The central role of the tail in switching off myosin II in cells

Myosin II is a motor protein playing an essential role in cell motility. The molecule can exist as a polymer that pulls on actin to generate motion, or as an inactive monomer with a compact structure, in which its tail is folded and its two heads interact with each other. This conformation functions in cells as an energy-conserving storage and transport molecule. The mechanism of inhibition is not fully understood. We have carried out a 3D reconstruction of the switched-off form revealing for the first time multiple interactions between the tail and the two heads that trap ATP hydrolysis products, block actin binding, obstruct head phosphorylation, and prevent filament formation. Blocking these essential features of myosin function can explain the high degree of inhibition of the folded form of myosin, serving its energy-conserving, storage function in cells. The structure also suggests a mechanism for unfolding when activated by phosphorylation.