Hackney worked with Hung Yi Kristal Kaan and Frank Kozielski at the Beatson Institute for Cancer Research in Glasgow, Scotland, who crystallized a key portion of the kinesin molecule a tail that was bound to the heads. The crystal structure confirmed that the complex contained two head domains and only one tail domain. Hackney then carried out biochemical manipulations to determine precisely how the tail interacts with the heads, which turned out to be what the authors refer to as a "double lockdown."
"It was actually a big surprise," Hackney said, "because it ruled out all of the obvious things that had been proposed for how the tail domain autoinhibits the motor domain. It does not cause a conformational change, and it does not block the surfaces that interact with ATP or the microtubular track."
Kinesin's heads are typically joined together at one spot, called the hinge. In the new structure, the heads swing in toward each other and are bridged by the tail domain, effectively cross-linking the heads at the site of tail binding. This double lockdown at the hinge and at the bridge prevents the heads from separating. Because the heads need to be separate from each other to break down ATP, the double lockdown effectively stops the molecule from generating fuel to power the motor.
The researchers suggest that other kinesins may be regulated by the same autoinhibitory mechanism. Humans have dozens of different kinesin motors that transport a variety of cargo, including proteins associated with Alzheimer's, Huntington's and Parkinson's diseases. Kinesins are also involved in separating chromosomes during cell division, making t
|Contact: Jocelyn Duffy|
Carnegie Mellon University