Peroxiredoxins wear many hats: Factors that fashion their peroxide sensing personalities

Abstract

Peroxiredoxins (Prdxs) sense and assess peroxide levels, and signal through protein interactions. Understanding the role of the multiple structural and post-translational modification (PTM) layers that tunes the peroxiredoxin specificities is still a challenge. In this review, we give a tabulated overview on what is known about human and bacterial peroxiredoxins with a focus on structure, PTMs, and protein-protein interactions. Armed with numerous cellular and atomic level experimental techniques, we look at the future and ask ourselves what is still needed to give us a clearer view on the cellular operating power of Prdxs in both stress and non-stress conditions.

Keywords: Hydrogen peroxide (H(2)O(2)); Peroxiredoxin; Post-translational modification (PTM); Prdx; Protein-protein interactions (PPI); Prx; Redox signaling.

Fig. 1

Mechanism of the redox cycle and the redox-relay of typical 2-Cys Prdxs (shown family members are the cytosolic human Prdx1 and Prdx2). Prdx scavenges H₂O₂through the formation of a sulfenic acid (Cys-SOH) on the peroxidatic cysteine (Cys_P) with the subsequent formation of a disulfide bond between Cys_Pand the resolving cysteine (Cys_R) [10]. Prdx is recycled via the thioredoxin pathway (Trx-TrxR-NADPH) [11]. Via a redox-relay, oxidative equivalents can be transferred to a binding partner in a process that, depending on the partner, may involve an additional scaffold protein.

Fig. 2

Oligomeric states of Prdxs. There is dynamic equilibrium between dimer and decamer when Prdx is reduced, with the reduced (SH) decamer being the most efficient. Oxidation loosens the decamers causing them to dissociate back into dimers. The structures depicted are WT Salmonella typhimurium Prdx1/AhpC (reduced form (green): 4MA9; oxidized form (light blue): 1EYP). The decamers can stack also to form HMW oligomers, and this is usually linked to overoxidation, like what is shown in purple (human Prdx3: 5JCG). Overoxidized Prdxs are repaired by sulfiredoxin (Srx) in an ATP-dependent mechanism, shown with the Prdx-Srx complex structure (dark blue, human Prdx1: 2RII). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 3

Active site organization of peroxiredoxins. A.The low pKa of the peroxidatic cysteine (Cys_P) and the conserved hydrogen bonding network that stabilizes the transition state determine the high second order rate constant of H₂O₂sensing. Adapted from Hall et al. [6].B.The formation of the intersubunit disulfide bond (Cys_P-S-S-Cys_R) in the presence of H₂O₂requires the structural rearrangement of the active site from a fully folded (green) to a locally unfolded (light blue) loop for the Cys_R-S to access the oxidized Cys_P-S.C.The distance between the resolving Cys in the reduced (Cys_R-SH) and oxidized (Cys_R-S-) peroxiredoxin is shown. The structures depicted in b) and c) are WT Salmonella typhimurium Prdx1/AhpC (reduced form (green): 4MA9; oxidized form (blue): 1EYP). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)