Titre
Oxidative folding and N-terminal cyclization of onconase
Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Périodique
Auteur(s)
Welker, E.
Auteure/Auteur
Hathaway, L.
Auteure/Auteur
Xu, G.
Auteure/Auteur
Narayan, M.
Auteure/Auteur
Pradeep, L.
Auteure/Auteur
Shin, H. C.
Auteure/Auteur
Scheraga, H. A.
Auteure/Auteur
Liens vers les unités
ISSN
0006-2960
Statut éditorial
Publié
Date de publication
2007-05
Volume
46
Numéro
18
Première page
5485
Dernière page/numéro d’article
93
Notes
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't --- Old month value: May 8
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't --- Old month value: May 8
Résumé
Cyclization of the N-terminal glutamine residue to pyroglutamic acid in onconase, an anti-cancer chemotherapeutic agent, increases the activity and stability of the protein. Here, we examine the correlated effects of the folding/unfolding process and the formation of this N-terminal pyroglutamic acid. The results in this study indicate that cyclization of the N-terminal glutamine has no significant effect on the rate of either reductive unfolding or oxidative folding of the protein. Both the cyclized and uncyclized proteins seem to follow the same oxidative folding pathways; however, cyclization altered the relative flux of the protein in these two pathways by increasing the rate of formation of a kinetically trapped intermediate. Glutaminyl cyclase (QC) catalyzed the cyclization of the unfolded, reduced protein but had no effect on the disulfide-intact, uncyclized, folded protein. The structured intermediates of uncyclized onconase were also resistant to QC catalysis, consistent with their having a native-like fold. These observations suggest that, in vivo, cyclization takes place during the initial stages of oxidative folding, specifically, before the formation of structured intermediates. The competition between oxidative folding and QC-mediated cyclization suggests that QC-catalyzed cyclization of the N-terminal glutamine in onconase occurs in the endoplasmic reticulum, probably co-translationally.
Sujets
PID Serval
serval:BIB_E0A78220B70A
PMID
Date de création
2008-01-24T13:40:48.483Z
Date de création dans IRIS
2025-05-21T07:08:29Z