Molecular Mechanisms of Muscle Weakness Associated with E173A Mutation in Tpm3.12. Troponin Ca2+ Sensitivity Inhibitor W7 Can Reduce the Damaging Effect of This Mutation

Yurii S. Borovikov, Armen O. Simonyan, Stanislava V. Avrova, Vladimir V. Sirenko, Charles S. Redwood, Olga E. Karpicheva

Результат исследований: Научные публикации в периодических изданияхстатья

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Аннотация

Substitution of Ala for Glu residue in position 173 of γ-tropomyosin (Tpm3.12) is associated
with muscle weakness. Here we observe that this mutation increases myofilament Ca2+-sensitivity
and inhibits in vitro actin-activated ATPase activity of myosin subfragment-1 at high Ca2+. In order
to determine the critical conformational changes in myosin, actin and tropomyosin caused by the
mutation, we used the technique of polarized fluorimetry. It was found that this mutation changes
the spatial arrangement of actin monomers and myosin heads, and the position of the mutant
tropomyosin on the thin filaments in muscle fibres at various mimicked stages of the ATPase cycle.
At low Ca2+ the E173A mutant tropomyosin shifts towards the inner domains of actin at all stages of
the cycle, and this is accompanied by an increase in the number of switched-on actin monomers and
myosin heads strongly bound to F-actin even at relaxation. Contrarily, at high Ca2+ the amount of the
strongly bound myosin heads slightly decreases. These changes in the balance of the strongly bound
myosin heads in the ATPase cycle may underlie the occurrence of muscle weakness. W7, an inhibitor
of troponin Ca2+-sensitivity, restores the increase in the number of myosin heads strongly bound to
F-actin at high Ca2+ and stops their strong binding at relaxation, suggesting the possibility of using
Ca2+-desensitizers to reduce the damaging effect of the E173A mutation on muscle fibre contractility.
Язык оригиналаанглийский
Номер статьи4421
Число страниц17
ЖурналInternational Journal of Molecular Sciences
Том21
Номер выпуска12
СостояниеОпубликовано - 22 июн 2020
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