Myosin VI: an innovative motor that challenged the swinging lever arm hypothesis

Abstract

Myosins are mechanoenzymes that convert the chemical energy derived from ATP hydrolysis into mechanical work. The kinetic cycle of myosin-driven movement consists of four basic steps. First, the myosin catalytic head binds ATP, which releases the head from actin. Second, ATP hydrolysis results in a conformational change of the catalytic head into a pre-stroke state. Third, associated with phosphate release, the head rebinds strongly to actin and undergoes a transition from the pre-stroke state to a post-stroke state. Finally, ADP is released from the catalytic head, allowing ATP to rebind to complete the cycle. The relative movement at the actin–myosin interface is thought to come from the swing of the light chain-binding region during the kinetic cycle. The light chain-binding region therefore acts as a lever arm to amplify small movements in the catalytic head. Myosin VI has challenged this swinging lever arm hypothesis as it moves much larger distances than the initial interpretation of its structure would allow. A combination of single molecule, biophysical and biochemical studies have now examined the unique structural features of myosin VI that allow it to function in accordance with the lever arm theory of myosin motion. The tail domain of myosin VI, which contains a globular three-helix bundle and an unusual stable and relatively rigid single ER/K motif-containing α-helix, explains the ability of myosin VI to take large steps along actin filaments. Myosin VI carries out diverse functions in various cellular processes. An exciting new area in myosin VI research, and for molecular motors in general, is understanding how multiple myosin VI molecules coordinate to function in different cellular processes.