Conformational Changes in the Myosin Head Couple ATP Hydrolysis to Movement

The results of studies of muscle contraction provided the first evidence that myosin heads slide or walk along actin filaments. Unraveling the mechanism of muscle contraction was greatly aided by the development of in vitro motility assays and single-molecule force measurements. On the basis of information obtained with these techniques and the three-dimensional structure of the myosin head, researchers developed a general model for how myosin harnesses the energy released by ATP hydrolysis to move along an actin filament. Because all myosins are thought to use the same mechanism to generate movement, we will ignore whether the myosin tail is bound to a vesicle or is part of a thick filament as it is in muscle. One assumption in this model is that the hydrolysis of a single ATP molecule is coupled to each step taken by a myosin molecule along an actin filament. Evidence supporting this assumption is discussed in Chapter 19.

As shown in Figure 3-25, myosin undergoes a series of events during each step of movement. In the course of one cycle, myosin must exist in at least three conformational states: an ATP state unbound to actin, an ADP-Pi state bound to actin, and a state after the power-generating stroke has been completed. The major question is how the nucleotide-binding pocket and the distant actin-binding site are mutually influenced and how changes at these sites are converted into force. The results of structural studies of myosin in the presence of nucleotides and nucleotide analogs that mimic the various steps in the cycle indicate that the binding and hydrolysis of a nucleotide cause a

small conformational change in the head domain that is amplified into a large movement of the neck region. The small conformational change in the head domain is localized to a "switch" region consisting of the nucleotide- and actin-binding sites. A "converter" region at the base of the head acts like a fulcrum that causes the leverlike neck to bend and rotate.

Homologous switch, converter, and lever arm structures in kinesin are responsible for the movement of kinesin motor proteins along microtubules. The structural basis for dynein movement is unknown because the three-dimensional structure of dynein has not been determined.

M FIGURE 3-25 Operational model for the coupling of ATP hydrolysis to movement of myosin along an actin filament.

Shown here is the cycle for a myosin II head that is part of a thick filament in muscle, but other myosins that attach to other cargo (e.g., the membrane of a vesicle) are thought to operate according to the same cyclical mechanism. In the absence of bound nucleotide, a myosin head binds actin tightly in a "rigor" state. Step 1: Binding of ATP opens the cleft in the myosin head, disrupting the actin-binding site and weakening the interaction with actin. Step 2|: Freed of actin, the myosin head hydrolyzes ATP causing a conformational change in the head that moves it to a new position, closer to the (+) end of the actin filament, where it rebinds to the filament. Step 3: As phosphate (Pi) dissociates from the ATP-binding pocket, the myosin head undergoes a second conformational change—the power stroke— which restores myosin to its rigor conformation. Because myosin is bound to actin, this conformational change exerts a force that causes myosin to move the actin filament. Step 4: Release of ADP completes the cycle. [Adapted from R. D. Vale and R. A. Milligan, 2002, Science 288:88.]

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