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Chemical switch triggers critical cell activities

ft hand; and that the other NEDD8 then hops over from the right hand to E1's empty left hand. That leaves the right hand free to grab yet another NEDD8. By continually passing the NEDD8 proteins from the right hand to the left hand and on to E2, E1 keeps a relay of these batons flowing. In turn, that keeps the specific biochemical cascade triggered by NEDD8 in action.

But in order for the handoff to work, E2 must first insert itself into a docking site on E1, next to E1's left hand, so it can grab NEDD8, Schulman explained. However, the E2 docking site is initially turned away from E1: so if E2 hopped into the docking site at that point, it would be too far away from NEDD8 to grab it, she noted. And that was the puzzle the St. Jude researchers solved.

Specifically, the St. Jude study showed that when NEDD8 forms a thioester bond with E1's left hand, it squeezes itself next to the E2 docking site, which is facing away from NEDD8, according to Danny Huang, Ph.D., HHMI postdoctoral research associate and Harold Hunt, HHMI research technologist,. These researchers in Schulman's laboratory did most of the work on this project.

In such close quarters, NEDD8 bumps the docking site, making it rotate like the paddle wheel on a riverboat that carries a notch on one of its paddles. As the docking site rotates, it carries the notch all the way around to the other side, next to NEDD8. As soon as the notch of the docking site is next to NEDD8, the notch catches E2, so E2 is bound to the notch, right next to NEDD8. NEDD8 then breaks its thioester bond with E1 and reforms it with E2. As soon as NEDD8 breaks its thioester bond to E1 and forms a thioester bond with E2 instead, E2 falls away from E1 taking NEDD8 with it. Then E2 can interact with E3 to pass NEDD8 onto the target.

The investigators were able to make sense of this combination of relay race and rotating paddle wheel by using a technique called X-ray crystallography. In X-ray cr
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Source:St. Jude Children's Research Hospital


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