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FEATURES: One Foot in Front of the Other
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For devising ways to study molecular motors in detail, Ronald Vale, along with colleagues Michael Sheetz and James Spudich, received the 2012 Lasker Basic Medical Research Award.
Beyond that, some of the goods must first be packaged and then picked up by vehicles that follow an ever-changing highway to the right destination.
In the past half-century, scientists have revealed how cells build these thoroughfares, and they’ve uncovered specialized proteins that walk along the roads’ lengths carrying freight. But plenty of questions remain: How does the cell control the transportation? How do the walking proteins coordinate their steps to keep grounded on their tracks? How can materials hitch a ride on cellular freeways if there isn’t energy to spare?
“It’s become clear that there is an enormous platter of movements that have to be executed by the cell,” says HHMI investigator Ronald Vale of the University of California, San Francisco. “Chromosomes have to be separated, a cell has to pinch in two, materials made in one place have to be delivered to another place in the cell. All of those features of life are dependent on physical motion.”
“It’s become clear that there is an enormous platter of movements that have to be executed by the cell.”
That physical motion is generated by three types of molecular motors that can walk down tracks inside cells: myosin, which walks on actin filaments, and two microtubule motors—kinesin, which carries cargo from the center of a cell outward, and dynein (the largest and least understood), which carries cargo from the periphery toward the cell’s center. Most of the motors in the cell have “two feet,” which alternate steps as they move. But each protein also has distinct quirks in its movement, a unique form of regulation, and a different role in keeping cells alive.
Research by HHMI investigators and others has revealed that when any of the molecular motors fails, it causes not only traffic jams and lost messages but also faulty construction and demolition of the cells’ roads, and that can lead to disease. Understanding the process better, scientists think, can help them learn how to rev up the engines of the motors, keep their steps on track, and rebuild the transport systems that are needed to keep a cell alive.
The Right Motor for the Job
Since the dawn of microscopy, scientists peering into the innards of cells have seen many moving parts. The earliest experiments on mobile proteins studied muscle cells, an obvious place to look for molecular movement. More than 50 years ago, scientists isolated two proteins—myosin and actin—from muscle cells. Andrew Huxley and Hugh Huxley (no relation) independently proposed that actin thin filaments slide across myosin thick filaments in the presence of the cellular energy molecule ATP. As this idea gained traction, it also became clear that isolated molecules of myosin could walk along actin filaments, suggesting a way that materials in the cell could be transported as well as providing a way to study myosin motors (see sidebar, “Stepping Back in Time”).
Stepping Back in Time
2012 Albert Lasker Basic Medical Research Award.
By the mid-1980s, scientists at Stanford University were using a microscope to watch myosin carry plastic beads along actin filaments in non-muscle cells. Vale, a graduate student at Stanford at the time, got caught up in the excitement of seeing cellular movement and wanted to try the same experiments on proteins from nerve cells, where materials could be seen moving through the cells’ long axons. He expected to turn up myosin as the vehicle responsible for this transportation. Instead, Vale, together with Mike Sheetz and Tom Reese, isolated another molecular motor—kinesin—and they began focusing their attention on it.
Myosin trucks along on actin filaments, aiding in muscle contraction, vesicle transport and many other processes.
Within 10 years, Vale and colleague Robert Fletterick had solved the structure of kinesin, helping to explain the molecular underpinnings of how the molecule walks along microtubules, dynamic tubes that run throughout cells. And he showed that the three-dimensional arrangement of atoms that make up kinesin was highly comparable to that found in myosin. “By using what was known about myosin,” says Vale, “we could bootstrap experiments and apply prior knowledge on myosin to understand the workings of kinesin, the newer kid in town.”
The Microscopic Motors of Life Ronald Vale discusses efforts beginning in the early 1980s that uncovered how cytoskeletal motor proteins work.