The discovery of the exact structure of the tail and its role in cell replication holds promise that researchers can develop new types of drugs targeting the tail or the workshop itself, turning off the unrestrained multiplication of cancer cells.

The study also shows that a slight change in a structure common among many enzymes performing similar jobs can create a new enzyme with a unique activity.

The St. Jude researchers report that the stabilizing influence of Ubc12's protein tail is based on its ability to nestle within a groove of the larger molecule called APPBP1-UBA3. These two proteins, also known by the shorthand designation of E2 (Ubc12) and E1 (APPBP1-UBA3), cooperate with each other to form a workshop where the "on switch" that accelerates cell replication is cobbled together.

The workshop makes the switch by linking a tag called NEDD8 with its "target" a molecule called Cul1. NEDD8 then modifies Cul1, causing it to set off a cascade of biochemical reactions that eliminates the molecular brake controlling cell replication. In the absence of this brake, cell replication accelerates, and if left unchecked, could cause cancer.

Until now, the function of the E2 tail was unknown, according to Brenda Schulman, Ph.D., an assistant member of the St. Jude Genetics and Tumor Cell Biology and Structural Biology departments. Schulman is senior author of the NSMB report.

The current study shows that the tail of E2 plays a crucial role in a series of hand-offs in which NEDD8 passes from one enzyme to another. First, E2's tail helps E2 clamp onto E1. That allows E1 to activate NEDD8 through a process called adenylation (putting a
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Contact: Bonnie Cameron
bonnie.cameron@stjude.org
901-495-4815
St. Jude Children's Research Hospital
13-Sep-2004