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Switcheroo. A protein flips from off (cyan and blue) to on (yellow and orange).

Protein Switches That Won't Sit Still

Cells can respond to a host of environmental vicissitudes such as changes in nutrients, bursts of hormones, or encroaching neighbors, for instance. Protein switches give cells the power to adapt. Now scientists have captured a molecular switch in mid-flip, and it behaves something like a light switch that constantly jiggles by itself. The research adds to evidence that these switch proteins don't just sit still, waiting to be turned on--a conclusion that complicates the picture of how they function.

A well-studied cellular switch is a protein called NtrC in the bacterium Escherichia coli. When nitrogen is scarce, an enzyme tacks a phosphate group onto NtrC--a process known as phosphorylation--and thus "flips" NtrC from an inactive to an active form. Active NtrC binds to DNA and boosts the expression of certain genes that allow the cell to live without nitrogen. While such protein switches are often depicted as static structures that are either on or off, in reality these proteins are active molecules that are constantly changing shape. Capturing these dynamics is critical to understanding how such switches work.

To get a handle on the gymnastics, structural biologist Dorothee Kern of Brandeis University in Waltham, Massachusetts, used nuclear magnetic resonance (NMR) to measure the movement of individual atoms of NtrC. The flexibility of the unphosphorylated protein hinted to Kern and her co-workers that it might be flipping back and forth between the active and inactive forms. For confirmation, the researchers looked at mutant forms of the protein. They found that the more efficient a mutant was at turning on genes, the more time it spent flipped into the active shape, they report in the 23 March issue of Science. The unphosphorylated protein isn't static, concludes Kern, but is flipping on and off. Phosphorylation, she says, shifts the balance of the flip so that the protein spends more time in the active form.

The concept that proteins flip between multiple forms is not completely new, but others are impressed that the researchers captured these protein dynamics experimentally. NMR spectroscopist Ad Bax of the National Institutes of Health in Bethesda, Maryland, says the study tells "a very convincing story."

Related sites

Dorothee Kern's faculty page
Watch a movie of the protein flipping