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A cellular housekeeper, and potential target of obesity drugs, caught in action
Date:8/2/2010

Scientists from the U.S. Department of Energy's Lawrence Berkeley National Laboratory have obtained the closest look yet of how a gargantuan molecular machine breaks down unwanted proteins in cells, a critical housekeeping chore that helps prevent diseases such as cancer.

They pieced together the molecular-scale changes the machine undergoes as it springs into action, ready to snip apart a protein.

Their work provides valuable clues as to how the molecular machine, a giant enzyme called tripeptidyl peptidase II, keeps cells tidy and disease free. It could also inform the development of obesity-fighting drugs. A closely related enzyme in the brain can cause people to feel hungry even after they eat a hearty meal.

"We can now better understand how this very important enzyme carries out its work, which has not been described at a molecular scale until now," says Bing Jap, a biophysicist in Berkeley Lab's Life Sciences Division. He led the research with scientists from the University of California at Berkeley and Germany's Max Planck Institute of Biochemistry.

The scientists report their research August 1 in an advance online publication of the journal Nature Structural & Molecular Biology.

Tripeptidyl peptidase II is found in all eukaryotic cells, which are cells that a have membrane-bound nucleus. Eukaryotic cells make up plants and animals. The enzyme's chief duty is to support the pathway that ensures that cells remain healthy and clutter free by breaking down proteins that are misfolded or have outlived their usefulness.

It's not always so helpful, however. A variation of the enzyme in the brain degrades a hormone that makes people feel satiated after a meal. When this hormone becomes unavailable, a person can eat and eat without feeling full, which can lead to obesity.

Tripeptidyl peptidase II is also the largest protein-degrading enzyme, or protease, in eukaryotic cells. It's more than 100
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Contact: Dan Krotz
dakrotz@lbl.gov
510-486-4019
DOE/Lawrence Berkeley National Laboratory
Source:Eurekalert

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