Key result
Transient time-resolved FRET revealed that actin initiates the myosin power stroke before phosphate dissociation, supporting a model where power output is tuned by myosin structural states.
The study demonstrates that actin initiates the myosin power stroke before phosphate dissociation, challenging previous models of muscle contraction.
Hypothesis-generating for myosin-targeted therapies in cardiomyopathy; leaves open clinical translation pending intact-system validation.
A principal goal of molecular biophysics is to show how protein structural transitions explain physiology. We have developed a strategic tool, transient time-resolved FRET [(TR)(2)FRET], for this purpose and use it here to measure directly, with millisecond resolution, the structural and biochemical kinetics of muscle myosin and to determine directly how myosin's power stroke is coupled to the thermodynamic drive for force generation, actin-activated phosphate release, and the weak-to-strong actin-binding transition. We find that actin initiates the power stroke before phosphate dissociation and not after, as many models propose. This result supports a model for muscle contraction in which power output and efficiency are tuned by the distribution of myosin structural states. This technology should have wide application to other systems in which questions about the temporal coupling of allosteric structural and biochemical transitions remain unanswered.
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Muretta et al. (2015) studied this question. Transient time-resolved FRET [(TR)(2)FRET] was evaluated on Structural and biochemical kinetics of muscle myosin. Transient time-resolved FRET revealed that actin initiates the myosin power stroke before phosphate dissociation, supporting a model where power output is tuned by myosin structural states.
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