Unique Hand-Over-Hand Rotation Transports Molecules Through Cells

(Philadelphia, PA) - Within every neuron is a vast protein trail system traversed by a small protein engine called Myosin V. The long-standing question of how this molecule moves may have finally been resolved by researchers from the University of Pennsylvania School of Medicine. Their findings, presented in this week's issue of Nature, show how myosin V can move 'hand-over-hand' on tracks, composed of a protein called actin, without completely letting go at any point. According to the researchers, myosin V offers a fascinating example of how cells convert chemical energy into motion, and may offer a natural example of molecular motors for the purposes of nanotechnology.

"There are a number of theories on how this molecule moves. What concerned me was how this little myosin motor can move along the track without letting go and floating off into the cytoplasm of the cell," said Yale E. Goldman, MD, PhD, professor in Penn's Department of Physiology and director of the Pennsylvania Muscle Institute (PMI). "It turns out that myosin tilts as it steps along the actin track - one head attaches to the track and then the molecule rotates allowing the other head to attach - much like a child on a playground crosses the monkey-bars hand-over-hand."

Myosin V, which is also found in pigment cells, is a protein that consists of two heads attached to a long tail, which can bind to the motor's molecular 'cargo.' Myosin travels over long filaments of a protein called actin. This cytoskeletal network is a feature of all multicellular creatures, and it is used to transport molecules throughout a single cell. In humans, Griscelli disease, which is characterized by neurological deficits and a lack of pigment, stems from non-functioning myosin V.

Goldman and his colleagues were able to study the hand-over-hand motion of a single myosin motor in action thanks to an innovative microscopic technique created by Joseph N. Forkey, PhD, a post-doctoral researcher at Goldman's PMI laboratory. The technique, called single-molecule fluorescence polarization, involved labeling myosin V with a fluorescent tag. The researchers then used a laser beam to hit the tag, creating an electromagnetic field that could resolve the angle at which the molecule tilts.

"Using single-molecule fluorescence polarization, we could detect the three-dimensional orientation of myosin V tilting back and forth between two well-defined angles as it teetered along," said Goldman.

Researchers contributing to this work include Margot E. Quinlan and M. Alexander Shaw of PMI and John E. T. Corrie of the National Institute for Medical Research in London, UK.

This research was supported by grants from the National Institutes of Health and the Medical Research Council.

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Editor's Note: Click here for an illustration of myosinV in motion.


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