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Review
. 2014 Aug;1844(8):1335-43.
doi: 10.1016/j.bbapap.2014.03.007. Epub 2014 Mar 19.

Thiol-based redox switches

Bastian Groitl  1 , Ursula Jakob  2
Affiliations
Review

Thiol-based redox switches

Bastian Groitl et al. Biochim Biophys Acta. 2014 Aug.

Abstract

Regulation of protein function through thiol-based redox switches plays an important role in the response and adaptation to local and global changes in the cellular levels of reactive oxygen species (ROS). Redox regulation is used by first responder proteins, such as ROS-specific transcriptional regulators, chaperones or metabolic enzymes to protect cells against mounting levels of oxidants, repair the damage and restore redox homeostasis. Redox regulation of phosphatases and kinases is used to control the activity of select eukaryotic signaling pathways, making reactive oxygen species important second messengers that regulate growth, development and differentiation. In this review we will compare different types of reversible protein thiol modifications, elaborate on their structural and functional consequences and discuss their role in oxidative stress response and ROS adaptation. This article is part of a Special Issue entitled: Thiol-Based Redox Processes.

Keywords: Disulfide bond; Oxidative stress; Redox regulation; Sulfenic acid.

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Figures

Figure 1
Figure 1. Oxidative thiol modifications commonly found in redox-regulated proteins
Upon reaction with peroxide (H2O2) or hypochlorous acid (HOCl), redox-sensitive thiol groups (RSH) rapidly form sulfenic acids (RSOH). These sulfenates are highly reactive and tend to quickly react with nearby cysteine thiols to form inter- or intramolecular disulfide bonds (RSSR). Alternatively, they form mixed disulfides with the small tripeptide glutathione (GSH) (RSSG), or undergo cyclic sulfenamide formation (RSNHR). These oxidative thiol modifications are fully reversible, and reduction (RED) is catalyzed by members of the glutaredoxin (Grx) or thioredoxin (Trx) system. Further oxidation of sulfenic acid to sulfinic acid (RSO2H), sulfinamide (RSONHR) or sulfonic acid (RSO3H) is irreversible. One exception is the active site sulfinic acid in peroxiredoxin, whose reduction is mediated by the highly specialized ATP-dependent sulfiredoxin Srx1.
Figure 2
Figure 2. Redox cycle of Hsp33
Under non-stress conditions, the heat shock protein Hsp33 is reduced and chaperone-inactive. All four highly conserved cysteines coordinate one zinc ion with high affinity. (1) Upon exposure to bleach (HOCl) or hydrogen peroxide (H2O2) in combination with elevated temperatures, Hsp33’s cysteines form two disulfide bonds, causing the zinc to be released. Loss of zinc binding in combination with disulfide bond formation leads to the partial unfolding of Hsp33, the required step for Hsp33’s activation as a chaperone. Two partially unfolded monomers then associate to form a chaperone-active Hsp33 dimer. (2) Once activated, Hsp33 stabilizes oxidatively unfolding proteins and forms stable client protein – chaperone complexes. (3) Upon return to non-stress conditions, the thioredoxin system reduces Hsp33’s disulfide bonds, generating a chaperone-active reduced dimer – client protein complex. (4) In the last step, the client protein is transferred to the DnaK/DnaJ/GrpE system for productive refolding, and Hsp33 dissociates into its monomeric, inactive state.
Figure 3
Figure 3. Redox regulation of protein splicing
A. Mechanistic scheme of the protein splicing process. The small intervening protein intein (red) is embedded within a host protein (extein), which is inactive until intein is excised and its termini are re-ligated. (1) In the initial reaction, the active site nucleophile XH (cysteine Cys 1 or serine Ser 1) of intein forms a (thio)ester with the adjacent carbonyl carbon of N-extein (yellow). (2) In a subsequent trans-(thio)esterification reaction, the N-extein is transferred onto the side chain of the first C-extein residue (green), which is typically also a cysteine residue (Cys+1). (3) Complete excision of the intein is achieved by the formation of an aminosuccinimide, which involves a highly conserved Asn, located at the very C-terminus of the intein. (4) In the last step, a new peptide bond is formed between the N-extein and C-extein fragments. B. Schematic representation of the intein splicing process of the Mma PolII precursor protein. In the oxidized state, the active site cysteine Cys1 forms an intramolecular disulfide bond with Cys147, which is also located in the intein. This causes the inactivation of intein’s self-splicing function. Incubation with reducing agents (e.g., DTT, TCEP) reduces the disulfide bond, and the intein undergoes the previously described self-splicing process, leading to the activation of the host protein.
Figure 4
Figure 4. Mechanism of sulfenamide formation in protein tyrosine phosphatase B1 (PTPB1)
(1) Exposure of the catalytic cysteine 215 (RSH) of PTPB1 to H2O2 leads to the formation of a sulfenic acid (RSOH), which undergoes (2) intramolecular cyclization with a nearby amino group, yielding in sulfenamide (RSNR). (3) Reduction of the sulfenamide is mediated by forming a mixed disulfide formation with glutathione, which is subsequently resolved by glutaredoxin.
Figure 5
Figure 5. Peroxiredoxin – An Enzyme with Multiple Personalities
(1) Peroxiredoxins (orange) are responsible for the breakdown of hydrogen peroxide. In this process, their peroxidatic cysteines become oxidized to sulfenic acids. (2) Intermolecular disulfide bond formation with the resolving cysteines in Prx follows. (3) The disulfide bond is subsequently reduced by the Trx system. (4) In an alternative pathway, oxidized peroxiredoxin interacts with the thiol group of a reduced client protein (e.g. Yap1p), forming an intermolecular disulfide bond. (5) This disulfide bond is then resolved by a thiol-disulfide exchange reaction, yielding in an intramolecular disulfide bond within the client protein and reduced Prx. (6) High levels of peroxide lead to the formation of sulfinic acid at the active site cysteine and the inactivation of the peroxidase function. (7) Overoxidation triggers the assembly of peroxiredoxin into higher molecular weight structures, which exert chaperone function in vitro. (8) ATP-dependent sulfiredoxin (SRX) reduces the sulfinic acid in peroxiredoxin.
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