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      Ero1-α and PDIs constitute a hierarchical electron transfer network of endoplasmic reticulum oxidoreductases

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          Abstract

          The interaction of Ero1-α and PDI facilitates the electron transfer function of Ero1-α, activating a hierarchical electron transfer network of endoplasmic reticulum oxidoreductases.

          Abstract

          Ero1-α and endoplasmic reticulum (ER) oxidoreductases of the protein disulfide isomerase (PDI) family promote the efficient introduction of disulfide bonds into nascent polypeptides in the ER. However, the hierarchy of electron transfer among these oxidoreductases is poorly understood. In this paper, Ero1-α–associated oxidoreductases were identified by proteomic analysis and further confirmed by surface plasmon resonance. Ero1-α and PDI were found to constitute a regulatory hub, whereby PDI induced conformational flexibility in an Ero1-α shuttle cysteine (Cys99) facilitated intramolecular electron transfer to the active site. In isolation, Ero1-α also oxidized ERp46, ERp57, and P5; however, kinetic measurements and redox equilibrium analysis revealed that PDI preferentially oxidized other oxidoreductases. PDI accepted electrons from the other oxidoreductases via its a′ domain, bypassing the a domain, which serves as the electron acceptor from reduced glutathione. These observations provide an integrated picture of the hierarchy of cooperative redox interactions among ER oxidoreductases in mammalian cells.

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          Most cited references 47

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          Protein disulfide isomerase: a critical evaluation of its function in disulfide bond formation.

          Disulfide bond formation is probably involved in the biogenesis of approximately one third of human proteins. A central player in this essential process is protein disulfide isomerase or PDI. PDI was the first protein-folding catalyst reported. However, despite more than four decades of study, we still do not understand much about its physiological mechanisms of action. This review examines the published literature with a critical eye. This review aims to (a) provide background on the chemistry of disulfide bond formation and rearrangement, including the concept of reduction potential, before examining the structure of PDI; (b) detail the thiol-disulfide exchange reactions that are catalyzed by PDI in vitro, including a critical examination of the assays used to determine them; (c) examine oxidation and reduction of PDI in vivo, including not only the role of ERo1 but also an extensive assessment of the role of glutathione, as well as other systems, such as peroxide, dehydroascorbate, and a discussion of vitamin K-based systems; (d) consider the in vivo reactions of PDI and the determination and implications of the redox state of PDI in vivo; and (e) discuss other human and yeast PDI-family members.
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            In and out of the ER: protein folding, quality control, degradation, and related human diseases.

            A substantial fraction of eukaryotic gene products are synthesized by ribosomes attached at the cytosolic face of the endoplasmic reticulum (ER) membrane. These polypeptides enter cotranslationally in the ER lumen, which contains resident molecular chaperones and folding factors that assist their maturation. Native proteins are released from the ER lumen and are transported through the secretory pathway to their final intra- or extracellular destination. Folding-defective polypeptides are exported across the ER membrane into the cytosol and destroyed. Cellular and organismal homeostasis relies on a balanced activity of the ER folding, quality control, and degradation machineries as shown by the dozens of human diseases related to defective maturation or disposal of individual polypeptides generated in the ER.
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              The human PDI family: versatility packed into a single fold.

              The enzymes of the protein disulfide isomerase (PDI) family are thiol-disulfide oxidoreductases of the endoplasmic reticulum (ER). They contain a CXXC active-site sequence where the two cysteines catalyze the exchange of a disulfide bond with or within substrates. The primary function of the PDIs in promoting oxidative protein folding in the ER has been extended in recent years to include roles in other processes such as ER-associated degradation (ERAD), trafficking, calcium homeostasis, antigen presentation and virus entry. Some of these functions are performed by non-catalytic members of the family that lack the active-site cysteines. Regardless of their function, all human PDIs contain at least one domain of approximately 100 amino acid residues with structural homology to thioredoxin. As we learn more about the individual proteins of the family, a complex picture is emerging that emphasizes as much their differences as their similarities, and underlines the versatility of the thioredoxin fold. Here, we primarily explore the diversity of cellular functions described for the human PDIs.
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                Author and article information

                Journal
                J Cell Biol
                J. Cell Biol
                jcb
                The Journal of Cell Biology
                The Rockefeller University Press
                0021-9525
                1540-8140
                16 September 2013
                : 202
                : 6
                : 861-874
                Affiliations
                [1 ]Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Koto-ku, Tokyo 135-0064, Japan
                [2 ]Laboratory of Molecular and Cellular Biology, Faculty of Life Sciences, Kyoto Sangyo University, Kita-ku, Kyoto 603-8047, Japan
                [3 ]Innovative drug development translational research section, Fukushima Medical University, Fukushima 960-1295, Japan
                [4 ]Institute for Molecular Science and Okazaki Institute for Integrative Bioscience, National Institutes of Natural Sciences, Okazaki 444-8787, Japan
                [5 ]Graduate School of Pharmaceutical Sciences, Nagaya City University, Nagoya 467-8603, Japan
                [6 ]Metabolic Research Laboratories ; and [7 ]National Institute for Health Research Cambridge Biomedical Research Centre, Addenbrooke’s Hospital; University of Cambridge, Cambridge CB2 0QQ, England, UK
                [8 ]The Glycoscience Institute, Ochanomizu University, Tokyo 112-8610, Japan
                Author notes
                Correspondence to Kazuhiro Nagata: nagata@ 123456cc.kyoto-su.ac.jp

                Y. Kamiya’s present address is Graduate School of Engineering, Nagoya University, Chikusa-ku, Nagoya 464-8603, Japan.

                Article
                201303027
                10.1083/jcb.201303027
                3776355
                24043701
                © 2013 Araki et al.

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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