Breakdown: how three chemists took the prize: Nobel laureates discovered how cells label proteins for destruction

Science News, Oct 16, 2004 by A. Goho

This years Nobel Prize in Chemistry has gone to three scientists--two Israeli and one U.S.--for their discovery of the molecular machinery that cells use to dispose of defective or unnecessary proteins. The 25-year-old discovery laid the foundation for what has since become a vast area of medical research. Faulty protein-breakdown equipment, for instance, underlies cystic fibrosis, several neurodegenerative diseases, and certain types of cancer.

Aaron Ciechanever, 57, and Avram Hershko, 67, of the Technion-Israel Institute of Technology in Haifa and Irwin Rose, 78, of the University of California, Irvine will share the roughly $1.4 million prize.

"It's the story of three generations of scientists," says Ciechanover.

In the late 1970s, Ciechanover was a postdoctoral student in Hershko's lab. The two scientists were investigating why some types of protein degradation require energy, while other types, such as the breakdown of food proteins by the stomach's digestive enzymes, do not.

To solve the mystery, the Technion team began collaborating with Rose, a more senior scientist who was then working on the same problem at the Fox Chase Cancer Center in Philadelphia. Through this collaboration, the researchers discovered that protein degradation in cells relies on a molecular tag called ubiquitin. A cell marks proteins with this "kiss of death" molecule--itself a small protein--and then shuttles the doomed proteins to its waste-disposal units, called proteasomes. These barrel-shaped structures chop the proteins into tiny pieces for reuse.

Through this ubiquitin-mediated process, cells regulate various activities. Among them is ceil division, a complicated task that requires the sequential synthesis and destruction of multiple proteins. Ubiquitin is also central to a quality control mechanism that monitors newly synthesized proteins.

Several types of enzymes participate in labeling proteins with a chain of ubiquitin molecules, the Nobel laureates found. TO ensure that the right proteins get the label, this set of enzymes coordinates its activities through a process that requires energy from the cell.

"In order to degrade a protein and keep the 30,000 other proteins alive, you need control, and energy provides the control," says Ciechanover. By switching the supply of energy on and off, the cell can direct the degradation process.

The work of the three chemistry laureates "has had such an enormous influence on changing the way we think about cell regulation," says Alfred Goldberg of Harvard Medical School in Boston.

After Hershko and his colleagues published their findings about protein degradation in ceils, researchers around the world flocked to the field.

The resulting knowledge about the mechanism of protein breakdown is now proving valuable in the search for new medicines. Last year, the Food and Drug Administration approved the proteasome inhibitor bortezomib (Velcade) for the treatment of multiple myeloma, a cancer of the blood.