N-Terminal Fragment of Cardiac Myosin Binding Protein C Modulates Cooperative Mechanisms of Thin Filament Activation in Atria and Ventricles

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Anastasia M. Kochurova¹, Evgenia A. Beldiia^1,2, Victoria V. Nefedova³, Natalia S. Ryabkova^4,5, Daria S. Yampolskaya³, Alexander M. Matyushenko³, Sergey Y. Bershitsky¹, Galina V. Kopylova¹, and Daniil V. Shchepkin^1,a*

¹Institute of Immunology and Physiology, Russian Academy of Sciences, 620049 Yekaterinburg, Russia

²Ural Federal University, 620002 Ekaterinburg, Russia

³Bach Institute of Biochemistry, Research Center of Biotechnology, Russian Academy of Sciences, 119071 Moscow, Russia

⁴Department of Biochemistry, Faculty of Biology, Lomonosov Moscow State University, 119234 Moscow, Russia

⁵HyTest Ltd., 20520 Turku, Finland

Received November 16, 2023; Revised December 9, 2023; Accepted December 11, 2023

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Cardiac myosin binding protein C (cMyBP-C) is one of the essential control components of the myosin cross-bridge cycle. The C-terminal part of cMyBP-C is located on the surface of the thick filament, and its N-terminal part interacts with actin, myosin, and tropomyosin, affecting both kinetics of the ATP hydrolysis cycle and lifetime of the cross-bridge, as well as calcium regulation of the actin–myosin interaction, thereby modulating contractile function of myocardium. The role of cMyBP-C in atrial contraction has not been practically studied. We examined effect of the N-terminal C0-C1-m-C2 (C0-C2) fragment of cMyBP-C on actin–myosin interaction using ventricular and atrial myosin in an in vitro motility assay. The C0-C2 fragment of cMyBP-C significantly reduced the maximum sliding velocity of thin filaments on both myosin isoforms and increased the calcium sensitivity of the actin–myosin interaction. The C0-C2 fragment had different effects on the kinetics of ATP and ADP exchange, increasing the affinity of ventricular myosin for ADP and decreasing the affinity of atrial myosin. The effect of the C0-C2 fragment on the activation of the thin filament depended on the myosin isoforms. Atrial myosin activates the thin filament less than ventricular myosin, and the C0-C2 fragment makes these differences in the myosin isoforms more pronounced.

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KEY WORDS: cardiac myosin binding protein C, atrial and ventricular myosin, cardiac muscle, regulatory proteins, actin–myosin interaction, calcium regulation, thin filament activation, in vitro motility assay

DOI: 10.1134/S0006297924010073

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