HARVARD GAZETTE ARCHIVES

Structure of Cancer-Causing Protein Revealed

By William J. Cromie

Gazette Staff

Hidden in the core of most human cells is a Jekyll and Hyde gene that can help your bones grow normally or give you cancer. For 27 years, scientists have been trying to discover the structure of the protein produced by this gene, and how it goes from good to bad.

The puzzle has now been solved by a team of Harvard researchers. By working out the atom-by-atom structure of the Src protein, they have taken a major step toward learning how to control the subversive side of the two-faced gene.

What is more, Src is only one member of a family of proteins involved in rejection of transplants and autoimmune diseases such as rheumatoid arthritis and juvenile-onset diabetes. Knowing the intimate structural secrets of one protein should provide clues to the workings of the other family members.

Src's construction was revealed by the persistent efforts of Stephen Harrison, a Howard Hughes Medical Institute investigator and professor of molecular and cellular biology (FAS); Michael Eck, an assistant professor at the Medical School; and Wenqing Xu, a postdoctoral fellow at Children's Hospital.

"Src is a fancy little machine," says Eck. "It has an incredible amount of information technology built into a tiny package, where every bit matters and is used creatively."

Good Gene Goes Bad

No one knew that a good gene could go bad until 1970, when Src was found by Harold Varmus and Michael Bishop. They shared a Nobel Prize in 1989 for their discovery of the first cancer-causing gene.

"All of us have a collection of inherited genes normally involved in doing good for us," Varmus, now head of the National Institutes of Health, noted during his 1996 Commencement Address at Harvard. "The gene we discovered is important in regulating bone growth. But mutations caused by a virus or other factors can alter it in a way that contributes to the development of cancer."

Most of the time, Src is shut off. When growth is required, a complex series of reactions turns it on. So far, so good. But, if Src has been mutated, it can lock in the "on" position, causing the wild growth known as cancer.

With its three-dimensional structure now known, researchers can see how this happens. Diagrams published last month in the British scientific journal Nature, look like four crumpled curls of crepe tied together with string. Two of the curls, or lobes, are responsible for catalyzing growth. The other two regulate this activity, i.e., they function as an on-off switch.

When "off," a tail of string wraps around the regulatory lobes in such a way that the performance lobes cannot be activated. When the signals for growth come along, the string unravels and the switch turns on.

More research needs to be done to determine how the switch stays on. One guess is that mutations in the tail fail to return the molecule to its off position when the Src protein is no longer needed for growth.

Keep in mind, this whole molecular machine is too small and quick-changing to be viewed in the most powerful microscope. The researchers had to crystallize the protein to hold it in one position. High energy, short-wave x-rays were then shot through the crystal, creating a pattern of scattered beams that enabled researchers to find the position of each atom in the molecule.

Sara Courtneidge, a biochemist at Sugen Inc., a California biotechnology company, described the resulting Src structure as "very beautiful. It's exciting and satisfying to see it finally."

To enable the structure of other proteins and molecules on which life depends to be seen in the same way, the Medical School has created the Center for Structural Biology. It supports structural research in all parts of the University and its affiliated hospitals. Stephen Harrison, who is also professor of biological chemistry and molecular pharmacology at the Medical School, directs the Center.