Novel Mutation Glu98Lys in Cardiac Tropomyosin Alters Its Structure and Impairs Myocardial Relaxation

Matyushenko, A.M.; Nefedova, V.V.; Kochurova, A.M.; Kopylova, G.V.; Koubassova, N.A.; Shestak, A.G.; Yampolskaya, D.S.; Shchepkin, D.V.; Kleymenov, S.Y.; Ryabkova, N.S.; Katrukha, I.A.; Bershitsky, S.Y.; Zaklyazminskaya, E.V.; Tsaturyan, A.K.; Levitsky, D.I.

Авторы: Matyushenko Alexander M., Nefedova Victoria V., Kochurova Anastasia M., Kopylova Galina V., Koubassova Natalia A., Shestak Anna G., Yampolskaya Daria S., Shchepkin Daniil V., Kleymenov Sergey Y., Ryabkova Natalia S., Katrukha Ivan A., Bershitsky Sergey Y., Zaklyazminskaya Elena V., Tsaturyan Andrey K., Levitsky Dmitrii I.
Журнал: International Journal of Molecular Sciences
Том: 24
Номер: 15
Год издания: 2023
Издательство: MDPI
Местоположение издательства: Basel, Switzerland
Первая страница: 12359
Последняя страница: 12359
DOI: 10.3390/ijms241512359
Аннотация: We characterized a novel genetic variant c.292G > A (p.E98K) in the TPM1 gene encoding cardiac tropomyosin 1.1 isoform (Tpm1.1), found in a proband with a phenotype of complex cardiomyopathy with conduction dysfunction and slow progressive neuromuscular involvement. To understand the molecular mechanism by which this mutation impairs cardiac function, we produced recombinant Tpm1.1 carrying an E98K substitution and studied how this substitution affects the structure of the Tpm1.1 molecule and its functional properties. The results showed that the E98K substitution in the N-terminal part of the Tpm molecule significantly destabilizes the C-terminal part of Tpm, thus indicating a long-distance destabilizing effect of the substitution on the Tpm coiled-coil structure. The E98K substitution did not noticeably affect Tpm’s affinity for F-actin but significantly impaired Tpm’s regulatory properties. It increased the Ca2+ sensitivity of the sliding velocity of regulated thin filaments over cardiac myosin in an in vitro motility assay and caused an incomplete block of the thin filament sliding at low Ca2+ concentrations. The incomplete motility block in the absence of Ca2+ can be explained by the loosening of the Tpm interaction with troponin I (TnI), thus increasing Tpm mobility on the surface of an actin filament that partially unlocks the myosin binding sites. This hypothesis is supported by the molecular dynamics (MD) simulation that showed that the E98 Tpm residue is involved in hydrogen bonding with the C-terminal part of TnI. Thus, the results allowed us to explain the mechanism by which the E98K Tpm mutation impairs sarcomeric function and myocardial relaxation.
Добавил в систему: Кубасова Наталия Алексеевна

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Novel Mutation Glu98Lys in Cardiac Tropomyosin Alters Its Structure and Impairs Myocardial Relaxationстатья Исследовательская статья

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