How
Two-Foot Molecular Motors May Walk
Kazuhiko Kinosita, Jr.1,
M. Yusuf Ali1,2, Kengo Adachi1, Katsuyuki Shiroguchi1, and Hiroyasu Itoh1,3,4
1Okazaki Institute for Integrative Bioscience, National Institutes of Natural Sciences, Higashiyama 5-1,
Myodaiji,
2Department of Physics, Faculty of Physical
Sciences, Shahjalal
3Tsukuba Research Laboratory,
Myosins
and kinesins each constitute a large family of linear molecular motors that
track along a filamentous rail, myosins along an actin filament and kinesins
along a microtubule. These motors
are powered by free energy derived from ATP hydrolysis, and their mechanisms of
chemo-mechanical conversion have been under intensive study. Most of myosins and kinesins have two
globular domains that bind to the filamentous rail and that hydrolyze ATP in a
rail-dependent manner. The two
domains are usually called ‘heads’ and are connected via a neck-like structure
to a common stalk. Some of the
two-headed motors are processive, in that a single molecule moves along a rail
for many ATPase cycles without detaching from the rail. These processive motors appear to ‘walk,’
using the two heads alternately in a hand-over-hand fashion, as has recently
been demonstrated for myosin V and conventional kinesin. How, then, do they walk forward even in
the presence of a backward load? For
the discussion of walking mechanisms, let us call the heads ‘feet’ and necks ‘legs.’ So far, researchers working on myosin
and kinesin had somewhat different views.
Myosin’s legs are reinforced with light chains and are likely stiff. A prevailing theory thus states that a
landed leg acts as a lever: when a landed ankle is bent forward, the leg leans
forward, carrying the body forward.
The lifted leg thus easily finds a forward landing site. Kinesin’s legs, in contrast, are
flexible and unlikely to serve as a stiff lever. Instead, a lower part of a landed leg
docks onto the landed foot such that the upper leg emerges from a forward part
of the foot. This biases the
Brownian motion of the lifted foot forward, and the foot lands on a forward
site. The relatively small bias
could be efficient, because kinesin’s legs are short and must be fully extended
to reach a forward or backward site: of the two sites that are available, only
the forward site can be reached after the docking. Recently, we have shown that myosin VI,
hitherto considered to be short-legged, walks with the longest strides known. There is an indication that the legs are
actually long, an upper portion being flexible over a sizable length. Then, myosin VI walks almost like
kinesin, relying on biased diffusion.
In myosin V, too, the lifted foot likely undergoes diffusion. Thus, myosin and kinesin both appear to
walk forward by biasing the diffusion of the lifted foot by an action of the
landed ankle, either lever action or docking. Is it really so? Such a mechanism, alone, would not work properly
when the body is pulled backward, particularly when the legs are flexible. Yet these motors are known to move
forward under a few pN of backward load.
We propose that the ankle action in the lifted foot is equally, or probably
more, important: toe up-down in the lifted foot will orient the sole correctly
such that landing on a forward site is favored over a backward site even if the
body is pulled backward. The toe
up-down mechanism warrants forward motion even if legs are completely flexible.