Myopathy-causing mutation R91P in the TPM3 gene drastically impairs structural and functional properties of slow skeletal muscle tropomyosin æ-heterodimer

Tropomyosin (Tpm) is a regulatory actin -binding protein involved in Ca2+ activation of contraction of striated muscle. In human slow skeletal muscles, two distinct Tpm isoforms, gamma and beta, are present. They interact to form three types of dimeric Tpm molecules: gamma gamma-homodimers, gamma beta-heterodimers, or beta beta-homodimers, and a majority of the molecules are present as gamma beta-Tpm heterodimers. Point mutation R91P within the TPM3 gene encoding gamma-Tpm is linked to the condition known as congenital fiber -type disproportion (CFTD), which is characterized by severe muscle weakness. Here, we investigated the influence of the R91P mutation in the gamma-chain on the properties of the gamma beta-Tpm heterodimer. We found that the R91P mutation impairs the functional properties of gamma beta-Tpm heterodimer more severely than those of earlier studied gamma gamma-Tpm homodimer carrying this mutation in both gamma-chains. Since a significant part of Tpm molecules in slow skeletal muscle is present as gamma beta-heterodimers, our results explain why this mutation leads to muscle weakness in CFTD.