Effects of Phosphorylation of Tropomyosin with Cardiomyopathic Mutations on Calcium Regulation of Myocardial Contraction

Mutations in the TPM1.1 gene lead to the development of cardiomyopathies. It has been shown that in cardiomyopathies there is a change in the degree of tropomyosin phosphorylation (Tpm). We investigated the molecular mechanisms of the effect of Tpm phosphorylation with mutations associated with dilated (K15N) and hypertrophic (I172T, E180G, and I284V) cardiomyopathies on calcium regulation of actin–myosin interaction using myosin from the atria and ventricles in an in vitro motility assay. Tpm with S283D substitution was used as the phosphorylated form. We found that phosphorylation differently affected regulatory properties of Tpm with mutations depending on their location in the molecule. The phosphorylation did not affect the properties of Tpm with mutations at the N- and C-terminal regions and increased the calcium sensitivity of thin filaments containing Tpm with substitutions in the central part of the molecule. Since hypertrophic cardiomyopathy is accompanied by an increase in the calcium sensitivity, the phosphorylation of the Tpm molecule carrying cardiomyopathic mutations can aggravate the violation of the contractility of the heart chambers.