Abstract
Post-translational modifications regulate the structure and function of proteins that can result in changes to the activity of different pathways. These include modifications altering the redox state of thiol groups on protein cysteine residues, which are sensitive to oxidative environments. While mass spectrometry has advanced the identification of protein thiol modifications and expanded our knowledge of redox-sensitive pathways, the quantitative aspect of this technique is critical for the field of redox proteomics. In this review, we describe how mass spectrometry-based redox proteomics has enabled researchers to accurately quantify the stoichiometry of reversible oxidative modifications on specific cysteine residues of proteins. We will describe advancements in the methodology that allow for the absolute quantitation of thiol modifications, as well as recent reports that have implemented this approach. We will also highlight the significance and application of such measurements and why they are informative for the field of redox biology.
Highlights
Cysteine is one of the least abundant amino acids in proteins [2,3], yet it plays an important role in modulating protein structure and activity
A constant challenge in thiol redox proteomics is maximizing the proteome coverage of oxidatively modified proteins, as current methods yield a coverage of hundreds to several thousand cysteine sites
Thiol redox proteomics has improved our understanding about redox-sensitive proteins and how the redox state is perturbed by a mutation or in response to stimuli
Summary
The activation or integration of proteins in signaling pathways results from regulatory mechanisms that control their function. The physiological relevance of these aggregates continues to be investigated; some studies point to different effects, such as mitochondrial dysfunction [29] These findings strongly suggest that thiol redox modifications act as critical regulators of GAPDH’s structural and functional properties (Figure 2A). Switches to activate pathways sensitive to changes in the redox state under physiological or oxidative stress conditions [3,6,39,41,42] This can lead to the modulation of protein activity and differential functions, resulting in alternate signaling outcomes [43]. As noted by Go and Jones, thiol redox modifications can be classified into four different types of switches that have a modulatory effect: on-off (protein in-/activation), interaction (binding), allosteric (regulates activity), and thiolation (alternate function) [44]. Other redoxsensitive pathways, are properly executed, there are a variety of factors that work to prevent the overoxidation of proteins and maintain a balanced redox environment
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