Tropomyosin pseudo-phosphorylation can rescue the effects of cardiomyopathy-associated mutations.

Victoria V Nefedova, Natalia A Koubassova, Vera A Borzova, Sergey Y Kleymenov, Andrey K Tsaturyan, Alexander M Matyushenko, Dmitrii I Levitsky

International journal of biological macromolecules 2021 Jan 01

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We applied various methods to investigate how mutations S283D and S61D that mimic phosphorylation of tropomyosin (Tpm) affect structural and functional properties of cardiac Tpm carrying cardiomyopathy-associated mutations in different parts of its molecule. Using differential scanning calorimetry and molecular dynamics, we have shown that the S61D mutation (but not the S283 mutation) causes significant destabilization of the N-terminal part of the Tpm molecule independently of the absence or presence of cardiomyopathy-associated mutations. Our results obtained by cosedimentation of Tpm with F-actin demonstrated that both S283D and S61D mutations can reduce or even eliminate undesirable changes in Tpm affinity for F-actin caused by some cardiomyopathy-associated mutations. The results indicate that Tpm pseudo-phosphorylation by mutations S283D or S61D can rescue the effects of mutations in the TPM1 gene encoding a cardiac isoform of Tpm that lead to the development of such severe inherited heart diseases as hypertrophic or dilated cardiomyopathies. Copyright © 2020 Elsevier B.V. All rights reserved.

Citation

Victoria V Nefedova, Natalia A Koubassova, Vera A Borzova, Sergey Y Kleymenov, Andrey K Tsaturyan, Alexander M Matyushenko, Dmitrii I Levitsky. Tropomyosin pseudo-phosphorylation can rescue the effects of cardiomyopathy-associated mutations. International journal of biological macromolecules. 2021 Jan 01;166:424-434