The redox switch that regulates molecular chaperones

Abstract

Modification of reactive cysteine residues plays an integral role in redox-regulated reactions. Oxidation of thiolate anions to sulphenic acid can result in disulphide bond formation, or overoxidation to sulphonic acid, representing reversible and irreversible endpoints of cysteine oxidation, respectively. The antioxidant systems of the cell, including the thioredoxin and glutaredoxin systems, aim to prevent these higher and irreversible oxidation states. This is important as these redox transitions have numerous roles in regulating the structure/function relationship of proteins. Proteins with redox-active switches as described for peroxiredoxin (Prx) and protein disulphide isomerase (PDI) can undergo dynamic structural rearrangement resulting in a gain of function. For Prx, transition from cysteine sulphenic acid to sulphinic acid is described as an adaptive response during increased cellular stress causing Prx to form higher molecular weight aggregates, switching its role from antioxidant to molecular chaperone. Evidence in support of PDI as a redox-regulated chaperone is also gaining impetus, where oxidation of the redox-active CXXC regions causes a structural change, exposing its hydrophobic region, facilitating polypeptide folding. In this review, we will focus on these two chaperones that are directly regulated through thiol-disulphide exchange and detail how these redox-induced switches allow for dual activity. Moreover, we will introduce a new role for a metabolic protein, the branched-chain aminotransferase, and discuss how it shares common mechanistic features with these well-documented chaperones. Together, the physiological importance of the redox regulation of these proteins under pathological conditions such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis will be discussed to illustrate the impact and importance of correct folding and chaperone-mediated activity.

Novel Blood Biomarkers that Correlate with Cognitive Performance and Hippocampal Volumetry: Potential for Early Diagnosis of Alzheimer’s Disease

“…However, as with most biological systems, an imbalance in metabolism could generate secondary consequences, such as increased glutamate production leading to neuronal toxicity, a recognised contributing factor to AD pathology. If BCATis oxidised it could assume a moonlighting neurotoxic role [69]. Together both the BCAT proteins and their metabolites hold promise as markers of AD pathology and may also serve as targets for future therapy-related approaches.…”

Insights into the Function of a Second, Nonclassical Ahp Peroxidase, AhpA, in Oxidative Stress Resistance in Bacillus subtilis

“…Indeed, some peroxiredoxins have molecular chaperone activity, which is used to prevent protein aggregation under stress conditions (67,68). This chaperone activity is correlated with the overoxidation of the active-site cysteine and the formation of high-molecular-weight complexes (67,68).…”

“…Indeed, some peroxiredoxins have molecular chaperone activity, which is used to prevent protein aggregation under stress conditions (67,68). This chaperone activity is correlated with the overoxidation of the active-site cysteine and the formation of high-molecular-weight complexes (67,68). While this chaperone activity has mostly been associated with eukaryotic peroxiredoxins, it was shown that AhpC (a nonclassical Ahp) from Helicobacter pylori acts as a molecular chaperone under conditions of oxidative stress (69).…”

Visualization of aging-associated chromatin alterations with an engineered TALE system

“…We treated the cells with N -acetyl-cysteine (NAC), a strong antioxidant that increases cellular reductive levels 37 , and found that suppression of oxidative stress by NAC did not result in correct genomic targeting by conventional TALEs (Supplementary information, Figure S2H). Finally, we compared the effect of TRX with another small redox protein, glutaredoxin (GRX) 38,39 . The GRX-fused TALE telo did not exhibit telomere-specific distribution (Supplementary information, Figure S2I).…”