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Caltech scientists show how ubiquitin chains are added to cell-cycle proteins
Date:12/2/2009

o far apart in time, you would have no idea whether the child ate the ice cream one bite at a time, or swallowed the entire scoop in one gulp."

The new method revealed the biological equivalent of small, single bites of ice cream. "Using our approach," Deshaies says, "we could see that our ubiquitin ligase builds ubiquitin chains one ubiquitin at a time."

"Once we knew what the steps were, we calculated the rates at which they occur," adds Pierce. "And from those rates, we were able to really describe the biology of how this system works."

The quest doesn't stop there, of course. "One thing we have to understand now is, how do ubiquitin ligases achieve the speeds that they do?" asks Deshaies. "What special mechanisms do they have to enable them to build chains rapidly? And the flip side of the coin: What sets the speed limit? Why can't our ubiquitin ligase work even faster?"

A recent paper published in the journal Cell by Gary Kleiger, a postdoctoral scholar in the Deshaies lab, answered some of these speed-related questions. By measuring the rates at which E2 and E3 interacted with one another, Kleiger was able to demonstrate their unusually fast associationfaster than predicted for normal proteins. E2 and E3 use oppositely-charged surfaces to attract each other, thereby speeding up the formation of a functional complex of the two proteins. This helps explain how the rapid sequential additions of ubiquitin described in the Nature paper are possible.

Gaining these kinds of insights into the ubiquitin system is important, Deshaies says, because ubiquitin ligases play a critical role in a number of human diseases, including cancer, due to their role in the regulation of the cell cycle.

"Once we understand these aspects of how ubiquitin ligases work, and what limits their speed, we will be in an excellent position to think about how we might develop drugs that attack the ligase's Achilles' heel, to mak
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Contact: Lori Oliwenstein
lorio@caltech.edu
626-395-3631
California Institute of Technology
Source:Eurekalert  

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