Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2009 Jun 9;48(22):4666-76.
doi: 10.1021/bi9003556.

Redox-regulated chaperones

Caroline Kumsta  1 , Ursula Jakob
Affiliations
Review

Redox-regulated chaperones

Caroline Kumsta et al. Biochemistry. .

Abstract

Redox regulation of stress proteins, such as molecular chaperones, guarantees an immediate response to oxidative stress conditions. This review focuses on the two major classes of redox-regulated chaperones, Hsp33 in bacteria and typical 2-Cys peroxiredoxins in eukaryotes. Both proteins employ redox-sensitive cysteines, whose oxidation status directly controls their affinity for unfolding proteins and therefore their chaperone function. We will first discuss Hsp33, whose oxidative stress-induced disulfide bond formation triggers the partial unfolding of the chaperone, which, in turn, leads to the exposure of a high-affinity binding site for unfolded proteins. This rapid mode of activation makes Hsp33 essential for protecting bacteria against severe oxidative stress conditions, such as hypochlorite (i.e., bleach) treatment, which leads to widespread protein unfolding and aggregation. We will compare Hsp33 to the highly abundant eukaryotic typical 2-Cys peroxiredoxin, whose oxidative stress-induced sulfinic acid formation turns the peroxidase into a molecular chaperone in vitro and presumably in vivo. These examples illustrate how proteins use reversible cysteine modifications to rapidly adjust to oxidative stress conditions and demonstrate that redox regulation plays a vital role in protecting organisms against reactive oxygen species-mediated cell death.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Oxidative thiol modifications. Exposure of redox-sensitive cysteine residues to oxidants such as H2O2 leads to reversible sulfenic acid formation. Sulfenic acids readily react with nearby thiols of the same protein to form intramolecular disulfide bonds. They can also react with thiols of other proteins or the small tripeptide glutathione to form intermolecular or mixed disulfide bonds. Reduced cysteines can be directly oxidized to disulfide bonds by disulfide exchange reactions with oxidized glutathione (GSSG). These oxidative thiol modifications are reduced by members of the glutaredoxin (Grx) or thioredoxin (Trx) system, which draw their reducing power from cellular NADPH. In the presence of high levels of H2O2, overoxidation to sulfinic acid or sulfonic acid can occur. While sulfiredoxins (Srx) specifically reduce sulfinic acids in 2-Cys peroxiredoxins, no general sulfinic or sulfinic reductases have been identified to date.
Figure 2
Figure 2
Model of Hsp33’s activation. Under nonstress conditions, Hsp33 is monomeric and inactive. All four invariant cysteines are reduced and bind one zinc ion (red), forming a compactly folded zinc center (orange). (1) Exposure to oxidants causes the formation of the first disulfide bond connecting Cys265 with Cys268, which triggers zinc release and the unfolding of the zinc binding domain. (2) Unfolding of the zinc binding domain destabilizes the adjacent linker region (green), which is now in a dynamic equilibrium between a folded and partially unfolded conformation. At nonstress temperatures, the equilibrium favors the folded conformation and kinetically slow oxidants, like H2O2, cannot access the cysteines or activate Hsp33. (3) Mild denaturing conditions (e.g., elevated temperatures) shift the equilibrium and allow H2O2 to induce formation of the second disulfide bond between Cys232 and Cys234. (4) This disulfide bond apparently locks the linker region in an unfolded conformation. It causes the exposure of large hydrophobic surfaces on the N-terminal Hsp33 domain (blue), the proposed binding sites for unfolded proteins, and causes the formation of highly chaperone active Hsp33 dimers.
Figure 3
Figure 3
Functional switch of 2-Cys peroxiredoxin. Crystal structures of (A) overoxidized, fully folded human PrxII (Protein Data Bank entry 1QMV) and (B) disulfide-bonded, locally unfolded human PrxI (Protein Data Bank entry 1QQS).The two subunits of the homodimer are colored orange and blue, respectively. The peroxidatic (CP) and resolving cysteines (CR) are depicted as balls and sticks. Asterisks mark the ends of the disordered C-termini in panel B. (C)Model of reaction and activation cycle of 2-Cys peroxiredoxins. Under nonstress conditions, (1) Prx catalyzes the reduction of H2O2 to H2O. This leads to sulfenic acid (SOH) formation at the peroxidatic cysteine, CP. (2) The resolving cysteine (CR) of the other subunit attacks CP-SOH, and an intermolecular disulfide bond is formed. (3)The disulfide bond is reduced by the thioredoxin system. Under oxidative stress conditions, (4) CP-SOH reacts with a second H2O2 molecule and a sulfinic acid (CP-SO2H) is formed. Sulfinic acid formation inactivates the peroxidase activity and (5) supports the assembly into chaperone-active high-molecular weight (HMW) complexes, which prevent the aggregation of unfolding proteins in vitro. Neither the precise structure of the HMW complexes nor the binding site for unfolding proteins has been identified. (6) Reduction of overoxidized Prx is catalyzed by sulfiredoxin upon the return to nonstress conditions. The fate of the bound substrate proteins remains to be determined.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Schrader M, Fahimi HD. Peroxisomes and oxidative stress. Biochim Biophys Acta. 2006;1763:1755–1766. - PubMed
    1. Michiels C, Raes M, Toussaint O, Remacle J. Importance of Se-glutathione peroxidase, catalase, and Cu/Zn-SOD for cell survival against oxidative stress. Free Radical Biol Med. 1994;17:235–248. - PubMed
    1. D’Autreaux B, Toledano MB. ROS as signalling molecules: Mechanisms that generate specificity in ROS homeostasis. Nat Rev Mol Cell Biol. 2007;8:813–824. - PubMed
    1. Rhee SG. Cell signaling. H2O2, a necessary evil for cell signaling. Science. 2006;312:1882–1883. - PubMed
    1. Stadtman ER. Protein oxidation in aging and age-related diseases. Ann NY Acad Sci. 2001;928:22–38. - PubMed