Cysteine thiol-to-sulfonate oxidation induces unfolding for the functional switching of the extracellular HMGB1 protein - PubMed

3 days ago

Oxidation of cysteine thiols to sulfonate groups by reactive oxygen species regulates protein function.
Thiol-to-sulfonate oxidation of cysteine 106 induces unfolding of the HMGB1 B-box domain, abolishing its proinflammatory activity.
Other chemical modifications at cysteine 106, like S-glutathionylation, do not cause unfolding.
NMR spectroscopy reveals that oxidation leads to global unfolding but retains residual α-helical propensity near certain helices.
A cysteine 106 aspartate variant mimics sulfonate charge but remains folded.
The sulfonate group drastically slows folding kinetics compared to carboxylate, suggesting a large desolvation penalty.
The mechanism of functional switching involves protein unfolding via thiol-to-sulfonate oxidation in a hydrophobic environment.
HMGB1 is a therapeutic target for inflammatory diseases; understanding this inactivation aids in designing covalent inhibitors.

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