Wag the Tail: Structural Dynamics of Actomyosin

reduces rotational mobility of the CD. Upon release of P i from the active site, actomyosin affinity increases and stress is applied to the LC domain. A fulcrum (probably near residue Cys-707, Figure 1) translates this stress into rotation of the neck toward the barbed end of the University of Pennsylvania actin filament (downward in Figures 1 and 2) transmitting Philadelphia, Pennsylvania 19104-6083 force to the tail of myosin and the filament backbone. If the load is movable, the filaments slide and the LC domain tilts downward (states 5 to 6). The neck is Introduction thought to function as a lever arm that magnifies sub-In partnership with actin cytoskeletal filaments, at least nanometer structural changes at the active site into sev-15 classes of myosins accomplish diverse tasks in cell eral nanometers of motion at the LC–tail junction, like motility such as muscle contraction, chemotaxis, cyto-a dog wagging its tail. Filament sliding is followed by kinesis, pinocytosis, targeted vesicle transport and, ADP release and then rapid ATP binding which causes possibly, signal transduction (Mermall et al., 1998). Bio-detachment. ATP is then hydrolyzed to tightly bound chemical and mechanical studies have established the link ADP and P i. Repeated cross-bridge cycles translocate between elementary events in the actomyosin ATPase myosin and its attached cargo toward the barbed end cycle and work output (Cooke, 1997), but the associated of the actin filament. changes in molecular structure are still vague. X-ray Kinesin and polynucleotide motors are processive; crystallography (Rayment et al., 1996), in vitro mechan-i.e., they repeat many mechanochemical cycles before ics of the purified proteins, mutagenesis (Sweeney and dissociating from their filamentous track. Single myo-Holzbaur, 1996), and time-resolved structural studies on sins, however, will not continuously translocate actin in muscle fibers (Irving and Piazzesi, 1997) are providing vitro because actin and myosin diffuse apart after rapid new insights into this problem. Data from of all of these ATP-induced dissociation (state 7 to 1). In muscle, hun-approaches must be integrated to understand energy dreds of molecules in each filament cooperate to sustain transduction by motor proteins. force and sliding, although the number of heads simulta-The typical design in cell motility of a motor protein neously attached is uncertain (Cooke, 1997; Linari et al., sliding along a linear filamentous track was first discovered in muscle cells because these elegant machines express and assemble concentrated and highly periodic interdigitating arrays of myosin and actin filaments that …