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Proteins at the growing ends of microtubules also likely help the microtubules find their targets. At the University of California, San Francisco, HHMI investigators Lily Jan and Yuh Nung Jan have discovered one apt example. The Jans study ion channel proteins located in neurons’ plasma membranes, which selectively allow potassium in and out of the cells. They knew that, after the channel proteins were produced inside the cell, the proteins were delivered to the membrane by hitching a ride on kinesins that stepped along microtubules to the cell’s edge. But they were puzzled to see that the channel proteins were always delivered to clusters of the proteins specifically located in the axons of neurons. How did the microtubules know in which direction to head?
“In central neurons like the motor neurons, across the board evolutionarily, the channel goes down to the same spot,” says Lily Jan. “In giant squid, in humans, in mice. So we wanted to know how this destination is reached.”
The Jans discovered that a protein called EB1 is key—without it, the microtubules guiding the channels’ paths don’t reach the right spot. Their lab group has gone on to show that EB1 is also important in guiding channel proteins to the right spot in heart cells.
Not all neuronal proteins, of course, are delivered to the channel cluster that the Jans study. In fact, most neurons are heavily dotted with another common delivery site: synapses—the structures between cells that neurons use to communicate. So microtubules and motor proteins must find an astonishing array of locations.
“You can imagine kinesins as cars driving the length of microtubule roads,” says HHMI investigator Kang Shen of Stanford University. “But not every car will drive to the end of the road; they’ll get off at different exits.” Shen has discovered that kinesins, not surprisingly, are critical to placing the synapses at different exits along the roads that traverse a neuron’s axon. Kinesins carry synaptic vesicle precursors—sacs containing the components of synapses—along microtubules and then distribute them at different points on the axon.
“We’ve found that when kinesins have some mutations, they appear to drop off their cargo too early,” says Shen. “Other mutations do the opposite, traveling the whole length of the road without depositing the cargo.” In his latest work, Shen has shown that kinesins also carry microtubules to ensure they are oriented correctly in the dendrite, where neurons receive chemical messages. This finding, slated to be published soon, illustrates the diverse jobs that molecular motors have, he says, and the complexity of their functions. He plans to use synapse placement as a system to study how kinesins are regulated in the cell to carry cargo to precise locations.
Throughout mammalian cells there are 45 types of kinesins, 40 versions of myosin, and at least 14 different dyneins. Each carries goods—ranging from entire organelles, such as mitochondria and large chromosomes, to signaling chemicals—to a distinct destination. Yet the various motor proteins display small differences in how they process ATP, how they step along actin or microtubules, what cargo they can carry, and how their function is regulated. Now that the basic structure of each has been elucidated, and the complexity of their pathways revealed, scientists are primed to delve into questions about these differences and the regulation of each.
“We have these 45 kinesins that are involved in an enormous range of biological activities,” says Vale. “And for the vast majority of them, we don’t understand how they’re deployed or targeted within cells.”
But as the implication of gaining knowledge about these motor proteins becomes clearer, the interest in them is growing, says Vale. “This field has broadened as many more scientists have become involved,” he says. “People studying cancer or signaling or developmental biology often encounter some kind of molecular motor that is relevant to their research problem. I think that will continue to be true.” The road to understanding molecular motors, he says, is far from over.