Structural biologists are good at producing static snapshots of proteins, but seeing them in action is the ultimate goal. This is exactly what Kodera et al. have achieved in a remarkable study that appears elsewhere in this issue (N. Kodera, D. Yamamoto, R. Ishikawa and T. Ando Nature 468, 72–76; 2010). They have been able to directly visualize myosin V, a cytoskeletal motor protein, as it 'walks' along actin filaments.
The authors have developed a high-speed atomic force microscopy (HS-AFM) method that enables them to generate rapid images of proteins at much higher resolution than light microscopy. Here they apply this technological advance to visualize the stepwise movement of myosin V. The protein consists of two heads connected by long necks (lever arms) to a globular tail domain through a coiled-coil helix. The tail binds to various cargo molecules to transport them along the actin filaments, the energy required being generated by hydrolysis of ATP to ADP.
The HS-AFM images showing the leading (L) and trailing (T) heads of the tail-truncated motor can be seen in Figure 1a of the paper on page 73, part of which is reproduced here. In frame 1, myosin is advancing from the left; in frames 2 and 3, it has marched into full view, the two heads and necks now being visible; in frame 4, it has moved on a step. See http://go.nature.com/DHBOY9 for the full movie.
The authors' analysis confirms the known behaviour of myosin motors, including the use of successive 36-nanometre steps along the actin filament and the 'hand-over-hand' movement of the motor heads. However, the study also provides convincing evidence for the hypothesized 'lever-arm swing'. In this feature, tiny changes in myosin's head domain are amplified by the lever arm to produce large displacements at the far end of the neck that translate into movement of the whole protein along the actin filaments.
The new analysis also uncovers novel characteristics of the myosin V mechanism, such as a 'stomping' behaviour, in which either the L or T head becomes detached then rebinds to actin. The stomp is observed more frequently for the L than for the T head, but the T-head stomp often leads to a forward movement on the actin filament.
The insight into the behaviour of myosin V that Kodera et al. reveal will have a major impact on understanding the mechanisms involved in biological molecular motors. More generally, the technological advance provided by HS-AFM looks set to take a prominent place in the field of biomolecular imaging.
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Nath, D. Myosin in motion. Nature 468, 43 (2010). https://doi.org/10.1038/468043a