Modulation of striated muscle contraction by binding of myosin binding protein C to actin

Myosin-binding protein C (MyBP-C) is a thick filament protein consisting of 1274 amino acid residues (149 kDa) that was identified by Starr and Offer over 30 years ago as a contaminant present in a preparation of purified myosin. Since then, numerous studies have defined the muscle-specific isoforms, the structure, and the importance of the proteins in normal striated muscle structure and function. Underlying the critical role the protein plays, it is now apparent that mutations in the cardiac isoform (cMyBP-C) are responsible for a substantial proportion (30–40%) of genotyped cases of familial hypertrophic cardiomyopathy. Although generally accepted that MyBP-C can interact with all three filament systems within the sarcomere (the thick, thin, and titin filaments), the exact nature of these interactions and the functional consequences of modified binding remain obscure. In addition to these structural considerations, cMyBP-C can serve as a point of convergence for signaling processes in the cardiomyocyte via post-translational modifications mediated by kinases that phosphorylate residues in the cardiac-specific isoform sequence. Thus, cMyBP-C is a critical nodal point that has both important structural and signaling roles and whose modifications are known to cause significant human cardiac disease.

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Myosin Binding Protein-C: A Regulator of Actomyosin Interaction in Striated Muscle

Journal of Biomedicine and Biotechnology ◽

10.1155/2011/636403 ◽

2011 ◽

Vol 2011 ◽

pp. 1-9 ◽

Cited By ~ 32

Author(s):

Maegen A. Ackermann ◽

Aikaterini Kontrogianni-Konstantopoulos

Keyword(s):

Actin Filaments ◽

Protein C ◽

Striated Muscle ◽

Current Knowledge ◽

Binding Protein ◽

Familial Hypertrophic Cardiomyopathy ◽

Striated Muscles ◽

Myosin Binding Protein ◽

Myosin Binding Protein C ◽

Myosin Binding

Myosin-Binding protein-C (MyBP-C) is a family of accessory proteins of striated muscles that contributes to the assembly and stabilization of thick filaments, and regulates the formation of actomyosin cross-bridges, via direct interactions with both thick myosin and thin actin filaments. Three distinct MyBP-C isoforms have been characterized; cardiac, slow skeletal, and fast skeletal. Numerous mutations in the gene for cardiac MyBP-C (cMyBP-C) have been associated with familial hypertrophic cardiomyopathy (FHC) and have led to increased interest in the regulation and roles of the cardiac isoform. This review will summarize our current knowledge on MyBP-C and its role in modulating contractility, focusing on its interactions with both myosin and actin filaments in cardiac and skeletal muscles.

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Myosin Binding Protein C Positioned to Play a Key Role in Regulation of Muscle Contraction: Structure and Interactions of Domain C1

Journal of Molecular Biology ◽

10.1016/j.jmb.2008.09.065 ◽

2008 ◽

Vol 384 (3) ◽

pp. 615-630 ◽

Cited By ~ 66

Author(s):

Abdessamad Ababou ◽

Elena Rostkova ◽

Shreena Mistry ◽

Clare Le Masurier ◽

Mathias Gautel ◽

...

Keyword(s):

Muscle Contraction ◽

Protein C ◽

Binding Protein ◽

Myosin Binding Protein ◽

Myosin Binding Protein C ◽

Myosin Binding ◽

Regulation Of Muscle Contraction

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ID: 77: FAST-SKELETAL MYOSIN BINDING PROTEIN-C REGULATES SKELETAL MUSCLE CALCIUM SENSITIVITY

Journal of Investigative Medicine ◽

10.1136/jim-2016-000120.13 ◽

2016 ◽

Vol 64 (4) ◽

pp. 917.1-917

Author(s):

BL Lin ◽

S Govindan ◽

S Sadayappan ◽

L Zhao ◽

J Xu ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Contraction ◽

Skeletal Muscles ◽

Protein C ◽

Molecular Level ◽

Binding Protein ◽

Myosin Binding Protein ◽

Myosin Binding Protein C ◽

Myosin Binding

Mutations in myosin binding protein-C (MyBP-C) cause both cardiac and skeletal muscle diseases, such as hypertrophic cardiomyopathy and distal arthrogryposis. There are three isoforms of MyBP-C: slow-skeletal, fast-skeletal, and cardiac (ssMyBP-C, fsMyBP-C, and cMyBP-C, respectively). These isoforms reside within the sarcomere, the functional unit of muscle contraction at the molecular level. However, the function of the three major MyBP-C isoforms remains unclear. The present study is the first to focus on the least characterized isoform, fsMyBP-C, which is expressed in fast- and mixed-type skeletal muscles. To determine the necessity of fsMyBP-C for regulation of contraction in the sarcomere, we generated a conventional fast-skeletal MyBP-C knockout (FSKO) mouse model. We analyzed both structural changes and regulatory function of skeletal muscles from heterozygous (FSKO−/+) and homozygous (FSKO−/−), compared to wild-type (WT) mice. Neither heterozygous nor homozygous FSKO mice exhibited changes in morbidity or mortality relative to WT mice. Molecular analyses revealed a complete knockout of fsMyBP-C in the FSKO−/− skeletal muscles compared to FSKO−/+ and WT mice. Histopathological analyses of both Extensor digitorum longus (EDL) and soleus muscles revealed no obvious abnormalities, such as fibrosis or calcification, in either heterozygous or homozygous FSKO mice. Though fiber structure is preserved, we demonstrated that EDL muscles from FSKO−/− mice increases Ca2+-sensitivity of force development, suggesting that fsMyBP-C regulates contraction at the molecular level by decreasing Ca2+-sensitivity. While others have previously proposed the role of cMyBP-C is to increase Ca2+-sensitivity to normalize a Ca2+ gradient imbalance in the heart, we propose that the role of fsMyBP-C in skeletal muscles is to reduce Ca2+-sensitivity of the thin filaments in order to normalize the reversed Ca2+ gradient imbalance. Despite opposite effects on Ca2+-sensitivity, MyBP-C share the same functional role in both cardiac and skeletal muscles. Thus, in addition to elucidating the role of fast-skeletal MyBP-C and its regulation of skeletal muscle contraction, the present study provides insight into the cardiac isoform and its regulation of cardiac contraction.

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Cardiac Myosin Binding Protein C and Its Phosphorylation Regulate Multiple Steps in the Cross-Bridge Cycle of Muscle Contraction

Biochemistry ◽

10.1021/bi300085x ◽

2012 ◽

Vol 51 (15) ◽

pp. 3292-3301 ◽

Cited By ~ 20

Author(s):

Arthur T. Coulton ◽

Julian E. Stelzer

Keyword(s):

Muscle Contraction ◽

Protein C ◽

Binding Protein ◽

Cardiac Myosin ◽

Cross Bridge ◽

Myosin Binding Protein ◽

Myosin Binding Protein C ◽

Myosin Binding ◽

The Cross

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Making waves: A proposed new role for myosin-binding protein C in regulating oscillatory contractions in vertebrate striated muscle

The Journal of General Physiology ◽

10.1085/jgp.202012729 ◽

2020 ◽

Vol 153 (3) ◽

Author(s):

Samantha P. Harris

Keyword(s):

Protein C ◽

Molecular Mechanisms ◽

Striated Muscle ◽

Binding Protein ◽

Muscle Performance ◽

Central Position ◽

Myosin Binding Protein ◽

Myosin Binding Protein C ◽

Myosin Binding ◽

Contraction And Relaxation

Myosin-binding protein C (MyBP-C) is a critical regulator of muscle performance that was first identified through its strong binding interactions with myosin, the force-generating protein of muscle. Almost simultaneously with its discovery, MyBP-C was soon found to bind to actin, the physiological catalyst for myosin’s activity. However, the two observations posed an apparent paradox, in part because interactions of MyBP-C with myosin were on the thick filament, whereas MyBP-C interactions with actin were on the thin filament. Despite the intervening decades since these initial discoveries, it is only recently that the dual binding modes of MyBP-C are becoming reconciled in models that place MyBP-C at a central position between actin and myosin, where MyBP-C alternately stabilizes a newly discovered super-relaxed state (SRX) of myosin on thick filaments in resting muscle and then prolongs the “on” state of actin on thin filaments in active muscle. Recognition of these dual, alternating functions of MyBP-C reveals how it is central to the regulation of both muscle contraction and relaxation. The purpose of this Viewpoint is to briefly summarize the roles of MyBP-C in binding to myosin and actin and then to highlight a possible new role for MyBP-C in inducing and damping oscillatory waves of contraction and relaxation. Because the contractile waves bear similarity to cycles of contraction and relaxation in insect flight muscles, which evolved for fast, energetically efficient contraction, the ability of MyBP-C to damp so-called spontaneous oscillatory contractions (SPOCs) has broad implications for previously unrecognized regulatory mechanisms in vertebrate striated muscle. While the molecular mechanisms by which MyBP-C can function as a wave maker or a wave breaker are just beginning to be explored, it is likely that MyBP-C dual interactions with both myosin and actin will continue to be important for understanding the new functions of this enigmatic protein.

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Evolution of the regulatory control of vertebrate striated muscle: the roles of troponin I and myosin binding protein-C

Physiological Genomics ◽

10.1152/physiolgenomics.00055.2010 ◽

2010 ◽

Vol 42 (3) ◽

pp. 406-419 ◽

Cited By ~ 20

Author(s):

Justin F. Shaffer ◽

Todd E. Gillis

Keyword(s):

Protein Kinase ◽

Protein C ◽

Troponin I ◽

Striated Muscle ◽

Contractile Function ◽

Binding Protein ◽

Tissue Specific ◽

Myosin Binding Protein ◽

Myosin Binding Protein C ◽

Myosin Binding

Troponin I (TnI) and myosin binding protein-C (MyBP-C) are key regulatory proteins of contractile function in vertebrate muscle. TnI modulates the Ca2+ activation signal, while MyBP-C regulates cross-bridge cycling kinetics. In vertebrates, each protein is distributed as tissue-specific paralogs in fast skeletal (fs), slow skeletal (ss), and cardiac (c) muscles. The purpose of this study is to characterize how TnI and MyBP-C have changed during the evolution of vertebrate striated muscle and how tissue-specific paralogs have adapted to different physiological conditions. To accomplish this we have completed phylogenetic analyses using the amino acid sequences of all known TnI and MyBP-C isoforms. This includes 99 TnI sequences (fs, ss, and c) from 51 different species and 62 MyBP-C sequences from 26 species, with representatives from each vertebrate group. Results indicate that the role of protein kinase A (PKA) and protein kinase C (PKC) in regulating contractile function has changed during the evolution of vertebrate striated muscle. This is reflected in an increased number of phosphorylatable sites in cTnI and cMyBP-C in endothermic vertebrates and the loss of two PKC sites in fsTnI in a common ancestor of mammals, birds, and reptiles. In addition, we find that His132, Val134, and Asn141 in human ssTnI, previously identified as enabling contractile function during cellular acidosis, are present in all vertebrate cTnI isoforms except those from monotremes, marsupials, and eutherian mammals. This suggests that the replacement of these residues with alternative residues coincides with the evolution of endothermy in the mammalian lineage.

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Understanding the Organisation and Role of Myosin Binding Protein C in Normal Striated Muscle by Comparison with MyBP-C Knockout Cardiac Muscle

Journal of Molecular Biology ◽

10.1016/j.jmb.2008.09.013 ◽

2008 ◽

Vol 384 (1) ◽

pp. 60-72 ◽

Cited By ~ 81

Author(s):

Pradeep K. Luther ◽

Pauline M. Bennett ◽

Carlo Knupp ◽

Roger Craig ◽

Raúl Padrón ◽

...

Keyword(s):

Cardiac Muscle ◽

Protein C ◽

Striated Muscle ◽

Binding Protein ◽

Myosin Binding Protein ◽

Myosin Binding Protein C ◽

Myosin Binding

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Biological variation of cardiac myosin-binding protein C in healthy individuals

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2021-0306 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Bashir Alaour ◽

Torbjørn Omland ◽

Janniche Torsvik ◽

Thomas E. Kaier ◽

Marit S. Sylte ◽

...

Keyword(s):

Risk Stratification ◽

Protein C ◽

Myocardial Injury ◽

Binding Protein ◽

Biological Variation ◽

Cardiac Myosin ◽

Analytical Quality ◽

Myosin Binding Protein ◽

Myosin Binding Protein C ◽

Myosin Binding

Abstract Objectives Cardiac myosin-binding protein C (cMyC) is a novel biomarker of myocardial injury, with a promising role in the triage and risk stratification of patients presenting with acute cardiac disease. In this study, we assess the weekly biological variation of cMyC, to examine its potential in monitoring chronic myocardial injury, and to suggest analytical quality specification for routine use of the test in clinical practice. Methods Thirty healthy volunteers were included. Non-fasting samples were obtained once a week for ten consecutive weeks. Samples were tested in duplicate on the Erenna® platform by EMD Millipore Corporation. Outlying measurements and subjects were identified and excluded systematically, and homogeneity of analytical and within-subject variances was achieved before calculating the biological variability (CVI and CVG), reference change values (RCV) and index of individuality (II). Results Mean age was 38 (range, 21–64) years, and 16 participants were women (53%). The biological variation, RCV and II with 95% confidence interval (CI) were: CVA (%) 19.5 (17.8–21.6), CVI (%) 17.8 (14.8–21.0), CVG (%) 66.9 (50.4–109.9), RCV (%) 106.7 (96.6–120.1)/−51.6 (−54.6 to −49.1) and II 0.42 (0.29–0.56). There was a trend for women to have lower CVG. The calculated RCVs were comparable between genders. Conclusions cMyC exhibits acceptable RCV and low II suggesting that it could be suitable for disease monitoring, risk stratification and prognostication if measured serially. Analytical quality specifications based on biological variation are similar to those for cardiac troponin and should be achievable at clinically relevant concentrations.

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