December 19, 2003
Cell's Motor Is a Mountain Climber, Not an Inchworm
Researchers have demonstrated that one of the most important
molecular motors for moving cargo within the cell does so with the
hand-over-hand motion of a mountain climber, rather than an
inchworm-like motion.
Their discovery reveals new information about how the tiny motor,
called kinesin, moves membrane components, messenger RNA, signaling
molecules and other cargo along highways called microtubules within the
cell.
“In a broad sense, a better basic understanding of the mechanisms of such motors will have implications for designing new anti-cancer drugs, as well as understadning the function of existing drugs that target these motors.”
Ronald D. Vale
Since similar motors are responsible for moving chromosomes during
cell division, basic understanding of kinesin could inform development
of cancer-fighting drugs that target the cancer cell’s machinery
for reproduction, said the researchers.
The scientists published their findings December 18, 2003, in
Science Express, the online version of the journal
Science. They were led by Paul Selvin of the University of
Illinois at Urbana-Champaign, and Howard Hughes Medical Institute
investigator Ronald
Vale at the University of California, San Francisco.
While most scientists believed that kinesin moved via a
hand-over-hand mechanism, said Vale, some studies have indicated that
it traveled in an inchworm-like mode. “These two competing
theories implied very different mechanisms of how the motility
works,” said Vale. “And if it was an inchworm-like
mechanism, our previous understanding of the motor and its structural
mechanisms would be incorrect.”
To distinguish between the two mechanisms, the scientists used a
tracking technique developed by Selvin and the paper’s first
author Ahmet Yildiz, working in Selvin’s laboratory. In this
technique, fluorescence imaging one nanometer accuracy (FIONA), a
fluorescent dye molecule is attached to the structure to be tracked,
and the motion of the dye molecule is followed with great precision
using a fluorescence-detecting microscope.
The kinesin molecule consists of two motor units (analogous to feet)
that are linked together to a common stalk that attaches to transported
cargo. Previous studies had shown that the kinesin molecule moves along
the microtubule in steps of eight nanometers, or eight billionths of a
meter.
“The tracking technique developed by Paul and his colleagues
is particularly effective for distinguishing between these two models
because of the distinctive differences in how the models would predict
the movement of the feet,” said Vale. “If the inchworm
model is correct, then each foot should move only in eight-nanometer
steps as the kinesin molecule’s center of mass moves. However, if
the kinesin molecule is moving in a hand-over-hand motion, then the
‘rear’ foot should take a step forward of sixteen nanometers
during one cycle, and then zero nanometers during the next
cycle.”
Indeed, Selvin and his colleagues detected approximately
16-nanometer motions of the labeled foot during a cycle. Although they
could not measure movements of zero nanometers, they performed a
statistical analysis of the timing of the kinesin molecule’s
steps, which indicated that one of the two feet did not move during a
cycle.
“So the evidence shows that there is an alternation of
displacement from one step to the other, contradicting the inchworm
model in which both feet are taking equal eight-nanometer steps,”
said Vale.
According to Vale, the new findings regarding kinesin —
together with earlier findings from Selvin’s laboratory about the
motor molecule myosin V — offer new insights into the function and
evolution of such molecules.
“Not all motors are going to move by this mechanism, but what
is unique about myosin V and kinesin is that both are utilized in the
cell for long distance cargo transport,” said Vale. “So it
makes a great deal of sense to have what is called a
‘processive’ motor that can reliably and continuously travel
long distances in a coordinated manner along a track.
“Particularly interesting is that while the processive
mechanisms of myosin V and kinesin are not identical, there are
certainly many similarities between the two,” said Vale.
“Many of these similarities were probably developed through
convergent evolution, in which nature independently evolved a similar
strategy for the same task.”
While such findings about the mechanism of cargo-carrying kinesins
do not have immediate clinical application, said Vale, similar
kinesin-like molecules involved in cell division are the targets of new
anti-cancer drugs that seek to thwart uncontrolled proliferation of
cancer cells.
“So, in a broad sense a better basic understanding of the
mechanisms of such motors will have implications for designing new
anti-cancer drugs, as well as understanding the function of existing
drugs that target these motors,” he said.
Future studies of the kinesin machinery will aim at using different
kinds of fluorescent tags to capture more precise details of how the
kinesin molecule changes its shape during the process of motion, said
Vale.
Such studies involve attaching fluorescent molecules to different
components of the kinesin molecule and measuring how the molecules
transfer energy to one another as the molecule moves. Such energy
transfer will reveal how the distance between components changes during
motion, yielding clues to the mechanism of the molecule’s
movement. These studies will get scientists one step closer to
understanding the molecular details of one of the oldest quests in the
biological sciences- how living organisms can generate purposeful
motion.
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