal of biological chemistry · 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
4 authors at 1 institution in 1 country.
Funding
Abstract
rationaleMutations in the gene encoding the sarcomeric protein cardiac myosin-binding protein C (cMyBP-C) are a leading cause of hypertrophic cardiomyopathy (HCM). Mouse models targeting cMyBP-C and use of recombinant proteins have been effective in studying its roles in contractile function and disease. Surprisingly, while the N-terminus of cMyBP-C is important to regulate myofilament binding and contains many HCM mutations, an incorrect sequence, lacking the N-terminal 8 amino acids has been used in many studies.
objectivesTo determine the N-terminal cMyBP-C sequences in ventricles and investigate the roles of species-specific differences in cMyBP-C on myofilament binding. METHODS AND
resultsWe determined cMyBP-C sequences in mouse and human by inspecting available sequence databases. N-terminal differences were confirmed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Cosedimentation assays with actin or myosin were used to examine binding in mouse, human and chimeric fusion proteins of cMyBP-C. Time-resolved FRET (TR-FRET) with site-directed probes on cMyBP-C was employed to measure structural dynamics. LC-MS/MS supported the sequencing data that mouse cMyBP-C contains an eight-residue N-terminal extension (NTE) not found in human. Cosedimentation assays revealed that cardiac myosin binding was strongly influenced by the presence of the NTE, which reduced binding by 60%. 75% more human C0-C2 than mouse bound to myosin. Actin binding of mouse C0-C2 was not affected by the NTE. 50% more human C0-C2 than mouse bound to actin. TR-FRET indicates that the NTE did not significantly affect structural dynamics across domains C0 and C1.
conclusionsOur functional results are consistent with the idea that cardiac myosin binding of N-terminal cMyBP-C is reduced in the mouse protein due to the presence of the NTE, which is proposed to interfere with myosin regulatory light chain (RLC) binding. The NTE is a critical component of mouse cMyBP-C, and should be considered in extrapolation of studies to cMyBP-C and HCM mechanisms in human.
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