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

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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Signaling and Myosin-binding Protein C

Journal of Biological Chemistry ◽

10.1074/jbc.r110.171801 ◽

2011 ◽

Vol 286 (12) ◽

pp. 9913-9919 ◽

Cited By ~ 34

Author(s):

Jeanne James ◽

Jeffrey Robbins

Keyword(s):

Protein C ◽

Striated Muscle ◽

Binding Protein ◽

Critical Role ◽

Nodal Point ◽

Familial Hypertrophic Cardiomyopathy ◽

Exact Nature ◽

Myosin Binding Protein ◽

Myosin Binding Protein C ◽

Myosin Binding

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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Skeletal myosin binding protein-C: An increasingly important regulator of striated muscle physiology

Archives of Biochemistry and Biophysics ◽

10.1016/j.abb.2018.10.007 ◽

2018 ◽

Vol 660 ◽

pp. 121-128 ◽

Cited By ~ 6

Author(s):

James W. McNamara ◽

Sakthivel Sadayappan

Keyword(s):

Protein C ◽

Striated Muscle ◽

Binding Protein ◽

Muscle Physiology ◽

Myosin Binding Protein ◽

Myosin Binding Protein C ◽

Skeletal Myosin ◽

Important Regulator ◽

Myosin Binding

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Mutations in β-myosin S2 that cause familial hypertrophic cardiomyopathy (FHC) abolish the interaction with the regulatory domain of myosin-binding protein-C 1 1Edited by J. Karn

Journal of Molecular Biology ◽

10.1006/jmbi.1998.2522 ◽

1999 ◽

Vol 286 (3) ◽

pp. 933-949 ◽

Cited By ~ 169

Author(s):

Mathias Gruen ◽

Mathias Gautel

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Protein C ◽

Binding Protein ◽

Familial Hypertrophic Cardiomyopathy ◽

Regulatory Domain ◽

Myosin Binding Protein ◽

Myosin Binding Protein C ◽

Myosin Binding

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Mutations in the Gene for Cardiac Myosin-Binding Protein C and Late-Onset Familial Hypertrophic Cardiomyopathy

New England Journal of Medicine ◽

10.1056/nejm199804303381802 ◽

1998 ◽

Vol 338 (18) ◽

pp. 1248-1257 ◽

Cited By ~ 520

Author(s):

Hideshi Niimura ◽

Linda L. Bachinski ◽

Somkiat Sangwatanaroj ◽

Hugh Watkins ◽

Albert E. Chudley ◽

...

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Protein C ◽

Late Onset ◽

Binding Protein ◽

Familial Hypertrophic Cardiomyopathy ◽

Cardiac Myosin ◽

Myosin Binding Protein ◽

Myosin Binding Protein C ◽

Myosin Binding

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Interaction between cardiac myosin-binding protein C and formin Fhod3

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1716498115 ◽

2018 ◽

Vol 115 (19) ◽

pp. E4386-E4395 ◽

Cited By ~ 7

Author(s):

Sho Matsuyama ◽

Yohko Kage ◽

Noriko Fujimoto ◽

Tomoki Ushijima ◽

Toshihiro Tsuruda ◽

...

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Cardiac Function ◽

Protein C ◽

Binding Protein ◽

Direct Interaction ◽

Familial Hypertrophic Cardiomyopathy ◽

Cardiac Myosin ◽

Myosin Binding Protein ◽

Myosin Binding Protein C ◽

Myosin Binding

Mutations in cardiac myosin-binding protein C (cMyBP-C) are a major cause of familial hypertrophic cardiomyopathy. Although cMyBP-C has been considered to regulate the cardiac function via cross-bridge arrangement at the C-zone of the myosin-containing A-band, the mechanism by which cMyBP-C functions remains unclear. We identified formin Fhod3, an actin organizer essential for the formation and maintenance of cardiac sarcomeres, as a cMyBP-C–binding protein. The cardiac-specific N-terminal Ig-like domain of cMyBP-C directly interacts with the cardiac-specific N-terminal region of Fhod3. The interaction seems to direct the localization of Fhod3 to the C-zone, since a noncardiac Fhod3 variant lacking the cMyBP-C–binding region failed to localize to the C-zone. Conversely, the cardiac variant of Fhod3 failed to localize to the C-zone in the cMyBP-C–null mice, which display a phenotype of hypertrophic cardiomyopathy. The cardiomyopathic phenotype of cMyBP-C–null mice was further exacerbated by Fhod3 overexpression with a defect of sarcomere integrity, whereas that was partially ameliorated by a reduction in the Fhod3 protein levels, suggesting that Fhod3 has a deleterious effect on cardiac function under cMyBP-C–null conditions where Fhod3 is aberrantly mislocalized. Together, these findings suggest the possibility that Fhod3 contributes to the pathogenesis of cMyBP-C–related cardiomyopathy and that Fhod3 is critically involved in cMyBP-C–mediated regulation of cardiac function via direct interaction.

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