Researchers discover how critical information is passed from one protein to another.

To get where they need to go, certain proteins receive ubiquitin or ubiquitin-like guiding proteins from enzymatic "relay teams."

Like athletes passing batons in a relay race, protein "teams" inside cells transfer smaller proteins, called ubiquitin-like proteins, to certain other proteins to set them on track to their final destiny.

HHMI investigator Brenda A. Schulman and her colleagues at St. Jude Children's Research Hospital have discovered new details about this process. The relay team is made up of three enzymes—E1, E2, and E3—that work in tandem to attach ubiquitin or ubiquitin-like tags to cellular proteins. The tags determine the modified proteins' ultimate fate, such as destruction in the cell's garbage disposal, the proteasome. Such degradation in turn can cause activation of a specific event like cell division.

The E1 enzyme selects the correct tag and forms a high-energy bond with it. Next, the activated tag is transferred to E2, which then works with E3 to ultimately hand the tag to the targeted protein. If the system gets out of sync, diseases—such as cancer and neurodegenerative disorders—may occur.

To dissect the transfer process, Schulman's group studied the enzymatic line-up associated with the ubiquitin-like protein NEDD8, which has a relatively simple E1-E2-E3 cascade. They genetically altered the E2 enzyme to stop action, in mid-handoff, during its receipt of NEDD8 from E1. The researchers then crystallized the structures and exposed them to x-ray beams to determine their three-dimensional shapes.

Previous studies could not explain how the relay worked because available models showed E1 and E2 positioned with E1's baton-carrying hand far away from E2's baton accepting hand. Instead, says Schulman, a switch occurs as if between two novice relayers: the second turns around to face the first for the handoff.

The ubiquitin-like protein (and probably ubiquitin) not only serves as a baton, she adds, but also as a coach. "When bound to E1, it says bind to E2; when bound to E2, it says run away from E1," says Schulman.

The group reported its results in the January 25, 2007, issue of Nature. They are now considering how an anchor enzyme, E3, completes the relay and adds ubiquitin or NEDD8 to the final target protein.

Image: Steve Chenn / CORBIS