Dynamics of β-cardiac myosin between the super-relaxed and disordered-relaxed states.

Abstract

The super-relaxed (SRX) state of myosin ATPase activity is critical for striated muscle function, and its dysregulation is linked to cardiomyopathies. It is unclear whether the SRX state exchanges readily with the disordered-relaxed (DRX) state, and whether the SRX state directly corresponds to the folded back interacting-head motif (IHM). Using recombinant β-cardiac heavy meromyosin (HMM) and subfragment 1 (S1), which cannot form the IHM, we show that the SRX and DRX populations transition at a rate substantially faster than the ATP turnover rate, dependent on myosin head-tail interactions. Some mutations which cause hypertrophic (HCM) or dilated (DCM) cardiomyopathies alter the SRX-DRX equilibrium, but not all mutations. The cardiac myosin inhibitor mavacamten slows nucleotide release by an equal factor for both HMM and S1, thus only indirectly influencing the occupancy time of the SRX state. These findings suggest that purified myosins undergo rapid switching between SRX and DRX states, refining our understanding of cardiomyopathy mechanisms.