Myosin VI

Figure 1: Models of MVI docked to actin that show the step size variability of Myosin VI. The rear head (bottom) is modeled in the rigor-like state with the converter in the conventional conformation (position 0). The leading heads (top) are modeled in the PPS state drawn in red at positions 11, 13, and 15. The numbers indicate the actin monomers relative to 0. The corresponding distances are 30.7nm, 36.1nm and 41.5nm,

A recent Xray structure of myosin VI indicates that the large step size can be explained in part by a novel conformation of the "converter'' subdomain in the prepowerstroke state, in which a 53-residue insert, unique to myosin VI, reorients the lever arm nearly parallel to the actin filament (see Figure 2). To determine whether the existence of the novel converter conformation could contribute to the step-size variability, a path-based free energy simulation tool, the String Method, was used to show that there is a small free energy difference between the novel converter conformation and the conventional conformation found in other myosins. This result suggests that myosin VI can bind to actin with the converter in either conformation. Models of MVI/MV chimeric dimers show that the variability in the tilting angle of the lever arm resulting from the two converter conformations can lead to step size variations ~12nm. These variations, in combination with other proposed mechanisms, could explain the experimentally determined step-size variability of ~25nm for wild-type MVI.