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Structure Of Fat-Depleting Protein Reveals Important Functional Clues

March 19, 1999—Following a mysterious crevice in a molecule that causes severe weight loss in some cancer patients may turn up a new generation of drugs to treat clinical obesity, say researchers from the Howard Hughes Medical Institute (HHMI) at the California Institute of Technology.

Zn-a 2-glycoprotein, otherwise known as ZAG, occurs naturally in most body fluids, including blood, sweat, saliva, and urine. Researchers first isolated ZAG from blood samples more than 30 years ago, "but it’s been a molecule in search of a function for a long time," said Pamela Bjorkman, an HHMI investigator at the California Institute of Technology in Pasadena. Bjorkman, Luís Sánchez and HHMI associate Arthur Chirino published ZAG’s structure in the March 19, 1999, issue of the journal Science.

One of the mysteries surrounding ZAG is that it seems to be related to a large family of proteins known as class I major histocompatibility complex (MHC) molecules. These molecules bind to small pieces of other proteins, known as antigenic peptides, and in so doing trigger an immune response to invading microorganisms and viruses. Yet despite ZAG's similarity to MHC proteins, it apparently does not have a role in the immune system, Bjorkman said.

Last year, however, researchers at Aston University in Birmingham, U.K., discovered that ZAG is involved in cachexia, a wasting syndrome that can affect people with cancer, AIDS and other terminal illnesses. Cachexia can result in rapid, life-threatening weight loss and lead to shedding of both fat and muscle.

ZAG appears to drive the fat-loss in cancer patients. When the British investigators added ZAG to fat cells, the cells rapidly metabolized lipids, a major component of fat. Further evidence of ZAG's role in fat breakdown came when researchers, who fed the protein
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Contact: Jim Keeley
keeleyj@hhmi.org
301-215-8858
Howard Hughes Medical Institute
19-Mar-1999


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