Se p 20 05 Influence of fluctuations in actin structure on myosin V step size

Myosin V is a motor protein from the myosin superfamily, involved in various intracellular transport processes [1]. It is a processive motor [2], which means that a single protein molecule can transport cargoes along actin filaments over distances of several micrometers. It is dimeric, consisting of two identical heads, each attached to a lever arm, joined with each other through a tail domain. It achieves processivity by alternately binding its two heads to an actin filament and thus walking in a hand-over-hand fashion [3]. Its step size is roughly determined by the periodicity of the actin filament, which is about 36 nm. In comparison with muscle myosin (myosin II), two major adaptations are found in myosin V: a longer leverarm, measuring around 26 nm [4] and a slower release of ADP. The duty cycle of each head is otherwise similar [5]: the head binds to actin in the ADP.Pi state, first releases Pi and performs a large conformational change (power stroke), then releases ADP and performs a smaller conformational change, and finally binds a new ATP molecule and detaches from actin. In a recent article [6], we have developed a model for myosin V, based on the elasticity of the lever arm. It assumes that the lever arm is stiffly anchored in the head, but the direction depends on the chemical state of that head. The distal ends of the lever arms are connected together through a flexible hinge, which represents the only means of “communication” between the heads. By calculating the bending energies in all relevant dimer states and its influence on transition rates, we have shown that the elastic lever-arm model explains the coordinated hand-over-hand motility by showing that the lead head is not likely to bind to actin before the trail head undergoes the major power stroke and that it cannot commit its power stroke before the trail head unbinds. The model also quantitatively reproduces the measured force-velocity relations and shows how the run length (the average distance a motor runs processively before it dissociates from actin) could be used to determine some kinetic rates. Although the original model reproduces the step size corresponding to about one halfturn of the actin helix (13 actin subunits), there is a small but significant deviation between the predicted distribution of step sizes (mainly on the 13th subunit, with a side peak on the 11th) and the statistics obtained from elec0 2 4 9 1113