Eva Nogales studies how proteins hitch a ride on microtubules as they shrink and grow. Kang Shen studies the way kinesins deliver cargo essential to nerve signaling.

Kinesin and myosin have globular heads that attach to their tracks and flexible tails that extend outward and carry cargo. The proteins’ heads break down ATP to convert energy into work. For each ATP consumed, the motor protein takes a step forward (see Web Extra animation).

		Kinesin Kinesin powers processes like meiosis and mitosis, hauling cargo out from the center of the cell. Learn More

Shortly after Vale’s discovery of kinesin, he and his colleagues found evidence for another motor that moved along microtubules in the opposite direction. Two years later, Richard Vallee discovered that this second motor protein was dynein, which had been identified decades earlier for its role in flagella—whiplike tails that can propel entire cells, such as sperm. This newly discovered dynein—called cytoplasmic dynein—transports cargo along microtubules, serving a different function from the dynein that propels cells. The key difference between cytoplasmic dynein and most kinesins is the direction of transport: dynein molecules move along microtubules pointed at the cell’s center; kinesin walks outward. Having a distinct molecule for each task lets cells fine-tune traffic control.

Cytoplasmic dynein, though, looks different from myosin and kinesin. It has a very large wheel-like motor domain that binds multiple ATPs and a more complex tail region to connect to cargo. Because of its large size and complex structure, it has been harder to study than myosin and kinesin. For Vale, the challenge is enticing—since 2002, his lab has primarily focused on studying dynein.

		Dynein Essential to cell survival, dynein marches along microtubules driving activities like organelle transport and centrosome assembly. Learn More

“One of the really intriguing parts of dynein is that the key nucleotide binding site is a very large distance from the microtubule binding site,” says Vale. The distance between dynein’s ATP-binding site and its feet is four times the size of the whole kinesin molecule, he says. So how does the energy-generating portion of the protein communicate with the walking feet?

In 2011, Vale’s team solved the crystal structure of dynein, more than a decade after the structure of kinesin, and got some hints as to how the long-distance communication could work. They discovered a buttress—a section that supports the lanky top of the protein—that may be involved in transferring information from the ATP-binding head to the protruding feet that bind to the microtubule track. But questions remain about how dynein takes steps with a structure that’s so different from the other two motors.

“At this point, we can’t articulate a complete model of how dynein produces motion,” says Vale.

This much is known: when dynein or kinesin stops carrying goods across the cell, the cell stops functioning. Mutations in kinesin have been linked to kidney disease and an inherited neuropathy. Mutations in dynein are involved in motor neuron degeneration and can cause chronic respiratory infections (because the movement of mucus through the respiratory tract is inhibited). In 1997, Vale along with three colleagues launched a drug-development company, Cytokinetics, based on their research on molecular motor proteins. Their first drug, omecamtiv mecarbil—an activator of cardiac myosin—is in phase 2 clinical trials for the treatment of heart failure. The company also is conducting early tests of a treatment for amyotrophic lateral sclerosis, or Lou Gehrig’s disease.

At Children’s Hospital Boston, HHMI investigator Elizabeth Engle has stumbled upon another class of diseases linked to mutations in molecular motors and their roadways. She studies inherited eye disorders in which the muscles of the eye don’t develop properly. The root of the problem, her lab has discovered, is that dynein and kinesin don’t properly carry messages up and down the microtubules of growing neurons. The consequence: the neurons don’t connect to the correct muscle tissues. In genetic screens designed to pinpoint the cause of this problem, Engle’s lab has revealed mutations in the proteins that make up microtubules as well as in a specific type of kinesin. Now, they’re probing how the kinesin mutation changes the motor protein’s function.

“These human genetic studies are highlighting amino acid residues vital to specific functions of both kinesins and microtubules,” says Engle. “Thus, we can translate the human findings backward to enlighten more basic studies of these proteins and their interactions.”

Tales from the Road

What about the other side of the cell cargo story, the roads themselves? Within the cell, road construction—and destruction—is an around-the-clock, nonstop job. To control the flow of goods between its neighborhoods, a cell is as likely to shut down or open new roads as it is to impose changes on vehicles.

Photos: Nogales: Ryan Anson / AP, ©HHMI; Shen: George Nikitin / AP, ©HHMI

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