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A PDI-catalyzed thiol-disulfide switch regulates the production of hydrogen peroxide by human Ero1

Ramming, Thomas and Okumura, Masaki and Kanemura, Shingo and Baday, Sefer and Birk, Julia and Moes, Suzette and Spiess, Martin and Jenö, Paul and Bernèche, Simon and Inaba, Kenji and Appenzeller-Herzog, Christian. (2015) A PDI-catalyzed thiol-disulfide switch regulates the production of hydrogen peroxide by human Ero1. Free radical biology & medicine, 83. pp. 361-372.

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Official URL: http://edoc.unibas.ch/dok/A6373598

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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.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Former Organization Units Biozentrum > Computational Biophysics (Bernèche)
05 Faculty of Science > Departement Biozentrum > Growth & Development > Biochemistry (Spiess)
05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Molecular and Systems Toxicology (Odermatt)
UniBasel Contributors:Ramming, Thomas and Birk, Julia and Moes, Suzanne and Spiess, Martin and Jenö, Paul and Appenzeller, Christian and Bernèche, Simon
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Pergamon Press
ISSN:0891-5849
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:05 Jul 2016 07:55
Deposited On:05 Jun 2015 08:52

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