Professor of Physics Paul Selvin and biophysics graduate student Ahmet Yildiz, in collaboration with colleagues from the Howard Hughes Medical Institute and the University of California, San Francisco, have demonstrated that one of the most important molecular motors for moving cargo within the cell does so with the hand-over-hand motion of a mountain climber, rather than an inchworm-like motion (Yildiz et al., Science 303, 676–678 [2004]). Their discovery reveals new information about how the tiny motor, called kinesin, moves membrane components, messenger RNA, signaling molecules and other cargo along highways called microtubules within the cell. Because similar motors are responsible for moving chromosomes during cell division, basic understanding of kinesin could inform development of cancer-fighting drugs that target the cancer cell's machinery for reproduction.

While most scientists believed that kinesin moves via a hand-over-hand mechanism, some studies have indicated that it travels like an inchworm. These two competing theories implied very different mechanisms of motility and hence our understanding of the motor and its structural mechanisms.

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To distinguish between the two mechanisms, the scientists used a tracking technique developed by Yildiz and Selvin (Yildiz et al., Science 300, 2061–2065) in collaboration with Professor Taekjip Ha and graduate student Sean A. McKinney. In this technique, dubbed "fluorescence imaging one nanometer accuracy (FIONA)," a fluorescent dye molecule is attached to the structure to be tracked, and the motion of the dye molecule is followed with great precision using a fluorescence-detecting microscope.

The kinesin molecule consists of two motor units (analogous to feet) that are linked together to a common stalk that attaches to cargo to be transported. Previous studies had shown that the kinesin molecule moves along the microtubule in steps of 8 nm, or eight one-billionths of a meter. FIONA is particularly effective for distinguishing between the two models (hand-over-hand vs. inchworm) because of the distinctive differences in how the models would predict the movement of the feet. If the inchworm model were correct, then both feet should move only in 8-nm steps as the kinesin molecule's center of mass moves. However, if the kinesin molecule moves in a hand-over-hand motion, then the 'rear' foot should take a 16-nm step forward during one cycle, and then 0 nm during the next cycle, as shown in Figure A above.
In the Science article, the researchers present a kinetic analysis of the dwell time between steps to show that there is an alternation of displacement from one step to the other, supporting that the hand-over-hand model.

    
Ahmit Yildiz and Sean McKinney