WASHINGTON, May 24, 2001 — No matter how luxurious or sporty your car may be, it’s pretty useless unless it actually gets you where you want to go. Similarly, every living cell needs a system for moving its contents around. That system could eventually give scientists new ways to build molecular machines or to fight disease, from Alzheimer’s and Parkinson’s to cancer.
Cells are the ultimate multitaskers: They can switch on genes and carry out their orders, talk to each other, divide in two, and much more, all at the same time. But they couldn’t do any of these tricks without a power source to generate movement.
The inside of a cell bustles with more traffic than the L.A. freeway system, and, like all vehicles, the cell’s moving parts need engines. In the April 7 issue of Science, physicists and biologists looked “under the hood” of the cell - and laid out the nuts and bolts of molecular engines.
The ability of such engines to convert chemical energy into motion is the envy of nanotechnology researchers looking for ways to power molecule-sized devices. Medical researchers also want to understand how these engines work. Because these molecules are essential for cell division, scientists hope to shut down the rampant growth of cancer cells by deactivating certain motors. Improving motor-driven transport in nerve cells may also be helpful for treating diseases such as Alzheimer’s, Parkinson’s or ALS, also known as Lou Gehrig’s disease.
Rowers and walkers
We wouldn’t make it far in life without motor proteins. Our muscles wouldn’t contract. We couldn’t grow, because the growth process requires cells to duplicate their machinery and pull the copies apart. And our genes would be silent without the services of messenger RNA, which carries genetic instructions over to the cell’s protein-making factories.
The movements that make these cellular activities possible occur along a complex network of threadlike fibers, or polymers, along which bundles of molecules travel like streetcars. The engines that power the cell’s freight are three families of proteins, called myosin, kinesin and dynein. For fuel, these proteins burn molecules of ATP, which cells make when they break down the carbohydrates and fats from the foods we eat.
The energy from burning ATP causes changes in the proteins’ shape that allow them to heave themselves along the polymer track. The results are impressive: In one second, these molecules can travel between 50 and 100 times their own diameter. If a car with a 5-foot-wide engine were as efficient, it would travel 170 to 340 mph.
Ronald Vale, a researcher at the Howard Hughes Medical Institute and the University of California at San Francisco, and Ronald Milligan of the Scripps Research Institute have realized a long-awaited goal by reconstructing the process by which myosin and kinesin move, almost down to the atom. The dynein motor, on the other hand, is still poorly understood.
Myosin molecules, best known for their role in muscle contraction, form chains that lie between filaments of another protein called actin. Each myosin molecule has a tiny head that pokes out from the chain like oars from a canoe. Just as rowers propel their boat by stroking their oars through the water, the myosin molecules stick their heads into the actin and hoist themselves forward along the filament.
While myosin moves along in short strokes, its cousin kinesin walks steadily along a different type of filament called a microtubule. Instead of using a projecting head as a lever, kinesin walks on two “legs.”
Based on these differences, researchers used to think that myosin and kinesin were virtually unrelated. But newly-discovered similarities in the motors’ ATP-processing machinery now suggest that they share a common ancestor molecule. At this point, scientists can only speculate as to what type of primitive cell-like structure this ancestor occupied as it learned to burn ATP and use the energy to change shape.
“We’ll never really know, because we can’t dig up the remains of ancient proteins, but that was probably a big evolutionary leap,” says Vale.
Springs and ratchets
On a slightly larger scale, loner cells like sperm or infectious bacteria are prime movers that resolutely push their way through to other cells. As L. Mahadevan and Paul Matsudaira of the Massachusetts Institute of Technology explain in a second Science article, the engines in this case are springs or ratchets that are clusters of molecules, rather than single proteins like myosin and kinesin. Researchers don’t yet fully understand these engines’ fueling process or the details of how they move, but the result is a force to be reckoned with.
Springs like this are coiled bundles of filaments that expand or contract in response to chemical cues. A wave of positively charged calcium ions, for example, neutralizes the negative charges that keep the filaments extended. Some sperm use springlike engines made of actin filaments to shoot out a barb that penetrates the layers that surround an egg. And certain viruses use a similar apparatus to shoot their DNA into the host’s cell.
Ratchets are also useful for moving whole cells, including some other sperm and pathogens. These engines are filaments that simply grow at one end, attracting chemical building blocks from nearby. Because the other end is anchored in place, the growing end pushes against any barrier that gets in its way.
Both springs and ratchets are made up of small units that each move just slightly, but collectively produce a powerful movement. Ultimately, Mahadevan and Matsudaira hope to better understand just how these particles create an effect that seems to be so much more than the sum of its parts.
Might such an understanding provide inspiration for ways to power artificial nano-sized devices in the future? “The short answer is absolutely,” says Mahadevan. “Biology has had a lot more time to evolve enormous richness in design for different organisms. Hopefully, studying these structures will not only improve our understanding of the biological world, it will also enable us to copy them, take apart their components and re-create them for other purposes.”
© 2013 American Association for the Advancement of Science