Glutathionylation of Peroxiredoxin I Induces Decamer to Dimers Dissociation with Concomitant Loss of Chaperone Activity

Laboratory of Biochemistry, Biochemistry and Biophysics Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892-8012, United States.
Biochemistry (Impact Factor: 3.02). 03/2011; 50(15):3204-10. DOI: 10.1021/bi101373h
Source: PubMed


Reversible protein glutathionylation, a redox-sensitive regulatory mechanism, plays a key role in cellular regulation and cell signaling. Peroxiredoxins (Prxs), a family of peroxidases that is involved in removing H(2)O(2) and organic hydroperoxides, are known to undergo a functional change from peroxidase to molecular chaperone upon overoxidation of its catalytic cysteine. The functional change is caused by a structural change from low molecular weight oligomers to high molecular weight complexes that possess molecular chaperone activity. We reported earlier that Prx I can be glutathionylated at three of its cysteine residues, Cys52, -83, and -173 [Park et al. (2009) J. Biol. Chem., 284, 23364]. In this study, using analytical ultracentrifugation analysis, we reveal that glutathionylation of Prx I, WT, or its C52S/C173S double mutant shifted its oligomeric status from decamers to a population consisting mainly of dimers. Cys83 is localized at the putative dimer-dimer interface, implying that the redox status of Cys83 may play an important role in stabilizing the oligomeric state of Prx I. Studies with the Prx I (C83S) mutant show that while Cys83 is not essential for the formation of high molecular weight complexes, it affects the dimer-decamer equilibrium. Glutathionylation of the C83S mutant leads to accumulation of dimers and monomers. In addition, glutathionylation of Prx I, both the WT and C52S/C173S mutants, greatly reduces their molecular chaperone activity in protecting citrate synthase from thermally induced aggregation. Together, these results reveal that glutathionylation of Prx I promotes changes in its quaternary structure from decamers to smaller oligomers and concomitantly inactivates its molecular chaperone function.

    • "In particular, nitrated Prx2 was identified in a proteomic analysis of early Alzheimer's disease brains [39] suggesting a possible pathophysiological role of this modification. We recently reported that peroxynitrite-mediated nitration of human Prx2 surprisingly increases its peroxidase activity and protects it from overoxidation by H 2 O 2 [28] while most of the reported posttranslational modifications (PTM) on Prx result in loss of peroxidase activity [15] [40] [41] [42]. "
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    • "Recently, we have shown the impairment of Glo1 activity by glutahionylation as another posttranslational modification [45]. In addition, other groups reported on changes of Glo1 dimer or oligomer stability by glutathionylation which was paralleled by dissociation and decreased protein function [46], [47], [48], [49]. Data about posttranslational modifications leading to Glo1 dimerization and their involvement and function in neuronal injury are still missing. "
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