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Effects of Phosphorylation of Tropomyosin with Cardiomyopathic Mutations on Calcium Regulation of Myocardial Contraction

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Abstract

Mutations in the TPM1.1 gene lead to the development of cardiomyopathies. It has been shown that in cardiomyopathies there is a change in the degree of tropomyosin phosphorylation (Tpm). We investigated the molecular mechanisms of the effect of Tpm phosphorylation with mutations associated with dilated (K15N) and hypertrophic (I172T, E180G, and I284V) cardiomyopathies on calcium regulation of actin–myosin interaction using myosin from the atria and ventricles in an in vitro motility assay. Tpm with S283D substitution was used as the phosphorylated form. We found that phosphorylation differently affected regulatory properties of Tpm with mutations depending on their location in the molecule. The phosphorylation did not affect the properties of Tpm with mutations at the N- and C-terminal regions and increased the calcium sensitivity of thin filaments containing Tpm with substitutions in the central part of the molecule. Since hypertrophic cardiomyopathy is accompanied by an increase in the calcium sensitivity, the phosphorylation of the Tpm molecule carrying cardiomyopathic mutations can aggravate the violation of the contractility of the heart chambers.

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Acknowledgments

The authors would like to thank V.Y. Berg for her assistance in the in vitro motility assay experiments.

Funding

This work was funded by the Russian Foundation for Basic Research grants 20-04-00130 (S.B.), State Program 122022200089-4 (S.B.), and State Program 122041100022-3 (A.M.). The work was performed using the equipment of the Shared Research Center of Scientific Equipment of IIP UB RAS and the equipment of the Shared-Access Equipment Centre “Industrial Biotechnology” of Federal Research Center “Fundamentals of Biotechnology” of the RAS.

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Authors and Affiliations

  1. Institute of Immunology and Physiology, Russian Academy of Sciences, Yekaterinburg, Russia

    G. V. Kopylova, A. M. Kochurova, S. Y. Bershitsky & D. V. Shchepkin

  2. A.N. Bach Institute of Biochemistry, Research Center of Biotechnology, Russian Academy of Sciences, Moscow, Russia

    A. M. Matyushenko

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  1. G. V. Kopylova
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  2. A. M. Matyushenko
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Contributions

G.V.K., A.M.M., S.Y.B., and D.V.S. conceptualized the work; A.M.M. expressed of tropomyosins; G.V.K., A.M.K., and D.V.S. performed in vitro motility experiments and analyzed data; G.V.K., S.Y.B., and D.V.S. wrote the manuscript; all authors read and approved the manuscript.

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Correspondence to G. V. Kopylova.

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Translated by A. Polyanovsky

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Kopylova, G.V., Matyushenko, A.M., Kochurova, A.M. et al. Effects of Phosphorylation of Tropomyosin with Cardiomyopathic Mutations on Calcium Regulation of Myocardial Contraction. J Evol Biochem Phys 58 (Suppl 1), S82–S91 (2022). https://doi.org/10.1134/S0022093022070092

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