Orphan PTMs: Rare, yet functionally important modifications of cysteine

Abstract

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.

Chemical Protein Modification through Cysteine

“…In terms of PTM mimics, S‐linked PTMs are naturally occurring, and so thiol addition to Dha will not always result in a structural mimic . The chemical introduction of S‐linked PTMs allows a facile method for exploration of the modification.…”

“…This, though, is highly dependent on its conformation and its environment in terms of buffer and neighbouring residues, and can be even lower . As well as a unique reactivity, cysteine also has an incredibly diverse reactivity profile, as exemplified by the abundance of post‐translational modifications (PTMs) it undergoes . It is able to interconvert between multiple oxidation states, often negates the need for co‐factors in vivo, and is essential in cellular redox regulation.…”

Modified cysteine S-phosphopeptide standards for mass spectrometry-based proteomics

“…Continuing progress in phosphoproteomics studies is elucidating cellular processes that are modulated by dynamic phosphorylation on hydroxyl (Duan and Walther 2015), carboxyl (Attwood et al 2011;Lai et al 2017) and amine groups (Marmelstein et al 2017) in protein amino acid residues. Moderately susceptible to acid hydrolysis, S-linked phosphorylation is among the least explored modifications (Shannon and Weerapana 2013;Piggott and Attwood 2017) and it is discussed mainly in the context of transient cysteine phosphorylation of protein tyrosine phosphatases (Tonks 2014). In 2012, the reversible cysteine phosphorylation of several global transcriptional regulators was reported in Staphylococcus aureus (Sun et al 2012).…”

The next frontier of post‐translational modifications

“…This leads to an array of both oxidative and enzymatic modifications. Shannon and Weerapana review rare cysteine PTMs, including methylation, phosphorylation, and ubiquitylation . They discuss the biological significance of the poorly characterized and scarce modifications that occur in both mammals and bacteria.…”

“…Shannon and Weerapana review rare cysteine PTMs, including methylation, phosphorylation, and ubiquitylation. 5 They discuss the biological significance of the poorly characterized and scarce modifications that occur in both mammals and bacteria. Pan and Carroll review recent advances in understanding cysteine sulfenylation, and the merging functional role in of oxidative regulation of key signaling pathways.…”