Working Out the Kinks: Fly enzyme reverses protein damage, extends life-span (Protein damage)

Abstract

Getting bent out of shape isn't good for a person's blood pressure--or for proteins. Over time, cellular proteins accumulate chemical changes that can distort their shapes and disrupt their functions. Keeping these alterations at bay might help an aging organism maintain its youthful vigor. New results support that idea by indicating that extra doses of a protein-repairing enzyme help flies live longer, at least under certain conditions. Two amino acids--aspartate and asparagine--can spontaneously undergo changes that convert them to another chemical form, called isoaspartate. The transformation reshuffles the carbon atoms in the amino acids. This perturbation puts a kink in the backbone of a protein that contains the amino acids, which distorts the shape of the protein and can prevent it from performing its cellular duties. To combat this affront, organisms carry an enzyme called protein carboxyl methyltransferase (PCMT), which converts isoaspartate back to aspartate and restores the backbone to its proper line. Because isoaspartates accumulate as organisms age, Chavous and colleagues wondered whether supplementary PCMT would increase an animal's life-span. To find out, the researchers manipulated amounts of PCMT in the fruit fly Drosophila melanogaster. They engineered some flies to produce large amounts of PCMT all the time and other flies to produce extra protein only at higher than normal temperatures. They grew both sets of flies, along with a control group, at either room temperature or the elevated temperature and waited for the flies to die. At the elevated temperature, both types of experimental flies lived about 35% longer on average than did control flies. At room temperature, however, neither set of test flies lived longer than normal. The results suggest that enhanced protein-repairing power can help flies endure, but only at elevated temperatures. It's not clear why supplemental PCMT doesn't extend the life-span of flies grown at room temperature. PCMT might require the assistance of heat shock proteins, whose amounts shoot up with temperature and which help cells maintain protein integrity. These proteins--which unfold and refold other proteins to help them maintain their proper shape--might help PCMT gain access to the altered amino acids. Alternatively, extra PCMT might make a measurable difference only when isoaspartates accumulate rapidly, as they do at higher temperatures. The work hints that keeping the kinks out of proteins--especially under stressful conditions such as high temperature--might stretch out an animal's life-span. --R. John Davenport; suggested by Amir A. Sadighi Akha D. A. Chavous, F. R. Jackson, C. M. O'Connor, Extension of the Drosophila lifespan by overexpression of a protein repair methyltransferase. Proc. Natl. Acad. Sci. U.S.A. 98 , 14814-14818 (2001). [Abstract] [Full Text]