Beschreibung:
<jats:title>Abstract</jats:title><jats:p>Many proteins provided with disulfide bridges in the native state undergo amorphous irreversible aggregation when these bonds are not formed. Here we show that egg lysozyme displays a clever strategy to prevent this deleterious aggregation during the nascent phase when disulfides are still absent. In fact, when the reduced protein assembles into a molten globule state, its cysteines acquire strong hyper-reactivity towards natural disulfides. The most reactive residue, Cys94, reacts with oxidized glutathione (GSSG) 3000 times faster than an unperturbed protein cysteine. A low p<jats:italic>K</jats:italic><jats:sub>a</jats:sub> of its sulfhydryl group (6.6/7.1) and a productive complex with GSSG (<jats:italic>K</jats:italic><jats:sub>D</jats:sub> = 0.3 mM), causes a fast glutathionylation of this residue (t<jats:sub>1/2</jats:sub> = 3 s) and a complete inhibition of the protein aggregation. Other six cysteines display 70 times higher reactivity toward GSSG. The discovery of extreme hyper-reactivity in cysteines only devoted to structural roles opens new research fields for Alzheimer’s and Parkinson diseases.</jats:p>