( In the March 3 issue of Nature Johns H...)Computational verification of protein-protein interactions by orthologous co-expression

In the March 3 issue of Nature, Johns Hopkins researchers report that two proteins best known for very different activities actually come together to turn the liver into a sugar-producing factory when food is scarce. Because the liver's production of sugar is a damaging problem in people with diabetes, the proteins' interaction might be a target for future drugs to fight the disease, the researchers say.

Under normal circumstances, the liver's production of sugar is a back-up plan that enables survival during food shortages; the brain and certain other critical organs rely on sugar -- specifically glucose -- for the energy to function. In people with diabetes, however, the liver doesn't sense the incoming calories, and it keeps making glucose when it shouldn't.

The researchers discovered that, in fasting mice, the liver's production of sugar kicked into high gear because amounts and activities of the two proteins, called sirtuin1 and PGC1-alpha, increased when dietary calories weren't available. Once mice were fed, levels of the two proteins went down and sugar production ceased.

"It isn't a coincidence," says Pere Puigserver, Ph.D., an assistant professor of cell biology at the Johns Hopkins University School of Medicine's Institute for Basic Biomedical Sciences. "The two proteins actually bind to each other, and without sirtuin1, PGC1 can't make glucose."

A current diabetes-fighting drug, metformin, blocks steps in the glucose-making process, but the new research identifies a critical regulatory step the researchers say could be targeted as well.

PGC1, which Puigserver isolated and cloned in 1998 as a postdoctoral fellow at Harvard, controls gene expression in the liver and other tissues. In the liver, it triggers the conversion of fats into sugar, particularly when access to food is limited. But no one knew exactly how it was controlled or what else it might need in order to launch the sugar-making process.

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