Different Interaction Modes for Protein-disulfide Isomerase (PDI) as an Efficient Regulator and a Specific Substrate of Endoplasmic Reticulum Oxidoreductin-1α (Ero1α)

Zhang, Lihui; Niu, Yingbo; Zhu, Linghua; Fang, Jingqi; Xie, Wang; Wang, Lei; Wang, Chih-chen

doi:10.1074/jbc.m114.602961

Cited by 54 publications

(59 citation statements)

References 41 publications

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“…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).…”

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confidence: 99%

“…PDI predominantly in its reduced state can reduce the regulatory disulfides of Ero1 to generate more activated Ero1, and once sufficient PDI is oxidized by Ero1, it can re-oxidize the regulatory disulfides of Ero1 to inhibit its activity (18, 24 -26). 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).…”

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confidence: 99%

“…Our previous studies on the human Ero1␣-PDI interplay revealed that the working modes of human PDI as an efficient regulator and as a specific substrate of Ero1␣ are fairly different (18). However, the mechanism of the yeast Ero1p-Pdi1p interplay still poses many intriguing questions needing to be answered.…”

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confidence: 99%

“…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).…”

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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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confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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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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“…2). 38 Structural and functional studies have been conducted mainly on mammalian Ero1, where there are 2 isoforms known (a, b). 39 Ero1-a is widely expressed, yet both isoforms have enzymatic activities that are controlled by regulatory disulfides formed among catalytic and non-catalytic cysteines to avoid futile oxidation cycles, which prevents excess hydrogen peroxide production.…”

Section: Protein Disulfide Isomerases -Pdi'smentioning

confidence: 99%

Interplay between redox and protein homeostasis

Feleciano

Arnsburg

Kirstein

2016

Worm

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The subcellular compartments of eukaryotic cells are characterized by different redox environments. Whereas the cytosol, nucleus and mitochondria are more reducing, the endoplasmic reticulum represents a more oxidizing environment. As the redox level controls the formation of intra-and inter-molecular disulfide bonds, the folding of proteins is tightly linked to its environment. The proteostasis network of each compartment needs to be adapted to the compartmental redox properties. In addition to chaperones, also members of the thioredoxin superfamily can influence the folding of proteins by regulation of cysteine reduction/oxidation. This review will focus on thioredoxin superfamily members and chaperones of C. elegans, which play an important role at the interface between redox and protein homeostasis. Additionally, this review will highlight recent methodological developments on in vivo and in vitro assessment of the redox state and their application to provide insights into the high complexity of redox and proteostasis networks of C. elegans.

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Protein disulfide isomerase is regulated in multiple ways: Consequences for conformation, activities, and pathophysiological functions

Wang

2020

BioEssays

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Protein disulfide isomerase (PDI) is one of the most abundant and critical protein folding catalysts in the endoplasmic reticulum of eukaryotic cells. PDI consists of four thioredoxin domains and interacts with a wide range of substrate and partner proteins due to its intrinsic conformational flexibility. PDI plays multifunctional roles in a variety of pathophysiological events, both as an oxidoreductase and a molecular chaperone. Recent studies have revealed that the conformation and activity of PDI can be regulated in multiple ways, including posttranslational modification and substrate/ligand binding. Here, we summarize recent advances in understanding the function and regulation of PDI in different pathological and physiological events. We propose that the multifunctional roles of PDI are regulated by multiple mechanisms. Furthermore, we discuss future directions for the study of PDI, emphasizing how different regulatory modes are linked to the conformational changes and biological functions of PDI in the context of diverse pathophysiologies.

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Different Interaction Modes for Protein-disulfide Isomerase (PDI) as an Efficient Regulator and a Specific Substrate of Endoplasmic Reticulum Oxidoreductin-1α (Ero1α)

Cited by 54 publications

References 41 publications

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

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

Interplay between redox and protein homeostasis

Protein disulfide isomerase is regulated in multiple ways: Consequences for conformation, activities, and pathophysiological functions

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