A PDI-catalyzed thiol-disulfide switch regulates the production of hydrogen peroxide by human Ero1
JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift)
 
ID 3021421
Author(s) Ramming, Thomas; Okumura, Masaki; Kanemura, Shingo; Baday, Sefer; Birk, Julia; Moes, Suzette; Spiess, Martin; Jenoe, Paul; Berneche, Simon; Inaba, Kenji; Appenzeller-Herzog, Christian
Author(s) at UniBasel Birk, Julia
Appenzeller-Herzog, Christian
Ramming, Thomas
Spiess, Martin
Bernèche, Simon
Baday, Sefer
Jenö, Paul
Moes, Suzanne
Year 2015
Title A PDI-catalyzed thiol-disulfide switch regulates the production of hydrogen peroxide by human Ero1
Journal Free radical biology & medicine
Volume 83
Pages / Article-Number 361-372
Keywords Endoplasmic reticulum, Hydrogen peroxide, Oxidative folding, Disulfide bond formation, Ero1, Peroxidase: Free radicals
Abstract Oxidative folding in the endoplasmic reticulum (ER) involves ER oxidoreductin 1 (Ero1)-mediated disulfide formation in protein disulfide isomerase (PDI). In this process, Ero1 consumes oxygen (O2) and releases hydrogen peroxide (H2O2), but none of the published Ero1 crystal structures reveal any potential pathway for entry and exit of these reactants. We report that additional mutation of the Cys(208)-Cys(241) disulfide in hyperactive Ero1α (Ero1α-C104A/C131A) potentiates H2O2 production, ER oxidation, and cell toxicity. This disulfide clamps two helices that seal the flavin cofactor where O2 is reduced to H2O2. Through its carboxyterminal active site, PDI unlocks this seal by forming a Cys(208)/Cys(241)-dependent mixed-disulfide complex with Ero1α. The H2O2-detoxifying glutathione peroxidase 8 also binds to the Cys(208)/Cys(241) loop region. Supported by O2 diffusion simulations, these data describe the first enzymatically controlled O2 access into a flavoprotein active site, provide molecular-level understanding of Ero1α regulation and H2O2 production/detoxification, and establish the deleterious consequences of constitutive Ero1 activity.
Publisher Pergamon Press
ISSN/ISBN 0891-5849
edoc-URL http://edoc.unibas.ch/dok/A6373598
Full Text on edoc No
Digital Object Identifier DOI 10.1016/j.freeradbiomed.2015.02.011
PubMed ID http://www.ncbi.nlm.nih.gov/pubmed/25697776
ISI-Number WOS:000355577600037
Document type (ISI) Article
 
   

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