A nerve cell resembles a vast tree with branches that communicate with thousands of other cells. To function, it depends on a motor protein that walks on two legs, hauling urgent cargo from the center of the cell to the faraway tips of every branch. Scientists have unveiled a new structure of this walking protein, showing how cells control it.
"This is the pinnacle of understanding how cells can turn on motors, precisely, to go to different places at different times," said lead author Jawdat Al-Bassam , an associate professor of molecular and cellular biology at UC Davis.
The kinesin-1 protein is crucial to nerves. If it malfunctions, brain cells can no longer send packages of neurotransmitters and other cargo to where they are needed. Cells sicken and die, triggering diseases that cause paralysis, seizures, and cognitive deficits.
The discovery, published July 15 in Science Advances, could lay a foundation enabling treatments for these incurable diseases, said coauthor Richard McKenney , a UC Davis professor of molecular and cellular biology: "If you want to design drugs, having these clear structures will be a major advance for that. This will open up a lot of new scientific questions."
Precise mechanics of a protein machine
Kinesin-1 captured the imagination of biologists from the moment it was discovered in the 1980s. It is a strange protein, tall and skinny with stubby legs, resembling the enchanted broomstick in The Sorcerer's Apprentice. It marches robotically forward at a breakneck pace of 100 steps per second. It travels on protein tracks called microtubules, which function as long-range highways, extending throughout the cell.
Scientists understand how kinesin-1's motor works — with each forward step powered by cracking an energy molecule called ATP. But one crucial question has remained unanswered for 40 years.
"It's a simple machine that will move in one direction if you turn it on," said McKenney. But as with the enchanted broomstick in the famous story, kinesin-1 has no common sense of its own — so the cell has to turn it on and off, exactly when needed.
McKenney and his collaborators knew that kinesin-1 normally exists in a turned-off state. The cell turns it on by latching a protein called MAP7 onto its back. But the mechanics of this on-off switch remained a mystery.
Al-Bassam's team, led by Md Ashaduzzaman, a postdoctoral fellow, used a method called cryo-electron microscopy to take thousands of pictures of the turned-off protein. Merging these images together, they produced a clear picture of how kinesin-1 looks when it's turned off.
"It's a very surprising structure," said Al-Bassam.
The turned-off broomstick was actually folded in half, with its top end wedged between its legs so it can't walk. A connector on one half of the broomstick latches onto the other half, acting as a rubber band to keep it folded.
This folded structure acts as a double lock, immobilizing the legs and obstructing the docking site where cargo attaches — so even if the legs moved, they'd have nothing to carry.
Al-Bassam and McKenney found that when MAP7 attaches to kinesin-1 to turn it on, it wedges in and pops the rubber band loose. This causes the broomstick to unfold, freeing its legs and exposing the top section where cargo is attached.
From structure to drug development
The discovery could shed light on closely related proteins present in all animals, plants, fungi, and single-celled protists. Importantly, it has implications for some incurable neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Charcot-Marie-Tooth Disease Type 2, and hereditary spastic paraplegia 10, which cause cognitive problems, seizures, blindness, paralysis, muscle weakness, pain, and other debilitating symptoms.
Mutations in kinesin-1 often underlie these diseases, and some of them exert their ill effects by preventing the protein from turning on or off. Now, with a clear picture of kinesin-1's structure, McKenney and Al-Bassam can study how mutations prevent the cell from controlling its broomstick.
"It might be possible to design a molecule that would bind the mutant protein and correct its defect," said Al-Bassam.
This research is funded by the National Institutes of Health. It used advanced scientific facilities at UC Davis, including the Biological Electron Microscopy Campus Core .
Additional coauthors include Kyoko Okada from the UC Davis Department of Molecular and Cellular Biology and Yuqi Tang and Stephen Fried from Johns Hopkins University.
