Orphan PTMs: Rare, yet functionally important modifications of cysteine

The enhanced nucleophilicity and redox sensitivity of the thiol group renders cysteine residues susceptible to numerous electrophilic and oxidative post-translational modifications to form disulfides, sulfenic acids, nitrosothiols, and lipid-modified species. Outside of these well-characterized modifications of cysteine, there are reports of cysteine modification through phosphorylation, methylation, and ubiquitination. Although these post-translational modifications are highly abundant on other amino acids, they play a less pervasive role in cysteine biology. Despite the rarity of these modifications of cysteine, they have been shown to play critical roles in catalysis and regulation. Here we describe these rare post-translational modifications of cysteine in detail, by describing their discovery and functional characterization on diverse proteins. Furthermore, we highlight potential proteomic tools that may aid in globally identifying these modifications to fully elucidate their abundance in biological systems.