An Interplay between Protein Disorder and Structure Confers the Ca2+ Regulation of Striated Muscle

The troponin (Tn) complex regulates the thin filament of striated muscle by transducing [Ca2+] fluctuations into conformational changes. These changes propagate to tropomyosin (Tm), which then assumes a new disposition with respect to actin, reversibly exposing actinʹs binding sites for the thick filament motor-ATPase (myosin). To date, the structural biology of thin filament regulation has been studied in the context of two equilibrium states corresponding to high (contraction-activated) and low (contraction-inhibited) sarcomeric [Ca2+]. New electron micrographic reconstructions of the thin filament have resolved Tn, actin, and Tm in high and low [Ca2+] states, integrating high-resolution structures of the Tn core, actin, and Tm. The resultant picture of thin filament regulation does not resolve all of the functionally significant portions of troponin I (TnI) or troponin C (TnC). Those regions of Tn have been shown (using NMR relaxation spectroscopy) to undergo conformational fluctuations, rationalizing the absence of these regions from micrograph-based reconstructions. The disordered portions of Tn are, to date, being interpreted within a canonical structure–activity paradigm.