Disulphide production by Ero1α–PDI relay is rapid and effectively regulated

Appenzeller-Herzog, Christian; Riemer, Jan; Zito, Ester; Chin, King Tung; Ron, David; Spiess, Martin; Ellgaard, Lars

doi:10.1038/emboj.2010.203

Cited by 131 publications

(149 citation statements)

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“…or by oxidized PDI, resulting in decreased Ero1 activity (18,22,24,25). Although this feedback regulation model has been widely accepted, our present studies have unraveled unique features of the yeast Ero1p-Pdi1p interplay, which are very different from the human Ero1␣-PDI system but were neglected in previous studies.…”

Section: Discussionmentioning

confidence: 67%

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Novel Roles of the Non-catalytic Elements of Yeast Protein-disulfide Isomerase in Its Interplay with Endoplasmic Reticulum Oxidoreductin 1

Niu

Zhang

et al. 2016

Journal of Biological Chemistry

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The formation of disulfide bonds in the endoplasmic reticulum (ER) of eukaryotic cells is catalyzed by the sulfhydryl oxidase, ER oxidoreductin 1 (Ero1), and protein-disulfide isomerase (PDI). PDI is oxidized by Ero1 to continuously introduce disulfides into substrates, and feedback regulates Ero1 activity by manipulating the regulatory disulfides of Ero1. In this study we find that yeast Ero1p is enzymatically active even with its regulatory disulfides intact, and further activation of Ero1p by reduction of the regulatory disulfides requires the reduction of non-catalytic Cys 90 -Cys 97 disulfide in Pdi1p. The principal client-binding site in the Pdi1p b domain is necessary not only for the functional Ero1p-Pdi1p disulfide relay but also for the activation of Ero1p. We also demonstrate by complementary activation assays that the regulatory disulfides in Ero1p are much more stable than those in human Ero1␣. These new findings on yeast Ero1p-Pdi1p interplay reveal significant differences from our previously identified mode of human Ero1␣-PDI interplay and provide insights into the evolution of the eukaryotic oxidative protein folding pathway.Correct disulfide bond formation is critical for the maturation and function of many secretory and membrane proteins. In the endoplasmic reticulum (ER) 3 lumen of eukaryotic cells, the pivotal enzymatic pathway for catalyzing faithful disulfide formation is composed of sulfhydryl oxidase ER oxidoreductin 1 (Ero1) and protein-disulfide isomerase (PDI), which is conserved from yeast (Ero1p-Pdi1p) to human (Ero1␣/␤-PDI) (1-3). Both yeast Pdi1p and human PDI consist of four thioredoxin (Trx)-like domains, in the order of a, b, bЈ, and aЈ, with an x-linker between domains bЈ and aЈ and a carboxyl-terminal tail c (4, 5). The a and aЈ domains each contain a -Cys-Gly-His-Cysactive site responsible for thiol-disulfide interchange reactions and the bЈ domain possesses a hydrophobic pocket, which serves as the principal client-binding site (6 -8). Yeast Pdi1p contains two additional non-catalytic cysteines within the a domain, which form a structural disulfide bridge (9), whereas human PDI has two non-essential cysteines in the bЈ domain (10) (Fig. 1A, upper). Ero1 oxidase generates a disulfide de novo in its inner active site (Cys 352 -Cys 355 in Ero1p) and a by-product H 2 O 2 by transferring electron to molecular oxygen via its FAD cofactor (11, 12). The disulfide is then transferred to the active site of PDI for the subsequent oxidation of reducing substrates (13, 14) via the outer active site (Cys 100 -Cys 105 in Ero1p) located on an intrinsically flexible loop (15, 16). In the human system, Ero1␣ binds to the bЈ domain of PDI via a strong hydrophobic interaction (12,17,18), which results in the preferential oxidation of the aЈ domain rather than the a domain of PDI (12,19,20). In contrast, the binding interaction between Ero1p and Pdi1p is weak (18), and Ero1p oxidizes domain a of Pdi1p faster than domain aЈ (21).The oxidase activity of Ero1 is important for oxidative protein fold...

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Section: Discussionmentioning

confidence: 67%

“…It has been found that human PDI reduces and also re-oxidizes the regulatory disulfides of Ero1␣ very fast (18), whereas yeast Pdi1p is more potent to inhibit Ero1p than to activate Ero1p (25). Coincidently, in cells endogenous Ero1␣ exists in mixed states of oxidized and semioxidized (24,27), whereas Ero1p is almost fully oxidized (25).…”

mentioning

confidence: 99%

Novel Roles of the Non-catalytic Elements of Yeast Protein-disulfide Isomerase in Its Interplay with Endoplasmic Reticulum Oxidoreductin 1

Niu

Zhang

et al. 2016

Journal of Biological Chemistry

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“…eukaryotes, is now thought to be the oxidative engine that serves as the primary oxidase of PDI (Appenzeller-Herzog et al 2010). Concomitantly, hydrogen peroxide (H 2 O 2 ) is thought to be produced from oxygen as an electron acceptor (Enyedi et al 2010).…”

Section: Er Redox Homeostasismentioning

confidence: 99%

Protein Folding and Quality Control in the ER

Araki

Nagata

2011

Cold Spring Harbor Perspectives in Biology

314

285

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The endoplasmic reticulum (ER) uses an elaborate surveillance system called the ER quality control (ERQC) system. The ERQC facilitates folding and modification of secretory and membrane proteins and eliminates terminally misfolded polypeptides through ER-associated degradation (ERAD) or autophagic degradation. This mechanism of ER protein surveillance is closely linked to redox and calcium homeostasis in the ER, whose balance is presumed to be regulated by a specific cellular compartment. The potential to modulate proteostasis and metabolism with chemical compounds or targeted siRNAs may offer an ideal option for the treatment of disease.

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“…Pdi1p was observed in vitro [22], and this phenomenon has been also demonstrated in Ero1-deficient cells as a possible alternative pathway for disulfide bond generation [36]. These findings suggest that the fine tuning of luminal redox homeostasis involves a direct thiol/disulfide exchange between GSH/GSSG and PDI, which also recycles the oxidizing power of GSSG into the machinery of oxidative folding [37].…”

mentioning

confidence: 89%