Journal
FASEB JOURNAL
Volume 34, Issue 10, Pages 13507-13520Publisher
WILEY
DOI: 10.1096/fj.202001318R
Keywords
actin-myosin interaction; Ca2+-regulation of muscle contraction; in vitro motility assay; myopathic mutations; slow skeletal muscles; tropomyosin
Categories
Funding
- Russian Science Foundation [16-14-10199]
- Ministry of Science and Higher Education of the Russian Federation [AAAA-A19-119010590010-3, AAAA-A18-118020590135-3]
- Russian Science Foundation [19-14-13032] Funding Source: Russian Science Foundation
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Several congenital myopathies of slow skeletal muscles are associated with mutations in the tropomyosin (Tpm)TPM3gene. Tropomyosin is an actin-binding protein that plays a crucial role in the regulation of muscle contraction. Two Tpm isoforms, gamma (Tpm3.12) and beta (Tpm2.2) are expressed in human slow skeletal muscles forming gamma gamma-homodimers and gamma beta-heterodimers of Tpm molecules. We applied various methods to investigate how myopathy-causing mutations M9R, E151A, and K169E in the Tpm gamma-chain modify the structure-functional properties of Tpm dimers, and how this affects the muscle functioning. The results show that the features of gamma gamma-Tpm and gamma beta-Tpm with substitutions in the Tpm gamma-chain vary significantly. The characteristics of the gamma gamma-Tpm depend on whether these mutations located in only one or both gamma-chains. The mechanism of the development of nemaline myopathy associated with the M9R mutation was revealed. At the molecular level, a cause-and-effect relationship has been established for the development of myopathy by the K169E mutation. Also, we described the structure-functional properties of the Tpm dimers with the E151A mutation, which explain muscle weakness linked to this substitution. The results demonstrate a diversity of the molecular mechanisms of myopathy pathogenesis induced by studied Tpm mutations.
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