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
- Autores: Kochurova A.M.1, Beldiia E.A.1, Antonets J.Y.1, Nefedova V.V.2, Ryabkova N.S.3,4, Katrukha I.A.3,4, Bershitsky S.Y.1, Matyushenko A.M.2, Kopylova G.V.1, Shchepkin D.V.1
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Afiliações:
- Institute of Immunology and Physiology of the Russian Academy of Sciences
- Research Center of Biotechnology, Russian Academy of Sciences
- Lomonosov Moscow State University
- HyTest Ltd.
- Edição: Volume 90, Nº 3 (2025)
- Páginas: 430-442
- Seção: Articles
- URL: https://journals.rcsi.science/0320-9725/article/view/294704
- DOI: https://doi.org/10.31857/S0320972525030075
- EDN: https://elibrary.ru/BJSOHI
- ID: 294704
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Resumo
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.
Sobre autores
A. Kochurova
Institute of Immunology and Physiology of the Russian Academy of Sciences
Email: dvshchepkin@gmail.com
Rússia, Yekaterinburg, 620049
E. Beldiia
Institute of Immunology and Physiology of the Russian Academy of Sciences
Email: dvshchepkin@gmail.com
Rússia, Yekaterinburg, 620049
J. Antonets
Institute of Immunology and Physiology of the Russian Academy of Sciences
Email: dvshchepkin@gmail.com
Rússia, Yekaterinburg, 620049
V. Nefedova
Research Center of Biotechnology, Russian Academy of Sciences
Email: dvshchepkin@gmail.com
Rússia, 119071 Moscow
N. Ryabkova
Lomonosov Moscow State University; HyTest Ltd.
Email: dvshchepkin@gmail.com
Department of Biochemistry, Faculty of Biology
Rússia, Moscow 119234; 20520 Turku, FinlandI. Katrukha
Lomonosov Moscow State University; HyTest Ltd.
Email: dvshchepkin@gmail.com
Department of Biochemistry, Faculty of Biology
Rússia, Moscow 119234; 20520 Turku, FinlandS. Bershitsky
Institute of Immunology and Physiology of the Russian Academy of Sciences
Email: dvshchepkin@gmail.com
Rússia, Yekaterinburg, 620049
A. Matyushenko
Research Center of Biotechnology, Russian Academy of Sciences
Email: dvshchepkin@gmail.com
Rússia, 119071 Moscow
G. Kopylova
Institute of Immunology and Physiology of the Russian Academy of Sciences
Email: dvshchepkin@gmail.com
Rússia, Yekaterinburg, 620049
D. Shchepkin
Institute of Immunology and Physiology of the Russian Academy of Sciences
Autor responsável pela correspondência
Email: dvshchepkin@gmail.com
Rússia, Yekaterinburg, 620049
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