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

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 in questo prodotto:
File Dimensione Formato  
Scientific Report 2018.pdf

accesso aperto

Licenza: Dominio pubblico
Dimensione 3.1 MB
Formato Adobe PDF
3.1 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/724698
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 7
  • ???jsp.display-item.citation.isi??? 7
social impact