The big green blob at left is an illustration of dynein’s motor protein. The ribbon-like structure is dynein’s ATP-binding domain. Image courtesy of Adrian Serohijos/Nikolay Dokholyan; ©2007 Endeavors.
Managing a Monster Protein
by Danielle Jacobs
Learning how to change dynein’s behavior could lead to better drugs for diseases such as ALS.
The large yellow sign on the back of Nikolay Dokholyan’s office door reads, “Caution: Children at Play.” But the only things playing here are the proteins. Dokholyan’s research group
is too busy figuring out the molecular mechanics behind cargo transport in cells.
Dynein is a motor protein. It shuttles freight — anything from mitochondria for cellular energy generation to chromosomes for cell division — across cells. It has been implicated in several neurodegenerative diseases, including Amyotrophic Lateral Sclerosis (ALS), which is more commonly known as Lou Gehrig’s disease. But dynein is so large and complex that its structure and mechanics have been a mystery. Most proteins range in size between thirty and forty-five kilodaltons; dynein is quite the monster at twelve hundred kilodaltons. Researchers haven’t been able to characterize it using traditional techniques such as x-ray crystallography, nuclear magnetic resonance imaging, or homology modeling.
But Dokholyan’s group conquered dynein by modeling its movement at different times and merging them. They used a strategy called multi-scale modeling, which works sort of like time-lapse photography.
The group discovered that dynein has three main elements: a stalk, a motor unit, and a tail that hauls cargo. Adrian Serohijos, a graduate student in Dokholyan’s lab, says you can understand dynein’s structure by comparing it to the human body. Dynein’s stalks are like our arms. They grab onto a microtubule — which are like monkey bars, Serohijos says — within the cell. Dynein’s motor unit is like our body, and its tail is like our legs. Imagine a person carrying himself from one monkey bar to the next; dynein’s motor unit “body” drives the movement of its “arms.” Except that dynein doesn’t stop just because its stalks get tired; it stops when its cargo has successfully reached the center of the cell.
The Power of Play
But how do dynein’s motor units get the energy to move their stalks?
Back in elementary school we were told that food provides us with the energy we need to move and play. This conversion of chemical energy into mechanical energy is called transduction, and the same concept trickles all the way down to the cellular level, Dokholyan says. In a Rube Goldberg-esque cascade known as the “power stroke,” ATP — which has been called the universal energy currency of all organisms — binds to dynein, releasing chemical energy that is propelled through what protein scientists call a “coiled coil,” which then induces small structural changes in dynein’s motor unit that further propagate its motion across the microtubulin. Phew.
Now that Dokholyan’s team understands how dynein converts chemical energy into mechanical motion, he says, they can modify its behavior, which could one day lead to better drugs to treat diseases such as ALS. And motor proteins such as dynein are the best candidates for nanomachines, which — trust me — are even cooler than Micro Machines.
Digging for Worms
Dokholyan says he’s opened a can of worms. “We’ve covered dynein’s structure and movement at a molecular level, so what we want to do now is go to the next level to see how it actually moves along the microtubules and transports cargo,” he says. The team wants to model the dynein stalk to see how it actually grips the microtubulin. So Serohijos is constructing a virtual macroscopic model of dynein that somewhat resembles the video game Sim City, putting highways (microtubulin) and cars (dynein) in a simulation and watching them move and interact.
“When you look at the way the molecule moves, it’s really a dance that means absolutely nothing to the naked eye,” Dokholyan says. “But when you start putting things together, it becomes more and more exciting.”
Danielle Jacobs is a doctoral student studying organic chemistry at Carolina.
Nikolay Dokholyan is an assistant professor of biochemistry and biophysics in UNC’s School of Medicine and a member of UNC’s Lineberger Comprehensive Cancer Research Center.
