July 13, 1999 Princeton scientists have answered several fundamental questions about one of the smallest devices in the human body -- molecules that function as motors, carrying substances from place to place within a cell.
The researchers used "laser tweezers" that allowed them to study the motion of individual molecules -- chemical entities so small that they cannot be viewed under even the most powerful optical microscope. Their experiments, published in the July 8 edition of Nature, revealed the workings of one type of molecular motor, including how it consumes fuel and how much power sustains its motion.
Biophysicist Steven Block, working with scientists Koen Visscher and Mark Schnitzer, looked at a molecular motor called kinesin, a protein that travels along the microtubules that form the skeleton of cells, carrying much larger pieces of cellular machinery along with it, packaged in vesicles.
In addition to offering fundamental insights into the one of the most enigmatic activities within cells, the findings may have implications for understanding and controlling certain cancers and for designing hybrid devices (biochips) that may someday combine molecular motors with computer chips. Biochips that harness the power of molecular motors could be used as sensors or actuators or within minute computers that imitate biological functions.
Like any motor, molecular motors burn fuel. For kinesin, the fuel is a molecule called ATP. Block's lab has previously shown that kinesin moves in uniform steps of just 8 nanometers (eight billionths of a meter), but they did not know whether there is a constant and direct relation between how fast kinesin moves and how much ATP it burns. Block's new work shows that kinesin's fuel consumption is "tightly coupled," that is, it burns exactly one ATP molecule for each 8 nm steps it takes, no matter how much resistance it faces. (That means it would take 3,000 to 5,000 ATP molecules for a kinesin molecule to travel the width of a typical cell, a distance of 25,000 to 40,000 nm.) A second discovery is that the maximum force needed stop a kinesin molecule in its tracks depends on the concentration of ATP in the vicinity -- the more ATP present, the harder one has to push on the kinesin to stop it.
That is a rather unexpected result, Block said, because previous experiments had suggested that it was a loosely coupled system in which kinesin burns more fuel per step when it meets resistance. The way motors burn fuel tells us a lot about how they work, Block said. For example, a tightly-coupled system could be compared to a bicycle's drive chain, which always produces a certain amount of movement with each link of chain that goes by. A loosely coupled system is like the automatic transmission of a car; the motor can turn and burn fuel even when the car is stopped, as in when you hold down the brake at a stop sign with the car in drive.
Block's work was made possible by his development of an invisibly small optical tweezers device modified to serve as a molecular force clamp. The new device trains a laser beam on a kinesin molecule that has been attached to a tiny plastic bead that serves as a handle. The light from the laser exerts a miniscule but measurable force on the bead. A computer-driven feedback circuit serves to keep the force constant even as the kinesin moves. Several research groups had used similar devices, but without feedback, and experienced margins of error as high as 20% in their measurements; Block's refinement permits measurements to be made with unprecedented accuracy (5% or so) and over longer distances that ever before.
"Knowing how motion is produced by living organisms is fundamental and basic to an understanding of life itself," Block said. Despite years of research, there are lingering questions about how all the various molecular motors work, including those that result in muscle contraction. In work published in the Oct. 30, 1998 issue of Science, Block and his lab members used similar techniques to study the motion of a motor called RNA polymerase, a molecule that reads the genetic code in DNA and transcribes it into a corresponding molecule of RNA. Block said his latest work shows that there are surprising similarities between these two very different motors.
Block, who has a joint appointment in the Department of Molecular Biology and the Princeton Materials Institute, received funding for the work from the NIH, NSF, and W.M. Keck Foundations.
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