Myopathy-causing mutation R91P in the TPM3 gene drastically impairs structural and functional properties of slow...

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, γ and β, are present. They interact to form three types of dimeric Tpm molecules: γγ-homodimers, γβ-heterodimers, or ββ-homodimers, and a majority of the molecules are present as γβ-Tpm heterodimers. Point mutation R91P within the TPM3 gene encoding γ-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 γ-chain on the properties of the γβ-Tpm heterodimer. We found that the R91P mutation impairs the functional properties of γβ-Tpm heterodimer more severely than those of earlier studied γγ-Tpm homodimer carrying this mutation in both γ-chains. Since a significant part of Tpm molecules in slow skeletal muscle is present as γβ-heterodimers, our results explain why this mutation leads to muscle weakness in CFTD.