Human ER Oxidoreductin-1-α (Ero1α) undergoes dual regulation through complementary redox interactions with protein-disulfide isomerase

Shingo Kanemura, Masaki Okumura, Katsuhide Yutani, Thomas Ramming, Takaaki Hikima, Christian Appenzeller-Herzog, Shuji Akiyama, Kenji Inaba

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)

Abstract

In the mammalian endoplasmic reticulum, oxidoreductin-1α (Ero1α) generates protein disulfide bonds and transfers them specifically to canonical protein-disulfide isomerase (PDI) to sustain oxidative protein folding. This oxidative process is coupled to the reduction ofO2 toH2O2 on the bound flavin adenine dinucleotide cofactor. Because excessive thiol oxidation and H2O2 generation cause cell death, Ero1α activity must be properly regulated. In addition to the four catalytic cysteines (Cys94, Cys99, Cys104, and Cys131) that are located in the flexible active site region, the Cys208-Cys241 pair located at the base of another flexible loop is necessary for Ero1α regulation, although the mechanistic basis is not fully understood. The present study revealed that the Cys208-Cys241 disulfide was reduced by PDI and other PDI family members during PDI oxidation. Differential scanning calorimetry and small angle X-ray scattering showed that mutation of Cys208-Cys241 did not grossly affect the thermal stability or overall shape of Ero1α, suggesting that redox regulation of this cysteine pair serves a functional role. Moreover, the flexible loop flanked by Cys208-Cys241 provides a platform for functional interaction with PDI, which in turn enhances the oxidative activity of Ero1α through reduction of the Cys208-Cys241 disulfide.Wepropose a mechanism of dual Ero1α regulation by dynamic redox interactions between PDIand the two Ero1αflexible loops that harbor the regulatory cysteines.

Original languageEnglish
Pages (from-to)23952-23964
Number of pages13
JournalJournal of Biological Chemistry
Volume291
Issue number46
DOIs
Publication statusPublished - 2016 Nov 11

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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