Protein Breakdance

The Royal Swedish Academy of Sciences last week awarded the 2004 Nobel Prize in Chemistry to three researchers "for the discovery of ubiquitin-mediated protein degradation," a regulated process by which proteins are cleaved into peptides inside cells.

The laureates are Aaron Ciechanover, 57, and Avram Hershko, 67, professors at the Rappaport Family Institute for Research in Medical Sciences at Technion, Haifa, Israel; and Irwin Rose, 78, a physiology and biophysics researcher at the University of California, Irvine. They will share equally an award of nearly $1.4 million.

Ubiquitin-mediated protein degradation plays a key role in cell division, DNA repair, protein synthesis, and the immune system; malfunctions can lead to diseases like cancer. A detailed understanding of the process is thus important to drug discovery. The first drug that inhibits this protein-degradation pathway--Millennium Pharmaceuticals' Velcade, a treatment for multiple myeloma--was recently approved, and other drugs are being tested.

"I was sitting and editing a review article," said Ciechanover by phone from Haifa to a Swedish press conference, 10 minutes after having been informed about the prize. "I was on my way out, and all of a sudden the phone call," he said. "I am not myself."

"It's the first Nobel Prize in sciences going to Israel," Ciechanover noted. "It shows you that a tiny ... country with little resources can nevertheless have imaginative scientists that are extremely successful."

In the digestive system, proteolytic enzymes break down the protein in food. But inside living cells, a completely different mechanism--the ubiquitin-proteasome pathway--regulates the degradation of most proteins that are problematic or no longer needed. The polypeptide ubiquitin marks each such protein for destruction, and the tagged proteins are then directed to the proteasome, a large protein complex where the tagged proteins are broken down and ubiquitins are released for reuse. Unlike protein digestion, this process is energy dependent, requiring adenosine triphosphate.

In the 1970s, cell biology professor Alfred L. Goldberg and coworkers at Harvard Medical School produced a cell-free extract in which this energy-dependent process occurred. Using such extracts, Ciechanover, Hershko, and Rose discovered the molecular mechanism of ubiquitination in the late 1970s and early 1980s. The multistep process involves the ubiquitin-activating and -transferring enzymes E1, E2, and E3. Much of the work was done while Ciechanover and Hershko were on sabbatical in Rose's lab.

"The selection committee did a very impressive job," Goldberg tells C&EN. "They surprised many people by deciding not to award the prize in medicine for the complete ubiquitin-proteasome pathway, but to do so in chemistry and focus on the tagging of proteins for degradation, which involved a new type of postsynthetic protein modification. For cell regulation and medicine, this is a critical step. In my view, there is no question that each laureate merits the honor. And the committee deserves credit for recognizing the major contributions of Rose."

The discovery shows "the power of a chemical insight" that intracellular protein degradation was energy dependent, says Jeremy M. Berg, director of the National Institute of General Medical Sciences, which has supported work in the field. "Over the last decade or so, the wide-ranging importance of this system in biology has become clear."