Abstract
Cysteine is susceptible to a variety of modifications by reactive oxygen and nitrogen oxide species, including glutathionylation; and when two cysteines are involved, disulfide formation. Glutathione-cysteine adducts may be removed from proteins by glutaredoxin, whereas disulfides may be reduced by thioredoxin. Glutaredoxin is homologous to the disulfide-reducing thioredoxin and shares similar binding modes of the protein substrate. The evolution of these systems is not well characterized. When a single Cys is present in a protein, conjugation of the redox buffer glutathione may induce conformational changes, resulting in a simple redox switch that effects a signaling cascade. If a second cysteine is introduced into the sequence, the potential for disulfide formation exists. In favorable protein contexts, a bistable redox switch may be formed. Because of glutaredoxin's similarities to thioredoxin, the mutated protein may be immediately exapted into the thioredoxin-dependent redox cycle upon addition of the second cysteine. Here we searched for examples of protein substrates where the number of redox-active cysteine residues has changed throughout evolution. We focused on cross-strand disulfides (CSDs), the most common type of forbidden disulfide. We searched for proteins where the CSD is present, absent and also found as a single cysteine in protein orthologs. Three different proteins were selected for detailed study—CD4, ERO1, and AKT. We created phylogenetic trees, examining when the CSD residues were mutated during protein evolution. We posit that the primordial cysteine is likely to be the cysteine of the CSD which undergoes nucleophilic attack by thioredoxin. Thus, a redox-active disulfide may be introduced into a protein structure by stepwise mutation of two residues in the native sequence to Cys. By extension, evolutionary acquisition of structural disulfides in proteins can potentially occur via transition through a redox-active disulfide state.
Highlights
Thiol-based redox signaling is the collective name for biochemical pathways that regulate cellular processes by post-translational modification of sulfur moieties in cysteine (Cys) and methionine (Met) residues of proteins
We focused on cross-strand disulfides (CSDs), the most common type of forbidden disulfide
Because CSDs can act as redox switches, failure to control conditions carefully results in the proteins adopting different structural states
Summary
Thiol-based redox signaling is the collective name for biochemical pathways that regulate cellular processes by post-translational modification of sulfur moieties in cysteine (Cys) and methionine (Met) residues of proteins. These pathways are pathologically dysregulated in diseases of oxidative stress which include cancer, neurodegenerative diseases, heart disease and aging. Cys can be nitrosated, glutathionylated, and can form covalent bonds with other Cys. RNS such as nitric oxide (NO) can mediate S-nitrosation to yield an S-nitrosothiol (RSNO). Oxidation by ROS or RNS can result in a disulfide bridge forming between two thiols, either within a protein chain or between protein chains (Wouters et al, 2011)
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