Purified cardiac myosins undergo rapid switching between SRX and DRX states, refining the understanding of cardiomyopathy mechanisms and the action of mavacamten.
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-heads motif. Using recombinant β-cardiac heavy meromyosin and subfragment 1, which cannot form the interacting-heads motif, 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 or dilated cardiomyopathies alter the SRX-DRX equilibrium, but not all mutations. The cardiac myosin inhibitor mavacamten slows nucleotide release by an equal factor for both heavy meromyosin and subfragment 1, 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.
Cail et al. (Wed,) studied this question.