Provides a high-resolution structural framework for how two myosin heads coordinate and integrate with thin filament components during cardiac force generation.
Cardiac contraction is driven by double-headed myosin cycling on cardiac thin filaments, where troponin-tropomyosin regulates myosin access to actin. Prior research used a single-headed myosin bound to bare actin, thereby limiting insight into coordination between myosin heads and the influence of troponin-tropomyosin on actomyosin interactions. Here, we report a high-resolution structure of the native cardiac rigor cross-bridge formed by heavy meromyosin bound to the thin filament. We show that direct communication between the two bound heads, uneven interactions between the heads and tropomyosin, and spatial constraints imposed by troponin govern myosin placement along the thin filament. Additionally, the two heads display non-equivalent motor-light chain interactions, yielding distinct lever-arm conformations indicative of asymmetric intramolecular strain. Together, these findings provide a structural framework for how the two myosin heads coordinate and how the components of the thin filament are integrated into force generation by active cross-bridges.
Risi et al. (Thu,) studied this question.