Many proteins provided with disulfde 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 disulfdes are still absent. In fact, when the reduced protein assembles into a molten globule state, its cysteines acquire strong hyper-reactivity towards natural disulfdes. The most reactive residue, Cys94, reacts with oxidized glutathione (GSSG) 3000 times faster than an unperturbed protein cysteine. A low pKa of its sulfydryl group (6.6/7.1) and a productive complex with GSSG (KD=0.3mM), causes a fast glutathionylation of this residue (t1/2=3s) 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 felds for Alzheimer’s and Parkinson diseases.
The extreme hyper-reactivity of Cys94 in lysozyme avoids its amorphous aggregation / Bocedi, Alessio; Cattani, Giada; Martelli, Claudia; Cozzolino, Flora; Castagnola, Massimo; Pucci, Pietro; Ricci, Giorgio. - In: SCIENTIFIC REPORTS. - ISSN 2045-2322. - 8:1(2018), pp. 1-10. [10.1038/s41598-018-34439-y]
The extreme hyper-reactivity of Cys94 in lysozyme avoids its amorphous aggregation
Flora Cozzolino;Pietro Pucci;
2018
Abstract
Many proteins provided with disulfde 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 disulfdes are still absent. In fact, when the reduced protein assembles into a molten globule state, its cysteines acquire strong hyper-reactivity towards natural disulfdes. The most reactive residue, Cys94, reacts with oxidized glutathione (GSSG) 3000 times faster than an unperturbed protein cysteine. A low pKa of its sulfydryl group (6.6/7.1) and a productive complex with GSSG (KD=0.3mM), causes a fast glutathionylation of this residue (t1/2=3s) 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 felds for Alzheimer’s and Parkinson diseases.File | Dimensione | Formato | |
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