April 10, 1998
Sponge Toxin Halts Molecular Motor
An ocean-dwelling sponge may provide a tool for understanding the
molecular motors that power cell division and other intracellular
transport processes, say researchers at the Howard Hughes Medical
Institute at the University of California, San Diego.
A toxin produced by the sponge Haliclona is the first
chemical to be identified that shuts down the ubiquitous cellular motor
proteins known as kinesins, according to Lawrence S. B.
Goldstein, a Hughes investigator. Goldstein and colleagues from the
Scripps Institute of Oceanography (SIO) published their findings in the
April 10 issue of the journal Science.
“A molecular model of the motor protein kinesin.”
Motor molecules that provide the power for cellular transportation
are divided into two superfamilies: dyneins and kinesins. Dyneins move
vesicles and organelles from the periphery of the cell into the cell's
center. Kinesin motors transport freight from the middle of the cell
outward. They also help to separate chromosomes during cell
division.
Transportation within a cell is carried out over a grid of tiny
track-like structures called microtubules. Each type of motor is
composed of two globular domains resembling "feet" that alternately
"step" down the microtubule track, some scientists believe. The feet
balance on the proteins that compose the track, while the other end of
the motor carries the cargo.
The toxin discovered by Goldstein and his colleagues puts a halt to
kinesin's life-sustaining transport by clogging the motor. Goldstein
theorizes that the small toxin mimics the motor's binding site on a
microtubule. The toxin effectively "locks up the motor," he says.
"It's an important proof of principle that the motor can be
inhibited," Goldstein said. With engineering and luck, the sponge toxin
may lead to compounds as powerful as the anticancer drug Taxol. Derived
from the bark of the yew tree, Taxol disrupts deadly cell division in
patients with ovarian cancer. Unfortunately, Taxol also perturbs the
growth of normal cells. It may be possible, Goldstein says, to design a
new drug that is more selective than Taxol based on information gleaned
from studying the sponge toxin.
"There's a universe of things in the natural world that might
ultimately be used therapeutically," Goldstein said. "It's a numbers
game. If you study enough things with odd chemistry, you just might
find what you need."
The rope-like, mauve-colored sponge is a member of the species
Haliclona (also known as Adocia). Scientists from SIO
plucked the sponge from the sea floor near Palau in the Western
Caroline Islands. Soon after returning from Palau, SIO chemist John
Faulkner began analyzing the organism's chemical treasure trove.
"Marine sponges are an amazing source of biologically active
materials," said Faulkner.
Of particular interest to Faulkner are the toxins that these sponges
use to defend themselves. While studying Haliclona, Faulkner
isolated the unusual toxin described in the Science article. In
search of the toxin's biochemical properties, Faulkner teamed up with
Goldstein, an expert in mechanisms involved in intracellular movement.
Goldstein's team analyzed the properties of the toxin and noticed to
their surprise that the toxin, which they named adociasulfate-2
(AS-2), stopped the kinesin motors.
"It has been a long wait for a specific inhibitor of kinesin. Now
the functions of kinesin can be experimentally separated from other
motor systems, such as dyneins and myosins," said Thomas Reese of the
National Institute of Neurological Disorders and Stroke. "AS-2 is the
first of what I am confident will be a family of exquisitely fine tools
with which to manipulate cells for therapeutic as well as experimental
purposes."
Goldstein says that AS-2 alone will not work as a drug because it
cannot permeate a cell's surface. Moreover, it inhibits many kinds of
kinesin motors, not just those responsible for movement during cell
division. Goldstein and his colleagues hope to refine the toxin to
allow inhibition of kinesins with roles in cell division but leave
intact those with other cargo transport capabilities.
Whatever the ultimate fate of AS-2, the scientists say that their
study highlights the potential of marine biomedicine to unlock the
secrets of human physiology.
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