Calcium gets myosin VI ready for work

The myosins are a large family of actin-binding motor proteins that convert stored chemical energy into work, with important functions in intracellular transport, force generation, and mechanosensation (1). Despite many advances in understanding the mechanical and kinetic properties of purified myosins in vitro, the signals that regulate the functions of these molecular motors in cells are not well characterized. In PNAS, Batters et al. (2) identify a key regulatory function for the universal intracellular signal calcium (Ca2+) in the control of myosin VI activation. Myosin VI is the only myosin that moves toward the minus end of actin filaments and contains many unusual structural features (3). Batters et al. (2) show that for this myosin Ca2+ links motor activation to cargo binding in a stepwise process by controlling the orientation and interactions of its binding protein calmodulin (CaM). Whereas Ca2+ has been shown to exert structural effects on other myosins, Batters et al. (2) unravel another distinct and unusual mechanism used by this most unconventional myosin. All myosin motors contain essentially three domains: a highly conserved N-terminal actin binding head domain, a lever arm, and a tail domain, which may contain coiled-coils that mediate dimerization and/or specialized cargo-binding domains (CBD). The N-terminal head domain is an actin-activated ATPase that undergoes conformational changes coupled to the hydrolysis of ATP (4). The lever arm, typically containing one or several IQ motifs, amplifies these relatively small (angstrom) movements within the head domain into nanometer displacements of the tail. Association of the Ca2+-binding protein CaM with the IQ motifs confers structural stability to the lever arm, enabling mechanical coupling between the head and tail domains. Variations in ATPase kinetics and lever arm structure and length across the different myosins translate into different molecular functions such as transport or tethering. … [↵][1]1To whom correspondence should be addressed. Email: tam55{at}cam.ac.uk. [1]: #xref-corresp-1-1