The order of things: phosphate release or the powerstroke, which does actomyosin do first?

Edward Debold^1*Christopher P Marang²Brent Scott³

• ¹University of Massachusetts Amherst, Amherst, United States
• ²Stanford University, Stanford, United States
• ³William & Mary, Williamsburg, United States

Myosins are a highly conserved super family of motor proteins that are responsible for powering a host of intracellular processes in eukaryotes, from muscle contraction to vesicular transport. Myosins can perform these tasks because they transduce chemical energy, from the hydrolysis of ATP into mechanical work, in the form of a powerstroke. The key event in the transduction process is the putative coupling of Pi release with the powerstroke, however the timing and mechanism of coupling of these events remains unclear. Atomic structures of myosin, captured in intermediate states of its cross-bridge cycle, suggest that Pi-release is required for the powerstroke to occur and therefore must precede the powerstroke. In contrast, most functional assays, that can measure myosin's structural dynamics with sub-millisecond temporal and nanometer spatial resolution, suggest that the powerstroke occurs less than 1ms after forming a strong bond with actin, while Pi-release occurs 10-200ms after binding to actin, suggesting the powerstroke precedes Pi-release. A host of new studies and a few new models have been put forth in recent years to attempt to reconcile these seemingly conflicting findings. While there is not yet a consensus on the order of these events the new information provided by these efforts is transforming our understanding of how myosin transduces energy. This knowledge has important implications for elucidating the molecular basis of a myriad of myosin-associated diseases, and therefore for the development of compounds to treat these diseases.