Sthiolation

S-thiolation is a reversible covalent post-translational modification in which a cysteine thiol on a protein forms a mixed disulfide with a low-molecular-weight thiol, most commonly glutathione. The resulting adduct is often written as protein-SSR, with P-S-S-G referring to protein S-glutathionylation.

The modification arises under oxidative or nitrosative stress when reactive oxygen or nitrogen species convert a cysteine thiol to a reactive intermediate, such as a sulfenic acid, which can then form a disulfide with another thiol. Alternatively, disulfide exchange between a protein thiol and a preexisting disulfide like glutathione disulfide (GSSG) can generate protein-SSG. While S-thiolation can protect essential cysteines from irreversible overoxidation, it also serves as a reversible switch that modulates protein function.

Deglutathionylation and reversal of S-thiolation are mediated primarily by redox enzymes such as glutaredoxins and thioredoxins, often using cellular reducing equivalents like NADPH. Non-enzymatic reduction can also occur under favorable cellular conditions. The process is dynamic and responsive to the cellular redox state.

Biological significance includes protection against oxidative damage and regulation of protein activity, localization, and interactions. Examples of targets include actin, glyceraldehyde-3-phosphate dehydrogenase, and peroxiredoxins, where S-glutathionylation can alter polymerization, catalytic activity, or substrate affinity. S-thiolation is studied in redox biology due to its role in signaling, metabolism, aging, and disease contexts such as cardiovascular and neurodegenerative disorders. Detection methods include mass spectrometry and antibodies against glutathione adducts.