X-ray Crystallography Exposes Multi-functional Activation Enzyme

Researchers have used x-ray crystallography to determine the sequence of biochemical events that take place when the E1 activating enzyme interacts with the ubiquitin-like protein NEDD8, a regulator of cell division, signaling, and embryogenesis. Their work was reported in the March 20, 2003, issue of Nature.

Each ubiquitin-like protein (Ublp) has a dedicated E1, or activating enzyme, that initiates its conjugation cascade. First, E1 associates with the Ublp and catalyses adenylation of the carboxy terminus of the Ublp. Second, E1 forms a thioester between its catalytic cysteine and the Ublp. Next, E1 is loaded with a second Ublp molecule, adenylating the C terminus of this second Ublp while still carrying the first thioester-bound Ublp. Last, E1 binds E2 and promotes Ublp transfer to the catalytic cysteine of E2. It is rare in nature for a single enzyme to catalyze three different chemical reactions.

"The cell uses E1-activating enzymes to keep a tight rein on all of the various biochemical pathways it must activate,” explained senior author Dr. Brenda Schulman, a researcher in the departments of structural biology, genetics and tumor cell biology at St. Jude Children's Research Hospital (Memphis, TN, USA). "Otherwise the cell would be chaotic and would not be able to perform the tasks it is supposed to do in the body. The more we learn about how these pathways are controlled, the more likely we will understand how to fix them when they get disrupted and cause a wide variety of diseases.”




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