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Tropomyosin is a two-chain coiled coil protein, which together with the troponin complex controls interactions of actin with myosin in a Ca 2+ -dependent manner. In fast skeletal muscle, the contractile actin filaments are regulated by tropomyosin isoforms Tpm1.1 and Tpm2.2, which form homo- and heterodimers. Mutations in the  TPM2  gene encoding isoform Tpm2.2 are linked to distal arthrogryposis and congenital myopathy—skeletal muscle diseases characterized by hyper- and hypocontractile phenotypes, respectively. In this work, in vitro functional assays were used to elucidate the molecular mechanisms of mutations Q93H and E97K in  TPM2 . Both mutations tended to decrease actin affinity of homo-and heterodimers in the absence and presence of troponin and Ca 2+ , although the effect of Q93H was stronger. Changes in susceptibility of tropomyosin to trypsin digestion suggested that the mutations diversified dynamics of tropomyosin homo- and heterodimers on the filament. The presence of Q93H in homo- and heterodimers strongly decreased activation of the actomyosin ATPase and reduced sensitivity of the thin filament to [Ca 2+ ]. In contrast, the presence of E97K caused hyperactivation of the ATPase and increased sensitivity to [Ca 2+ ]. In conclusion, the hypo- and hypercontractile phenotypes associated with mutations Q93H and E97K in Tpm2.2 are caused by defects in Ca 2+ -dependent regulation of actin–myosin interactions.

Mutations Q93H and E97K in TPM2 Disrupt Ca-Dependent Regulation of Actin Filaments