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 pK(a) of its sulfhydryl group (6.6/7.1) and a productive complex with GSSG (K-D = 0.3 mM), causes a fast glutathionylation of this residue (t(1/2) = 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.

Bocedi, A., Cattani, G., Martelli, C., Cozzolino, F., Castagnola, M., Pucci, P., et al. (2018). The extreme hyper-reactivity of Cys94 in lysozyme avoids its amorphous aggregation. SCIENTIFIC REPORTS, 8(1), 16050 [10.1038/s41598-018-34439-y].

The extreme hyper-reactivity of Cys94 in lysozyme avoids its amorphous aggregation

Bocedi A.;Ricci G.
2018-01-01

Abstract

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 pK(a) of its sulfhydryl group (6.6/7.1) and a productive complex with GSSG (K-D = 0.3 mM), causes a fast glutathionylation of this residue (t(1/2) = 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.
2018
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/10 - BIOCHIMICA
English
Bocedi, A., Cattani, G., Martelli, C., Cozzolino, F., Castagnola, M., Pucci, P., et al. (2018). The extreme hyper-reactivity of Cys94 in lysozyme avoids its amorphous aggregation. SCIENTIFIC REPORTS, 8(1), 16050 [10.1038/s41598-018-34439-y].
Bocedi, A; Cattani, G; Martelli, C; Cozzolino, F; Castagnola, M; Pucci, P; Ricci, G
Articolo su rivista
File in questo prodotto:
File Dimensione Formato  
Bocedi et al Sci Rep 2018 DEF-merged.pdf

solo utenti autorizzati

Licenza: Copyright dell'editore
Dimensione 3.41 MB
Formato Adobe PDF
3.41 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

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/2108/215439
Citazioni
  • ???jsp.display-item.citation.pmc??? 6
  • Scopus 8
  • ???jsp.display-item.citation.isi??? 7
social impact