Cysteines as Redox Molecular Switches and Targets of Disease

Abstract

Thiol groups can undergo numerous modifications, making cysteine a unique molecular switch. Cysteine plays structural and regulatory roles as part of proteins or glutathione, contributing to maintain redox homeostasis and regulate signaling within and amongst cells. Not surprisingly therefore, cysteines are associated with many hereditary and acquired diseases. Mutations in the primary protein sequence (gain or loss of a cysteine) are most frequent in membrane and secretory proteins, correlating with the key roles of disulfide bonds. On the contrary, in the cytosol and nucleus, aberrant post-translational oxidative modifications of thiol groups, reflecting redox changes in the surrounding environment, are a more frequent cause of dysregulation of protein function. This essay highlights the regulatory functions performed by protein cysteine residues and provides a framework for understanding how mutation and/or (in)activation of this key amino acid can cause disease.

Keywords: cellular redoxstasis; cysteine mutation; disulfide bonding; protein misfolding; signaling pathways.

Figure 1

Main post-translational modifications of cysteines. Intermolecular disulfide bonds can be formed with another protein or low molecular weight thiols (like glutathione). In general, intramolecular bonds are inserted into a reduced protein by disulfide exchange with oxidized glutathione (GSSG) or another oxidized protein (e.g., Protein disulfide isomerase, PDI), through the formation of mixed disulfides. Oxidation by reactive oxygen species (ROS) initially leads to sulfenylation (SOH). Because of its relative instability, sulfenylated cysteine can promote intramolecular disulfide bond formation or additionally react with ROS leading first to sulfinylation (SO₂H) and then to sulfonylation (SO₃H). While SO₂H can be reversed through the catalytic activity of the cytoplasmic enzyme sulfiredoxin-1 (SRXN-1; Biteau et al., 2003), SO₃H is so far considered irreversible. Palmitoylation can also take place through creation of thioester bonds between palmitate and cysteine (Fukata and Fukata, 2010).

Figure 2

Cellular compartments differ in their redox poise. The left part of the figure summarizes the data available in the literature concerning glutathione redox potential values (E_h GSSG) in intra- and extra-cellular compartments. Depending on the cell types, physiological conditions and methods used, the results can vary rather significantly. There remains no doubt, however, that mitochondria and cytosol are far more reducing than the endoplasmic reticulum (ER) and extracellular space. Noteworthy, Thioredoxin 1 (Trx1) and Trx2 display a more reducing Kox, confirming their pivotal role in maintaining a suitable redox in the cytosol. Owing to the permeability of nuclear pores, the nucleus is likely to have values similar to the cytosol (values are from Gutscher et al., ; Jones and Go, ; Kojer et al., ; Birk et al., ; Kirstein et al., 2015). The right part highlights instead the main redox control systems in the cytosol, mitochondria and ER. Note the presence in the ER of proteins promoting formation of disulfide bonds (endoplasmic reticulum oxidoreductin 1 (Ero1), quiescin sulfhydryl oxidase (QSOX), PDI, ERp44, etc.) and also the absence of Glutathione reductase (GR), thus contributing to higher GSSG/GSH ratios in the ER compared to the cytosol.