Balancing oxidative protein folding: The influences of reducing pathways on disulfide bond formation

Kojer, Kerstin; Riemer, Jan

doi:10.1016/j.bbapap.2014.02.004

Cited by 61 publications

(50 citation statements)

References 97 publications

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“…A number of pathways exist for the re-oxidation of PDIs, among these the best conserved -catalyzed by endoplasmic oxidoreductin 1 (Ero1a and Ero1b in human; encoded by ERO1L and ERO1LB, respectively) -exploit the oxidizing power of molecular oxygen (Box 1) (Bulleid and Ellgaard, 2011). At the same time, disulfide-reducing pathways are essential for the proof reading of incorrectly introduced disulfide bonds and for efficient degradation of ER proteins (Kojer and Riemer, 2014). As in probably every cell compartment (Schafer and Buettner, 2001), millimolar concentrations of the redox couple glutathione (GSH)-glutathione disulfide (Montero et al, 2013) are important for disulfide reduction and the maintenance of redox homeostasis in the ER (Appenzeller-Herzog, 2011).…”

Section: Introductionmentioning

confidence: 99%

Redox controls UPR to control redox

Eletto

Chevet

Argon

et al. 2014

Journal of Cell Science

152

137

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In many physiological contexts, intracellular reduction-oxidation (redox) conditions and the unfolded protein response (UPR) are important for the control of cell life and death decisions. UPR is triggered by the disruption of endoplasmic reticulum (ER) homeostasis, also known as ER stress. Depending on the duration and severity of the disruption, this leads to cell adaptation or demise. In this Commentary, we review reductive and oxidative activation mechanisms of the UPR, which include direct interactions of dedicated protein disulfide isomerases with ER stress sensors, protein S-nitrosylation and ER Ca 2+ efflux that is promoted by reactive oxygen species. Furthermore, we discuss how cellular oxidant and antioxidant capacities are extensively remodeled downstream of UPR signals. Aside from activation of NADPH oxidases, mitogen-activated protein kinases and transcriptional antioxidant responses, such remodeling prominently relies on ER-mitochondrial crosstalk. Specific redox cues therefore operate both as triggers and effectors of ER stress, thus enabling amplification loops. We propose that redox-based amplification loops critically contribute to the switch from adaptive to fatal UPR.

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Section: Introductionmentioning

confidence: 99%

Redox controls UPR to control redox

Eletto

Chevet

Argon

et al. 2014

Journal of Cell Science

152

137

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“…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)(2)(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).…”

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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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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“…Such catalytic cysteines are, e.g., found in many proteins of the thioredoxin superfamily (Deponte, 2013). In contrast, structural disulfides are formed under partially oxidizing conditions in the periplasm of Gramnegative bacteria or in the endoplasmic reticulum and the mitochondrial intermembrane space of eukaryotes (Deponte and Hell, 2009;Endo et al, 2010;Kodali and Thorpe, 2010;Codding et al, 2012;Oka and Bulleid, 2013;Hatahet et al, 2014;Kojer and Riemer, 2014). Once formed, such structural disulfides usually stabilize a protein in a defined tertiary or quaternary structure until the protein is degraded.…”

Section: Categories Of Cysteine Residues and Their Role As Redox Switmentioning

confidence: 99%

“…At least in some cases, conditions have been described under which these switches are operated. However, except for well-characterized oxidative protein folding pathways in the bacterial periplasm, the mitochondrial intermembrane space, and the endoplasmic reticulum (Deponte and Hell, 2009;Endo et al, 2010;Kodali and Thorpe, 2010;Codding et al, 2012;Oka and Bulleid, 2013;Hatahet et al, 2014;Kojer and Riemer, 2014), almost nothing is known about the molecular mechanisms of thiol oxidation.…”

Section: Electron Sources and Sinks For The Formation Of Thiols And Dmentioning

confidence: 99%

“…However, experimental evidence for this hypothesis outside the bacterial periplasm and the eukaryotic endoplasmic reticulum is sparse. Thiol-disulfide exchange reactions with analogous mechanisms are furthermore catalyzed by enzymes with alternative protein folds, i.e., (i) GR and TrxR, (ii) Mia40, which catalyzes the oxidative protein folding in the intermembrane space of mitochondria, or (iii) enzymes of the Erv/QSOX family as reviewed (Fass, 2008;Deponte and Hell, 2009;Endo et al, 2010;Kodali and Thorpe, 2010;Kojer and Riemer, 2014).…”

Section: Enzymatic Mechanisms To Flip a Switchmentioning

confidence: 99%

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Enzymatic control of cysteinyl thiol switches in proteins

Deponte

Lillig²

2015

Biological Chemistry

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Abstract:The spatiotemporal modification of specific cysteinyl residues in proteins has emerged as a novel concept in signal transduction. Such modifications alter the redox state of the cysteinyl thiol group, with implications for the structure and biological function of the protein. Regulatory cysteines are therefore classified as 'thiol switches'. In this review we emphasize the relevance of enzymes for specific and efficient redox sensing, evaluate prerequisites and general properties of redox switches, and highlight mechanistic principles for toggling thiol switches. Moreover, we provide an overview of potential mechanisms for the initial formation of regulatory disulfide bonds. In brief, we address the three basic questions (i) what defines a thiol switch, (ii) which parameters confer signal specificity, and (iii) how are thiol switches oxidized?

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Balancing oxidative protein folding: The influences of reducing pathways on disulfide bond formation

Cited by 61 publications

References 97 publications

Redox controls UPR to control redox

Redox controls UPR to control redox

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

Enzymatic control of cysteinyl thiol switches in proteins

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