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In vivo definition of cardiac myosin-binding protein C’s critical interactions with myosin

  • Molecular and genomic physiology
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Abstract

Cardiac myosin-binding protein C (cMyBP-C) is an integral part of the sarcomeric machinery in cardiac muscle that enables normal function. cMyBP-C regulates normal cardiac contraction by functioning as a brake through interactions with the sarcomere’s thick, thin, and titin filaments. cMyBP-C’s precise effects as it binds to the different filament systems remain obscure, particularly as it impacts on the myosin heavy chain’s head domain, contained within the subfragment 2 (S2) region. This portion of the myosin heavy chain also contains the ATPase activity critical for myosin’s function. Mutations in myosin’s head, as well as in cMyBP-C, are a frequent cause of familial hypertrophic cardiomyopathy (FHC). We generated transgenic lines in which endogenous cMyBP-C was replaced by protein lacking the residues necessary for binding to S2 (cMyBP-CS2−). We found, surprisingly, that cMyBP-C lacking the S2 binding site is incorporated normally into the sarcomere, although systolic function is compromised. We show for the first time the acute and chronic in vivo consequences of ablating a filament-specific interaction of cMyBP-C. This work probes the functional consequences, in the whole animal, of modifying a critical structure-function relationship, the protein’s ability to bind to a region of the critical enzyme responsible for muscle contraction, the subfragment 2 domain of the myosin heavy chain. We show that the binding is not critical for the protein’s correct insertion into the sarcomere’s architecture, but is essential for long-term, normal function in the physiological context of the heart.

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Authors and Affiliations

  1. Department of Pediatrics, Division of Molecular Cardiovascular Biology, The Heart Institute, Cincinnati Children’s Hospital Medical Center, MLC 7020, 240 Albert Sabin Way, Cincinnati, OH, 45229, USA

    Md. Shenuarin Bhuiyan, Patrick McLendon, Jeanne James, Hanna Osinska, James Gulick, Bidur Bhandary & Jeffrey Robbins

  2. Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center, Shreveport, LA, USA

    Md. Shenuarin Bhuiyan

  3. Department of Molecular and Cellular Physiology (J.N.L.), University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA

    John N. Lorenz

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  1. Md. Shenuarin Bhuiyan
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Correspondence to Jeffrey Robbins.

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Sources of funding

This work was supported by the National Institutes of Health grants P01HL69779, P01HL059408, R01HL05924, and R011062927 and a Trans-Atlantic Network of Excellence grant from Le Fondation Leducq (J.R.) as well as National Institutes of Health grant K99 HL122354 and an American Heart Association Postdoctoral Fellowship grant (M.S.B.).

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Bhuiyan, M.S., McLendon, P., James, J. et al. In vivo definition of cardiac myosin-binding protein C’s critical interactions with myosin. Pflugers Arch - Eur J Physiol 468, 1685–1695 (2016). https://doi.org/10.1007/s00424-016-1873-y

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  • DOI: https://doi.org/10.1007/s00424-016-1873-y

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