Mavacamten inhibits the effect of the N-terminal fragment of cardiac myosin-binding protein-C with the L352P mutation on actin-myosin interaction at low calcium concentrations

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Abstract

Mutations in sarcomeric proteins associated with hypertrophic cardiomyopathy (HCM) lead to disruption of actin-myosin interaction, its calcium regulation, and myocardial hypercontractility. About half of such mutations are found in the MYBPC3 gene encoding cardiac myosin binding protein C (cMyBP-C). A new approach to normalize cardiac contractile function in HCM is the use of inhibitors of β-cardiac myosin function, one of which is mavacamten. We studied the effect of mavacamten on calcium regulation of actin-myosin interaction using isolated cardiac contractile proteins in an in vitro motility assay. The L352P mutation did not affect the maximum sliding velocity of regulated thin filaments on myosin in an in vitro motility assay and the calcium sensitivity of the velocity and led to underinhibition of actin-myosin interaction at low calcium concentrations. Mavacamten decreased the maximum sliding velocity of thin filaments with WT and L352P C0-C2 fragments, and in the presence of L352P C0-C2 fragment stopped their movement at low calcium concentrations. Slowing down the kinetics of cross-bridge and inhibition of actin-myosin interaction at low calcium concentrations in the presence of mavacamten may reduce hypercontractility in HCM and the degree of myocardial hypertrophy.

About the authors

A. M. Kochurova

Institute of Immunology and Physiology of the Russian Academy of Sciences

Email: dvshchepkin@gmail.com
Russian Federation, Yekaterinburg, 620049

E. A. Beldiia

Institute of Immunology and Physiology of the Russian Academy of Sciences

Email: dvshchepkin@gmail.com
Russian Federation, Yekaterinburg, 620049

J. Y. Antonets

Institute of Immunology and Physiology of the Russian Academy of Sciences

Email: dvshchepkin@gmail.com
Russian Federation, Yekaterinburg, 620049

V. V. Nefedova

Research Center of Biotechnology, Russian Academy of Sciences

Email: dvshchepkin@gmail.com
Russian Federation, 119071 Moscow

N. S. Ryabkova

Lomonosov Moscow State University; HyTest Ltd.

Email: dvshchepkin@gmail.com

Department of Biochemistry, Faculty of Biology

Russian Federation, Moscow 119234; 20520 Turku, Finland

I. A. Katrukha

Lomonosov Moscow State University; HyTest Ltd.

Email: dvshchepkin@gmail.com

Department of Biochemistry, Faculty of Biology

Russian Federation, Moscow 119234; 20520 Turku, Finland

S. Y. Bershitsky

Institute of Immunology and Physiology of the Russian Academy of Sciences

Email: dvshchepkin@gmail.com
Russian Federation, Yekaterinburg, 620049

A. M. Matyushenko

Research Center of Biotechnology, Russian Academy of Sciences

Email: dvshchepkin@gmail.com
Russian Federation, 119071 Moscow

G. V. Kopylova

Institute of Immunology and Physiology of the Russian Academy of Sciences

Email: dvshchepkin@gmail.com
Russian Federation, Yekaterinburg, 620049

D. V. Shchepkin

Institute of Immunology and Physiology of the Russian Academy of Sciences

Author for correspondence.
Email: dvshchepkin@gmail.com
Russian Federation, Yekaterinburg, 620049

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