Myosin VI deafness mutation prevents the initiation of processive runs on actin

Significance

A number of molecular motors transport cargoes long distances on their cellular tracks as single, dimeric (two-headed) molecules. This processive movement requires specialized kinetic properties (high duty ratio) to ensure that each head of the dimeric motor spends most of its time tightly bound to its track. Additionally, processive motors exhibit intramolecular communication between the heads, called gating, whose importance is less clear. By examining a mutation in the reverse-direction myosin motor, myosin VI, that causes deafness, we provide evidence that the mutation destroys the initiation of processive runs under physiological ATP concentration. We further demonstrate that this defect may be amendable to correction by small-molecule therapeutics.