Why the study?
It was unclear whether the super-relaxed state exchanges readily with the disordered-relaxed state, and whether it directly corresponds to the interacting-head motif.
Purified cardiac myosins undergo rapid switching between SRX and DRX states, and mavacamten slows nucleotide release equally for HMM and S1, refining our understanding of cardiomyopathy mechanisms.
Refines myosin state dynamics in cardiomyopathy models; leaves open translation to human therapeutics.
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 are in rapid equilibrium, 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.
No takes yet. Share an insight, caveat, or question.
Cail et al. (2024) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: