"The limited number of targets NEDD8 has despite the fact that its E1, E2 and E3 enzymes look very much like those of the ubiquitin pathway makes the discovery of the E2 tail intriguing," said Danny T. Huang, Ph.D., a St. Jude postdoctoral fellow and first author of the paper. "Although most of the E2 that binds with E1 and NEDD8 looks like any other E2, its tail makes this enzyme unique."

The tail of the E2 that binds to NEDD8 and the way the tail holds E2 onto E1 give this workshop a different shape than the ones in the ubiquitin pathway. The slight modification in shape limits this workshop to working only with NEDD8 and NEDD8's few targets.

Knowing the exact shape and function of the E2 tail and the groove along E1 the tail fits into make these structures potential targets for new drugs.

"Novel drugs that are designed to disrupt the tail, the groove or both might block the ability of the NEDD8 pathway to accelerate replication of cancer cells."

The extensive study required a variety of techniques to tease apart the structure formed by the bonding of the E2 tail to E1. For example, the St. Jude team showed that deleting the tail from E2 significantly hinders the ability of E2 to transfer NEDD8 to Cul1, and blocks its ability to drive cell proliferation. This demonstrated the important role played by this unique protein.

In addition, using X-ray crystallography techniques, Schulman crystallized samples of the bonded proteins and bombarded them with a beam of X-rays. She then used the patterns formed by the diffraction of the beams off the crystals to create computer-generated, three-dimensional images of the shape of the bonded proteins.

However, images of the structure created using X-ray crystallography failed to provide detailed views of half of the individual amino acid building blocks making up the protein tail. This problem was overcome using a technique specially developed by Robert Cassell, a macromolecular special
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Contact: Bonnie Cameron
bonnie.cameron@stjude.org
901-495-4815
St. Jude Children's Research Hospital
13-Sep-2004