Strain in the leading head (red) drives myosin forward.

The longest journey may begin with a single step, but, in the case of myosin motor proteins moving along actin filaments, the start of the walking stride has been nearly impossible to observe. Now Burgess et al., reporting on page 983, reveal the prepower stroke conformation of myosin on actin, clearing a major hurdle to understanding myosin activity.

Previous work on myosin has focused primarily on myosin II, which has the unfortunate habit of dissociating from actin in the presence of ATP, making its prepower stroke conformation all but impossible to observe. As motor domains are highly conserved among different myosins, Burgess et al. looked at myosin V, a highly processive motor that drives mRNA, vesicle, and membrane trafficking. By combining electron microscope images of myosin V with crystallographic data from myosin II heads, the authors developed high resolution models of myosin conformations on and off actin and in the presence and absence of ATP.

The results provide a detailed model of myosin movement. When ATP is added to myosin V molecules not on actin, there is a gross change such that the myosin bends by ∼90° at the junction of the motor domain and lever arm. When attached to actin, the leading head has a similar bent structure, but its attachment to the trailing head results in distortion either at the junction of the motor domain and lever arm or throughout the lever arm. When the trailing head detaches, the leading head straightens, and the release of this distortion, combined with the reversal of the bending induced by ATP, drives movement along the actin filament.The work gives strong support to a longstanding hypothesis that ATP-driven shape changes within myosin heads generate motive force, but shows that cycles of distortion are also important. ▪