The D75N and P161S Mutations in the C0-C2 Fragment of cMyBP-C Associated with Hypertrophic Cardiomyopathy Disturb the Thin Filament Activation, Nucleotide Exchange in Myosin, and Actin–Myosin Interaction

Kochurova, A.M.; Beldiia, E.A.; Nefedova, V.V.; Yampolskaya, D.S.; Koubassova, N.A.; Kleymenov, S.Y.; Antonets, J.Y.; 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., Nefedova Victoria V., Yampolskaya Daria S., Koubassova Natalia A., Kleymenov Sergey Y., Antonets Julia Y., Ryabkova Natalia S., Katrukha Ivan A., Bershitsky Sergey Y., Matyushenko Alexander M., Kopylova Galina V., Shchepkin Daniil V.
Журнал: International Journal of Molecular Sciences
Том: 25
Номер: 20
Год издания: 2024
Издательство: MDPI
Местоположение издательства: Basel, Switzerland
Первая страница: 11195
Последняя страница: 11195
DOI: 10.3390/ijms252011195
Аннотация: About half of the mutations that lead to hypertrophic cardiomyopathy (HCM) occur in the MYBPC3 gene. However, the molecular mechanisms of pathogenicity of point mutations in cardiac myosin-binding protein C (cMyBP-C) remain poorly understood. In this study, we examined the effects of the D75N and P161S substitutions in the C0 and C1 domains of cMyBP-C on the structural and functional properties of the C0-C1-m-C2 fragment (C0-C2). Differential scanning calorimetry revealed that these mutations disorder the tertiary structure of the C0-C2 molecule. Functionally, the D75N mutation reduced the maximum sliding velocity of regulated thin filaments in an in vitro motility assay, while the P161S mutation increased it. Both mutations significantly reduced the calcium sensitivity of the actin–myosin interaction and impaired thin filament activation by cross-bridges. D75N and P161S C0-C2 fragments substantially decreased the sliding velocity of the F-actin-tropomyosin filament. ADP dose-dependently reduced filament sliding velocity in the presence of WT and P161S fragments, but the velocity remained unchanged with the D75N fragment. We suppose that the D75N mutation alters nucleotide exchange kinetics by decreasing ADP affinity to the ATPase pocket and slowing the myosin cycle. Our molecular dynamics simulations mean that the D75N mutation affects myosin S1 function. Both mutations impair cardiac contractility by disrupting thin filament activation. The results offer new insights into the HCM pathogenesis caused by missense mutations in N-terminal domains of cMyBP-C, highlighting the distinct effects of D75N and P161S mutations on cardiac contractile function.
Добавил в систему: Кубасова Наталия Алексеевна

	ИСТИНА	Войти в систему Регистрация
	ИСТИНА ИНХС РАН
	Главная Поиск Статистика О проекте Помощь

ИСТИНА

ИСТИНА ИНХС РАН

The D75N and P161S Mutations in the C0-C2 Fragment of cMyBP-C Associated with Hypertrophic Cardiomyopathy Disturb the Thin Filament Activation, Nucleotide Exchange in Myosin, and Actin–Myosin Interactionстатья

Прикрепленные файлы