Role of tropomyosin dynamics in regulation of cardiac muscle in health and disease
Background
Muscle contraction is powered by the interaction of contractile proteins, myosin and actin that form the thick and thin filaments in the skeletal and cardiac muscles. The contraction-relaxation cycle is controlled by Ca2+ ions via regulatory proteins, troponin (Tn) and tropomyosin (Tpm), associated with the thin actin filaments. Tpm is a long coiled-coil protein that polymerises into a long strand on the surface of the thin filament. In the absence of Ca2+, Tn binds actin and keeps the Tpm strand in a blocking position where it prevents myosin binding to actin. Upon Ca2+ binding to Tn, the Tpm strand releases from the blocking position, myosin binds actin and generates active force. The Ca2+-regulation depends on many factors including Tpm properties. Theoretical analysis suggests that bending stiffness of Tpm is important for the regulation. Some mutations in Tpm are believed to be associated with myopathies or cardiomyopathies.
Aims
To study the structural and functional role of some conserved Tpm residues and the molecular mechanisms of pathogenicity of some Tpm mutations.
Methods
A combined approach based on an experimental study of structural and functional properties of recombinant Tpm with various amino acid substitutions or posttranslational modification and the molecular dynamics (MD) simulation was employed.
Results
The non-canonical Tpm residues D137 and E218 that destabilize the Tpm coiled-coil are important for its proper regulation of the actin-myosin interaction. The formation of a disulphide bridge between residues Cys190 of two Tpm chains destabilizes the Tpm molecule and might be involved in the development of heart failure upon hypoxia while the phosphorylation (pseudo-phosphorylation) of Tpm residues S283 and S61 mutations can reduce or even eliminate undesirable changes in functional properties of Tpm caused by some cardiomyopathy-associated mutations.
Conclusions
MD simulation is a useful tool for understanding the mechanisms of the regulation of cardiac muscle and its impairment in some genetic cardiomyopathies.