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."
Linda 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.
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