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    A Peek Under the Hood at Molecular Motors

    Motors propel cars along highways and tractors on farms; they run air conditioners in office buildings, refrigerators at home and conveyor belts in factories. Motors are everywhere, even inside the cells of your body.

    Structural biologists at St. Jude Children’s Research Hospital are studying two types of biological motors critical to a cell’s ability to divide and produce healthy daughter cells. Those motors are called helicases and kinesins. Helicases help a cell make copies of all its chromosomes so that each daughter cell gets a full set. Kinesins transport each of those chromosomes into the daughter cells.

    Understanding the structure of these tiny protein motors may help scientists eventually bring the growth of cancer cells to a screeching halt.

    Helicases to the rescue

    The DNA molecule that makes up a chromosome is like a rubber ladder that is twisted into a coil, called a double helix. The cell contains two copies of each chromosome, one from the mother and one from the father.

    In cells preparing for division, every chromosome from both the mother and father must be copied, or replicated, so that each of the two daughter cells has a complete set of chromosomes. This requires the cell to uncoil each chromosome, split the “ladder” apart and rebuild the halves. The result is two copies of each chromosome.

    One type of helicase enzyme unwinds the double-stranded DNA molecule. If this process jams and stalls, the cell activates “rescue” helicases to cut through the gridlock and allow the DNA to continue the replication process.

    Stephen White, DPhil, Structural Biology chair, is studying how these rescue helicases work by using an enzyme called T4 helicase, which is found in the Escherichia coli (or E. coli) bacterium.

    “As structural biologists, we like to look at simple things,” White explains. “If you’re trying to look at a giant, human complex to understand how it works, it’s very difficult. But if you can find an equivalent complex in a bacterium or a virus that does essentially the same thing, it’s much easier to look at. So we’re looking at this in T4, a virus that invades E. coli. T4 has a helicase that acts like human helicases but in a much, much simpler system.”

    Using a technique called X-ray crystallography, White has created a model of the enzyme, which gives an intimate look at the graceful loops and turns that make up T4’s structure. Such images are helping White understand how these rescue helicases work. These enzymes are important because if they are defective, the cell might die or become a cancer cell.

    Movin’ down the highway

    Just before the parent cell divides, other motors, called kinesins, move chromosomes into place so that each daughter cell has a complete set of the same chromosomes the parent cell had. The kinesins transport the chromosomes along microscopic highways called microtubules.

    Two sets of microtubules lead, like east and west routes of a highway, to opposite sides of the cell. Kinesin II motors carry chromosomes from each set along one of those microtubule highways. When the cell divides down the center, each daughter cell then has a complete set of chromosomes.

    Hee-Won Park, PhD, of Structural Biology created an image of a kinesin motor called Ncd from the fruit fly Drosophila. “We picked the kinesin protein from Drosophila because we believe that it’s similar to the human version,” Park says. “This is important because cancer cells divide like crazy, and in cancer cells these kinesin proteins are used for DNA division.”

    Using the fruit fly model, Park developed a working theory of how this protein “walks” along the microtubule, carrying the chromosome with it. One end of each microtubule strand is called the positive or “plus” end to distinguish it from the other, negative or “minus” end.  Scientists have long assumed that kinesin proteins travel toward the “plus” end of a microtubule. But Park discovered that Ncd steadily moves toward the more stable “minus” end by grasping the microtubule and letting go, grasping and letting go in what he calls a “lever-arm model.”

    “Somehow the different types of kinesins know which end they’re supposed to move to,” Park says. “We are interested in learning how they know which end they’re supposed to travel to when they bind to the microtubule.”

    Learning about the Ncd motor is only one part of a mind-boggling picture. “There are about 124 different kinds of kinesins in the cell,” Park says. “This is only one of those.” Although the discovery process is arduous, it is also exciting. “It takes a couple of years to crystallize each protein,” he says, “but it’s a glorious thing to work on.”

    Malfunctions, misfolds and mutations

    When proteins malfunction, misfold or mutate, the outcome can be catastrophic. “DNA repair is the root cause of most cancers,” observes White. “If mutations in the DNA are not fixed properly, they produce mutated proteins. If the protein doesn’t do its job right, you end up with cancer.”

    Our DNA is bombarded constantly, so the cell’s DNA-repair mechanisms must work overtime to compensate. Usually, the cell can repair mutations. But if something is wrong with the actual apparatus—the motor—that does the overhaul, then the DNA doesn’t get repaired properly. Scientists hope to shut down such defective motors to treat certain diseases. And like the microscopic motors themselves, St. Jude researchers are working constantly, moving inexorably toward their destination.

    Reprinted from summer 2004 Promise magazine.

     

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