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Molecular Motor Structural Changes Imaged By Researchers

http://www.medicalnewstoday.com/medicalnews.php?newsid=51984

An international team of researchers has shed new light on how tiny

molecular motors that transport materials within cells generate the

energy that powers their movements.

The knowledge could lead to better understanding of the underlying

mechanisms of a range of human disorders such as Down syndrome caused

by faulty molecular motors, and possibly to the development of new

treatments, the researchers said. For example, molecular motors are

responsible for dividing genetic material during cell division, and

understanding how motors work in cancer cells, which undergo

unchecked cellular division, might lead to new anticancer therapies.

The team, from Duke University Medical Center, the National Institute

of Advanced Industrial Science and Technology in Japan, and the

Medical Research Council's Laboratory of Molecular Biology in the

United Kingdom, reported its findings Sept. 15, 2006, in the journal

Molecular Cell.

The research was supported by the U.S. National Institutes of Health;

Japan's Ministry of Education, Culture, Sports, Science and

Technology; the U.K.'s Medical Research Council, and the Human

Frontiers Science Program, an international agency that funds

innovative research.

As they move nutrients or other cellular loads around the cell,

molecular motors travel along microtubules, infinitesimal " railroad

tracks " within the cell. To date, cell biologists had not been able

to capture actual images of the structural changes that a molecular

motor undergoes as it breaks down adenosine triphosphate (ATP), the

source of energy in all cells, into the power necessary to move along

the microtubules.

" In order to visualize the actual structure of the motor molecule

bound to a microtubule, we combined the images generated by high-

resolution electron microscopy, " said study investigator Sharyn

Endow, Ph.D., a Duke cell biologist. " We were able to see for the

first time the actual point at which the molecular motors attach to

the microtubule. It is at this juncture that the motor undergoes

changes in its structure as it uses ATP to propel itself along the

microtubule. "

Humans are thought to have approximately 45 different molecular

motors -- proteins known as kinesins -- in their bodies. For the

study, Endow and her colleagues chose a kinesin found in baker's

yeast that closely resembles kinesins found in humans, and which is

well understood in terms of structure and biological activity.

Previous work by Endow and colleagues has shown how molecular

motors " walk " along microtubules. But they had not been able to

obtain images of the actual structural changes kinesins undergo as

they move along microtubules.

In the first step toward this breakthrough, the researchers used an

existing technology, electron microscopy, which normally enables

scientists to magnify very small biological structures up to 400,000

times their original size. Electron microscopes use beams of

electrons instead of light to produce images. The images recorded on

electron microscope films are two-dimensional, but three-dimensional

structures of the proteins can be calculated by computer image

processing.

Keiko Hirose, Ph.D., a researcher at Japan's National Institute of

Advanced Industrial Science and Technology, performed the elaborate

and time-consuming electron microscope imaging. She carefully made

multiple images of the kinesin-microtubule units, and performed the

computationally demanding analysis that produced the high-resolution

models of the motor and microtubule structures from the electron

microscope images.

" Fine details are not apparent unless you remove the extraneous noise

from electron microscopy images, " Hirose said. " This is done by

averaging many images to reinforce the common features that show the

structure of the protein molecules. "

Amos, Ph.D., from the U.K.'s Medical Research Council and

senior author of the paper, provided essential advice for the

computational analysis and analyzed the resolutions of the final

images. "

The researchers then took those high-resolution models and combined

them with models of kinesin and microtubule structures rendered using

another technology, x-ray crystallography. In this approach,

scientists send an x-ray beam through a crystallized protein target,

in this case, the motor molecules or microtubules, separately.

Detectors capture the signal as it exits the target and computers re-

create a three-dimensional model. Researchers have not yet been able

to image motors bound to micotubules using x-ray methods due to

technical challenges, they said.

According to the researchers, the new motor-microtubule models

provided structural details of the motor-microtubule interactions

that had not been observed previously.

The researchers believe their findings may lead to new insights into

a number of diseases, including some neuromuscular conditions, such

as Charcot-Marie-Tooth disease. These disorders are thought to be

linked to deficiencies in transport by the molecular motors of

chemical neurotransmitters that carry messages between nerve cells.

Down syndrome, in which chromosomes do not divide properly in egg

cells, also is thought to be caused by defects in kinesins. Finding

methods to stimulate kinesin activity might help in the treatment of

these human diseases, the researchers said.

Conversely, drugs that inhibit kinesin activity might be a potential

approach to slowing the uncontrolled cell division of cancer. For

example, the drug Taxol, which is used to treat breast and ovarian

cancers, works by stabilizing microtubules. But the problem with

using Taxol as a general inhibitor of cell division is that it works

on all dividing cells, not just those involved in tumors or cancers,

and so causes unwanted side effects, such as hair loss.

" With this new information about kinesins and how they interact with

microtubules, the hope is that we will be able to develop drugs that

can target specific kinesins, " Endow said.