“Microtubules are often considered the passive track for movement to occur on,” says Eva Nogales, an HHMI investigator at the University of California, Berkeley. “But in the cell they are extremely dynamic.”

As a model for understanding how microtubules shrink and grow, Nogales studies mitosis, the process by which a cell copies and divides its genetic material to separate into two cells. Once the cell divvies up its chromosomes—the structures that contain the genetic material—microtubules pull the chromosomes to opposite sides of the cell. Kinetochore proteins enable this movement by linking microtubules to a special region in each chromosome and then remaining attached as the microtubules shrink or grow. When the microtubules shorten at the proper time, the two copies of each chromosome—each attached to one set of tubules—separate. Nogales wants to know how the cell regulates this process and how the many other steps in mitosis are coordinated with microtubule arrangement and movement. Using cryoelectron microscopy, her lab group has shown how kinetochore proteins bind to microtubules and allow movement of chromosomes.

“Microtubules are often considered the passive track for movement to occur on. But in the cell they are extremely dynamic.”

Eva Nogales

“Somehow there has to be a feedback between the checkpoint that allows mitosis to proceed and the microtubules,” says Nogales. That feedback is mediated by phosphorylation of the protein complexes that tether microtubules to the chromosomes. To visualize the effect of this phosphorylation on the microtubule-chromosome attachments, Nogales has turned again to cryoelectron microscopy.

“Our studies are ultimately just snapshots in a movie that is very dynamic,” says Nogales. As technology evolves, she says, the process will become even clearer.

Disassembly and Reassembly of Tubulin into Microtubules
A computer animation of the disassembly and reassembly of tubulin into microtubules, illustrating the existence of structural intermediates and their relationship to the nucleotide state.
Credit: Produced for HHMI by Stylus Visuals, Kensington, California.

Like research on kinesin and dynein, understanding the role of microtubules in mitosis has applications in human health. For example, stopping the rearrangement of microtubules during cell division, or the separation of chromosomes, is one way to halt the out-of-control growth seen in cancer cells. Already, the drug Taxol (paclitaxel) is being used to treat some types of cancer, where it stops microtubules from rearranging, thus blocking mitosis and cell division. The company Cytokinetics is investigating additional drugs that target kinesin motors for treating cancer.

And as Nogales has probed deeper into the biological details of microtubules, she’s realized that their processes for shrinking and growing provide an interesting means of intracellular transportation of cargo. Her goal is to understand these processes at the molecular level.

“In addition to microtubules enabling the movement of these motor proteins, they’re also growing and shrinking themselves at the same time,” explains Nogales. “So the cell can actually couple this growing and shrinking with the movement of materials. They do this by a process that we are barely starting to understand.”

Scientists have shown, she says, that as microtubules grow, some proteins hop on and off the tips of the developing roads. It’s like getting a ride across the country by grabbing onto the back of a cement roller as it builds a new road, rather than paying for a bus. Many of the proteins that hitch a ride in this way are ultimately involved in contact with the outer membranes of cells. By riding the tip of a growing microtubule, a protein is assured a prime spot at the membrane when the microtubule reaches it. The process, Nogales thinks, could allow proteins to move to a distinct location without using energy.

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