Mavacamten Inhibits the Effect of the N-Terminal Fragment of Cardiac Myosin-Binding Protein C with the L352P Mutation on the Actin–Myosin Interaction at Low Calcium Concentrations

Kochurova, A.M.; Beldiia, E.A.; Antonets, J.Y.; Nefedova, V.V.; Ryabkova, N.S.; Katrukha, I.A.; Bershitsky, S.Y.; Matyushenko, A.M.; Kopylova, G.V.; Shchepkin, D.V.

Авторы: Kochurova Anastasia M., Beldiia Evgenia A., Antonets Julia Y., Nefedova Victoria V., Ryabkova Natalia S., Katrukha Ivan A., Bershitsky Sergey Y., Matyushenko Alexander M., Kopylova Galina V., Shchepkin Daniil V.
Журнал: Biochemistry (Moscow)
Том: 90
Номер: 3
Год издания: 2025
Издательство: Pleiades Publishing, Ltd
Местоположение издательства: Road Town, United Kingdom
Первая страница: 389
Последняя страница: 399
DOI: 10.1134/s0006297924604131
Аннотация: Hypertrophic cardiomyopathy (HCM)-associated mutations in sarcomeric proteins lead to the disruption of the actin-myosin interaction and its calcium regulation and cause 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 β-cardiac myosin function inhibitors, one of which is mavacamten. We studied the effect of mavacamten on the calcium regulation of the actin-myosin interaction using isolated cardiac contractile proteins in the in vitro motility assay. The L352P mutation did not affect the maximum sliding velocity of regulated thin filaments on myosin in the in vitro motility assay and the calcium sensitivity of the velocity but led to the underinhibition of the actin-myosin interaction at low calcium concentrations. Mavacamten decreased the maximum sliding velocity of thin filaments in the presence of the WT and L352P C0-C2 fragments, and abolished their movement in the presence of the L352P C0-C2 fragment at low calcium concentrations. Slowing down the kinetics of cross-bridges and inhibition of actin-myosin interaction at low calcium concentrations by mavacamten may reduce the hypercontractility in HCM and the degree of myocardial hypertrophy.
Добавил в систему: Катруха Иван Алексеевич

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Mavacamten Inhibits the Effect of the N-Terminal Fragment of Cardiac Myosin-Binding Protein C with the L352P Mutation on the Actin–Myosin Interaction at Low Calcium Concentrationsстатья