St. Jude study gives new insights into how cells accessorize thei...(Schulman's lab. Schulman and her co...)
Schulman's lab.
Schulman and her colleagues study the enzymatic machinery that manages the accessorizing process, whether the accessory is NEDD8 or ubiquitin. Both molecules depend on specialized cadres of enzymatic valets that attach them to their correct targets.
One question the researchers addressed about the NEDD8-attaching machinery was how NEDD8 can make a considerable molecular leap to cullin-RING from the previous enzyme in the cadre that manages the attachment process. Also, the researchers wanted to understand how, once NEDD8 attaches to cullin-RING, it activates the enzyme to attach ubiquitin to its target protein. In this activation process NEDD8 also somehow thwarts the action of another molecule called CAND1, which normally inhibits cullin-RING.
"It is important to solve these lingering mysteries to give greater insights into this critically important process in the cell," said Daniel Scott, Ph.D., the paper's co-first author and HHMI research specialist in Schulman's lab.
In their experiments, the researchers crystallized cullin-RING proteins both with and without modification by NEDD8 attachment. They then subjected the crystals to structural analysis using X-ray crystallography. In this widely used technique, X-rays are directed through the crystal of a protein to be analyzed and its structure deduced from the pattern of diffraction of the X-rays.
Comparison of the two structures revealed that, when NEDD8 attaches to cullin-RING, it dramatically modifies the conformation of the enzyme, causing it to blossom from a "closed" to an "open" state. This open state eliminates the binding site for the inhibitor CAND1, activating cullin-RING to then put ubiquitin onto a different target protein. The open state also frees a key component of the cullin-RING, called RING, making it flexible enough to function, helping cullin-RING transfer ubiquitin to its target protein.
Schulman said that their finding
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| Contact: Summer Freeman summer.freeman@stjude.org 901-595-3061 St. Jude Children's Research Hospital Source:Eurekalert |
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