Disease relevance of ERO1

• ERO1 apparently determines cellular oxidizing capacity since mutation of ERO1 causes hypersensitivity to the reductant DTT, whereas overexpression of ERO1 confers resistance to DTT [1].

High impact information on ERO1

• Remarkably, the Ero1p active site closely resembles that of the versatile thiol oxidase module of Erv2p, a protein with no sequence homology to Ero1p [2].
• The flavoenzyme Ero1p produces disulfide bonds for oxidative protein folding in the endoplasmic reticulum [2].
• Disulfides generated de novo within Ero1p are transferred to protein disulfide isomerase and then to substrate proteins by dithiol-disulfide exchange reactions [2].
• Furthermore, both Ero1p and Erv2p display essential dicysteine motifs on mobile polypeptide segments, suggesting that shuttling electrons to a rigid active site using a flexible strand is a fundamental feature of disulfide-generating flavoenzymes [2].
• The endoplasmic reticulum (ER) supports disulfide bond formation by a poorly understood mechanism requiring protein disulfide isomerase (PDI) and ERO1 [3].

Biological context of ERO1

• We describe a conserved yeast gene, ERO1, that is induced by the unfolded protein response and encodes a novel glycoprotein required for oxidative protein folding in the ER [1].
• KlERO1, an orthologue of Saccharomyces cerevisiae ERO1, was cloned by functional complementation of the ts phenotype of an Scero1 mutant [4].
• Endoplasmic reticulum (ER) oxidoreductin encoded by the ERO1 gene of the yeast Saccharomyces cerevisiae is essential for the formation of protein disulfide bonds in the ER and for cell viability [5].
• Heat shock transcription factor Hsf1 activates ERO1 in response to heat, ethanol, and oxidative stresses [5].
• Contrary to the situation in Saccharomyces cerevisiae, with a single Ero protein (Ero1p), the genomes of Schizosaccharomyces pombe and of humans encode two Ero-like proteins [6].

Anatomical context of ERO1

• FAD is synthesized in the cytosol but can readily enter the ER lumen and promote Ero1p-catalyzed oxidation [7].
• Ero1p is a key enzyme in the disulfide bond formation pathway in eukaryotic cells in both aerobic and anaerobic environments [8].

Associations of ERO1 with chemical compounds

• In the unfolded protein response induced by the reductant dithiothreitol, transcription factor Hac1 activates ERO1 transcription through a sequence that diverges from the consensus Hac1-binding sequence [5].
• We show that glutathione is not required for CPY folding and conclude that Ero1p functions in a novel mechanism that sustains the ER oxidizing potential, supporting net formation of protein disulfide bonds [1].
• Substitution of Cys100 with alanine impedes the capture of Ero1p-Pdi1p mixed-disulfide complexes from yeast, and also blocks oxidation of Pdi1p in vivo [9].
• In yeast, Ero1p-mediated oxidative folding was shown to depend on cellular flavin adenine dinucleotide (FAD) levels but not on ubiquinone or heme, and Ero1p was shown to be a FAD-binding protein [3].
• Here we show that the major pathway for oxidation in the yeast ER, defined by the protein Ero1, is responsible for the oxidation of both glutathione and protein thiols [10].

Other interactions of ERO1

• Genetic tests distinguish the essential function of ERO1 from that of PDI1 [1].

References