Aerobic organisms have elaborate defenses against reactive oxygen species (ROS), which are produced during normal aerobic metabolism and in response to various stresses and have been linked with disorders ranging from neurodegenerative disease to cancer. These defenses include antioxidant proteins such as the peroxiredoxins (Prxs), which reduce H2O2 and peroxinitrite, and chaperones, which protect against protein unfolding and aggregation. Surprisingly, peroxiredoxins, which regulate peroxide-mediated cell signaling and are implicated in numerous cellular processes, have relatively weak peroxidase activity and can be inactivated while reducing H2O2. Jang et al. found that, in yeast lacking the cytosolic cPrxI and cPrxII, both wild-type cPrxI and a form lacking peroxidase activity protected against heat shock. In a spectrophotometric assay, cPrxI inhibited protein aggregation in response to heat as well as dithiothreitol-mediated precipitation. Size exclusion chromatography and polyacrylamide electrophoresis indicated that cPrxI existed in different oligomeric forms. Moreover, electron microscopic analysis revealed large spheres in the highest molecular weight fraction (HMW, up to 1000 kD), rings in the middle fraction, and irregular particles in the lowest MW fraction (LMW, about 40 to 120 kD). HMW protein had chaperone activity, LMW protein had peroxidase activity, and protein from the middle fraction had both peroxidase and chaperone activity. Heat shock and H2O2 treatment promoted the HMW form and chaperone activity in yeast, at the expense of the LMW form and peroxidase activity. Similar results were found for cPrxII. Thus, under normal conditions, most cPrx1 and cPrxII are in low and mid-size forms and act as both peroxidase and chaperone; heat shock and oxidative stress promote formation of the HMW form and thereby increase chaperone activity and yeast survival.
H. H. Jang, K. O. Lee, Y. H. Chi, B. G. Jung, S. K. Park, J. H. Park, J. R. Lee, S. S. Lee, J. C. Moon, J. W. Yun, Y. O. Choi, W. Y. Kim, J. S. Kang, G.-W. Cheong, D.-J. Yun, S. G. Rhee, M. J. Cho, S. Y. Lee, Two enzymes in one: Two yeast peroxiredoxins display oxidative stress-dependent switching from a peroxidase to a molecular chaperone function. Cell 117, 625-635 (2004). [Online Journal]