Sci. Aging Knowl. Environ., 2 June 2004
Clustering sways antioxidant enzyme toward new behavior
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/full/2004/22/nf56
On her own, a Girl Scout might pick up trash on her street, but a whole troop can redecorate a nursing home. An antioxidant protein in yeast also changes its behavior when it congregates with others, according to a new study. It stops quenching free radicals and starts helping proteins fold. Although researchers don't yet know whether its mammalian counterpart behaves similarly, that protein could apply this newfound power to help fight cancer and aging.
Damage from free radicals might promote aging (see "The Two Faces of Oxygen"). Cells possess enzymes that defuse these pernicious molecules. About 10 years ago, researchers identified an antioxidant, peroxiredoxin, that quenches the free radical peroxide. They have characterized the enzyme's activity in test-tube experiments but haven't sorted out how it functions in animals. Nevertheless, it is crucial: Mice that lack the gene for peroxiredoxin develop anemia and cancer, and they die young.
Multiple copies of peroxiredoxin can bunch together into a doughnut shape, previous work revealed. Other proteins that help keep proteins folded--known as chaperones--assume a similar configuration, so Jang and colleagues investigated whether peroxiredoxin performed the same function.
The team prepared yeast that lack the peroxiredoxin gene and heated them to unfold proteins, which sickens cells. More cells without the gene died than cells with it; peroxiredoxin might help proteins maintain their shape after being cooked, the researchers reasoned. In a test tube, peroxiredoxin prevented a test protein from clumping after heating, a hallmark of chaperone activity.
Next, the scientists found that peroxiredoxin takes three shapes when produced by bacteria: assemblies of two or three molecules, the 10-protein doughnut shape, and a supersized cluster. The smallest one quenched peroxide; the extra-large one kept proteins from clumping; and the doughnut performed both jobs. Further studies revealed that heating or peroxide treatment shifted the proteins into the largest structure. Peroxide didn't induce peroxiredoxin to switch forms when the enzyme lacked a particular cysteine; oxidizing that cysteine inactivates the protein's antioxidant activity, according to previous work. The results suggest that heat and oxidative stress push peroxiredoxin into a grouping that shuts down its antioxidant power and stirs a new skill: keeping proteins properly folded. Other antioxidants surpass peroxiredoxin at quenching high concentrations of free radicals, so the switch might make the protein more useful under those conditions. This newly discovered activity could contribute to the protein's apparent capacity to stave off cancer in mammals, the authors speculate.
"I was very impressed," says biochemist Eric Muller of the University of Washington, Seattle. "It's a remarkable display of form following function." Structural biologist P. Andrew Karplus of Oregon State University in Corvallis agrees that the chaperone function is "brand-new and unexpected"; he'd like to know whether the findings apply to other organisms. No one knows yet whether the equivalent protein in mammals acts as a chaperone, he says, and cancer is typically associated with faulty molecular signaling rather than unfolded proteins. Further work should reveal how peroxiredoxin's group mentality plays into the physiology of cells and animals.
June 2, 2004
Science of Aging Knowledge Environment. ISSN 1539-6150