Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Science 24 November 2000:
Vol. 290. no. 5496, pp. 1571 - 1574
DOI: 10.1126/science.290.5496.1571
Prev | Table of Contents | Next

Reports

Biochemical Basis of Oxidative Protein Folding in the Endoplasmic Reticulum

Benjamin P. Tu,* Siew C. Ho-Schleyer,* Kevin J. Travers, Jonathan S. Weissmandagger

The endoplasmic reticulum (ER) supports disulfide bond formation by a poorly understood mechanism requiring protein disulfide isomerase (PDI) and ERO1. 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. We reconstituted efficient oxidative folding in vitro using FAD, PDI, and Ero1p. Disulfide formation proceeded by direct delivery of oxidizing equivalents from Ero1p to folding substrates via PDI. This kinetic shuttling of oxidizing equivalents could allow the ER to support rapid disulfide formation while maintaining the ability to reduce and rearrange incorrect disulfide bonds.

Howard Hughes Medical Institute, Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143, USA.
*   These authors contributed equally to this report.

dagger    To whom correspondence should be addressed. E-mail: jsw1{at}itsa.ucsf.edu

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Reconstitution of the Mia40-Erv1 Oxidative Folding Pathway for the Small Tim Proteins.
H. L. Tienson, D. V. Dabir, S. E. Neal, R. Loo, S. A. Hasson, P. Boontheung, S.-K. Kim, J. A. Loo, and C. M. Koehler (2009)
Mol. Biol. Cell 20, 3481-3490
   Abstract »    Full Text »    PDF »
Disulfide Formation in the ER and Mitochondria: Two Solutions to a Common Process.
J. Riemer, N. Bulleid, and J. M. Herrmann (2009)
Science 324, 1284-1287
   Abstract »    Full Text »    PDF »
A Notch updated.
A.-C. Tien, A. Rajan, and H. J. Bellen (2009)
J. Cell Biol. 184, 621-629
   Abstract »    Full Text »    PDF »
Reconstitution of Human Ero1-L{alpha}/Protein-Disulfide Isomerase Oxidative Folding Pathway in Vitro: POSITION-DEPENDENT DIFFERENCES IN ROLE BETWEEN THE a AND a' DOMAINS OF PROTEIN-DISULFIDE ISOMERASE.
L. Wang, S.-j. Li, A. Sidhu, L. Zhu, Y. Liang, R. B. Freedman, and C.-c. Wang (2009)
J. Biol. Chem. 284, 199-206
   Abstract »    Full Text »    PDF »
Tumor Hypoxia Blocks Wnt Processing and Secretion through the Induction of Endoplasmic Reticulum Stress.
M. Verras, I. Papandreou, A. L. Lim, and N. C. Denko (2008)
Mol. Cell. Biol. 28, 7212-7224
   Abstract »    Full Text »    PDF »
Ero1L, a thiol oxidase, is required for Notch signaling through cysteine bridge formation of the Lin12-Notch repeats in Drosophila melanogaster.
A.-C. Tien, A. Rajan, K. L. Schulze, H. D. Ryoo, M. Acar, H. Steller, and H. J. Bellen (2008)
J. Cell Biol. 182, 1113-1125
   Abstract »    Full Text »    PDF »
Arabidopsis Protein Disulfide Isomerase-5 Inhibits Cysteine Proteases during Trafficking to Vacuoles before Programmed Cell Death of the Endothelium in Developing Seeds.
C. Andeme Ondzighi, D. A. Christopher, E. J. Cho, S.-C. Chang, and L. A. Staehelin (2008)
PLANT CELL 20, 2205-2220
   Abstract »    Full Text »    PDF »
The Torsin-family AAA+ Protein OOC-5 Contains a Critical Disulfide Adjacent to Sensor-II That Couples Redox State to Nucleotide Binding.
L. Zhu, J. O. Wrabl, A. P. Hayashi, L. S. Rose, and P. J. Thomas (2008)
Mol. Biol. Cell 19, 3599-3612
   Abstract »    Full Text »    PDF »
Dynamic Interactions of the UL16 Tegument Protein with the Capsid of Herpes Simplex Virus.
D. G. Meckes Jr. and J. W. Wills (2007)
J. Virol. 81, 13028-13036
   Abstract »    Full Text »    PDF »
A novel role in cytokinesis reveals a housekeeping function for the unfolded protein response.
A. A. Bicknell, A. Babour, C. M. Federovitch, and M. Niwa (2007)
J. Cell Biol. 177, 1017-1027
   Abstract »    Full Text »    PDF »
Regulation of the protein disulfide proteome by mitochondria in mammalian cells.
Y. Yang, Y. Song, and J. Loscalzo (2007)
PNAS 104, 10813-10817
   Abstract »    Full Text »    PDF »
A Novel High-Throughput Screen Reveals Yeast Genes That Increase Secretion of Heterologous Proteins.
A. E. Wentz and E. V. Shusta (2007)
Appl. Envir. Microbiol. 73, 1189-1198
   Abstract »    Full Text »    PDF »
ERp27, a New Non-catalytic Endoplasmic Reticulum-located Human Protein Disulfide Isomerase Family Member, Interacts with ERp57.
H. I. Alanen, R. A. Williamson, M. J. Howard, F. S. Hatahet, K. E. H. Salo, A. Kauppila, S. Kellokumpu, and L. W. Ruddock (2006)
J. Biol. Chem. 281, 33727-33738
   Abstract »    Full Text »    PDF »
The DM{alpha} and DMbeta Chain Cooperate in the Oxidation and Folding of HLA-DM.
M. van Lith and A. M. Benham (2006)
J. Immunol. 177, 5430-5439
   Abstract »    Full Text »    PDF »
Endoplasmic reticulum stress signaling in disease..
S. J. Marciniak and D. Ron (2006)
Physiol Rev 86, 1133-1149
   Abstract »    Full Text »    PDF »
Mutations in the FAD Binding Domain Cause Stress-induced Misoxidation of the Endoplasmic Reticulum Oxidoreductase Ero1beta.
S. Dias-Gunasekara, M. van Lith, J. A. G. Williams, R. Kataky, and A. M. Benham (2006)
J. Biol. Chem. 281, 25018-25025
   Abstract »    Full Text »    PDF »
Redox Regulatory Mechanisms in Cellular Stress Responses.
N. FEDOROFF (2006)
Ann. Bot. 98, 289-300
   Abstract »    Full Text »    PDF »
A Screen for Genes of Heme Uptake Identifies the FLC Family Required for Import of FAD into the Endoplasmic Reticulum.
O. Protchenko, R. Rodriguez-Suarez, R. Androphy, H. Bussey, and C. C. Philpott (2006)
J. Biol. Chem. 281, 21445-21457
   Abstract »    Full Text »    PDF »
Disulfide Transfer between Two Conserved Cysteine Pairs Imparts Selectivity to Protein Oxidation by Ero1.
C. S. Sevier and C. A. Kaiser (2006)
Mol. Biol. Cell 17, 2256-2266
   Abstract »    Full Text »    PDF »
Domain Architecture of Protein-disulfide Isomerase Facilitates Its Dual Role as an Oxidase and an Isomerase in Ero1p-mediated Disulfide Formation.
M. S. Kulp, E.-M. Frickel, L. Ellgaard, and J. S. Weissman (2006)
J. Biol. Chem. 281, 876-884
   Abstract »    Full Text »    PDF »
Generating disulfides enzymatically: Reaction products and electron acceptors of the endoplasmic reticulum thiol oxidase Ero1p.
E. Gross, C. S. Sevier, N. Heldman, E. Vitu, M. Bentzur, C. A. Kaiser, C. Thorpe, and D. Fass (2006)
PNAS 103, 299-304
   Abstract »    Full Text »    PDF »
The Monocarboxylate Transporter Homolog Mch5p Catalyzes Riboflavin (Vitamin B2) Uptake in Saccharomyces cerevisiae.
P. Reihl and J. Stolz (2005)
J. Biol. Chem. 280, 39809-39817
   Abstract »    Full Text »    PDF »
Tissue-specific Expression and Dimerization of the Endoplasmic Reticulum Oxidoreductase Ero1{beta}.
S. Dias-Gunasekara, J. Gubbens, M. van Lith, C. Dunne, J. A. G. Williams, R. Kataky, D. Scoones, A. Lapthorn, N. J. Bulleid, and A. M. Benham (2005)
J. Biol. Chem. 280, 33066-33075
   Abstract »    Full Text »    PDF »
Interactions among Yeast Protein-Disulfide Isomerase Proteins and Endoplasmic Reticulum Chaperone Proteins Influence Their Activities.
T. Kimura, Y. Hosoda, Y. Sato, Y. Kitamura, T. Ikeda, T. Horibe, and M. Kikuchi (2005)
J. Biol. Chem. 280, 31438-31441
   Abstract »    Full Text »    PDF »
Riboflavin Deficiency Impairs Oxidative Folding and Secretion of Apolipoprotein B-100 in HepG2 Cells, Triggering Stress Response Systems.
K. C. Manthey, Y. C. Chew, and J. Zempleni (2005)
J. Nutr. 135, 978-982
   Abstract »    Full Text »    PDF »
Identification and Characterization of a Novel Thioredoxin-related Transmembrane Protein of the Endoplasmic Reticulum.
J. Haugstetter, T. Blicher, and L. Ellgaard (2005)
J. Biol. Chem. 280, 8371-8380
   Abstract »    Full Text »    PDF »
Glutathione Directly Reduces an Oxidoreductase in the Endoplasmic Reticulum of Mammalian Cells.
C. E. Jessop and N. J. Bulleid (2004)
J. Biol. Chem. 279, 55341-55347
   Abstract »    Full Text »    PDF »
CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum.
S. J. Marciniak, C. Y. Yun, S. Oyadomari, I. Novoa, Y. Zhang, R. Jungreis, K. Nagata, H. P. Harding, and D. Ron (2004)
Genes & Dev. 18, 3066-3077
   Abstract »    Full Text »    PDF »
Glutathione Is Required to Regulate the Formation of Native Disulfide Bonds within Proteins Entering the Secretory Pathway.
S. Chakravarthi and N. J. Bulleid (2004)
J. Biol. Chem. 279, 39872-39879
   Abstract »    Full Text »    PDF »
Redox signaling: thiol chemistry defines which reactive oxygen and nitrogen species can act as second messengers.
H. J. Forman, J. M. Fukuto, and M. Torres (2004)
Am J Physiol Cell Physiol 287, C246-C256
   Abstract »    Full Text »    PDF »
Two Conserved Cysteine Triads in Human Ero1{alpha} Cooperate for Efficient Disulfide Bond Formation in the Endoplasmic Reticulum.
G. Bertoli, T. Simmen, T. Anelli, S. N. Molteni, R. Fesce, and R. Sitia (2004)
J. Biol. Chem. 279, 30047-30052
   Abstract »    Full Text »    PDF »
Engineered DsbC chimeras catalyze both protein oxidation and disulfide-bond isomerization in Escherichia coli: Reconciling two competing pathways.
L. Segatori, P. J. Paukstelis, H. F. Gilbert, and G. Georgiou (2004)
PNAS 101, 10018-10023
   Abstract »    Full Text »    PDF »
ERp57 Is a Multifunctional Thiol-Disulfide Oxidoreductase.
E.-M. Frickel, P. Frei, M. Bouvier, W. F. Stafford, A. Helenius, R. Glockshuber, and L. Ellgaard (2004)
J. Biol. Chem. 279, 18277-18287
   Abstract »    Full Text »    PDF »
Hierarchical Formation of Disulfide Bonds in the Immunoglobulin Fc Fragment Is Assisted by Protein-disulfide Isomerase.
F. Vinci, S. Catharino, S. Frey, J. Buchner, G. Marino, P. Pucci, and M. Ruoppolo (2004)
J. Biol. Chem. 279, 15059-15066
   Abstract »    Full Text »    PDF »
The Subcellular Distribution of Multigene Family 110 Proteins of African Swine Fever Virus Is Determined by Differences in C-Terminal KDEL Endoplasmic Reticulum Retention Motifs.
C. Netherton, I. Rouiller, and T. Wileman (2004)
J. Virol. 78, 3710-3721
   Abstract »    Full Text »    PDF »
A Major Fraction of Endoplasmic Reticulum-located Glutathione Is Present as Mixed Disulfides with Protein.
R. Bass, L. W. Ruddock, P. Klappa, and R. B. Freedman (2004)
J. Biol. Chem. 279, 5257-5262
   Abstract »    Full Text »    PDF »
Oxidative protein folding in eukaryotes: mechanisms and consequences.
B. P. Tu and J. S. Weissman (2004)
J. Cell Biol. 164, 341-346
   Abstract »    Full Text »    PDF »
FAD Transport and FAD-dependent Protein Thiol Oxidation in Rat Liver Microsomes.
M. Varsanyi, A. Szarka, E. Papp, D. Makai, G. Nardai, R. Fulceri, P. Csermely, J. Mandl, A. Benedetti, and G. Banhegyi (2004)
J. Biol. Chem. 279, 3370-3374
   Abstract »    Full Text »    PDF »
Efficient oxidative folding of conotoxins and the radiation of venomous cone snails.
G. Bulaj, O. Buczek, I. Goodsell, E. C. Jimenez, J. Kranski, J. S. Nielsen, J. E. Garrett, and B. M. Olivera (2003)
PNAS 100, 14562-14568
   Abstract »    Full Text »
Structural Comparison of Human Monoamine Oxidases A and B: MASS SPECTROMETRY MONITORING OF CYSTEINE REACTIVITIES.
F. Hubalek, J. Pohl, and D. E. Edmondson (2003)
J. Biol. Chem. 278, 28612-28618
   Abstract »    Full Text »    PDF »
Functional Characterization of ERp18, a New Endoplasmic Reticulum-located Thioredoxin Superfamily Member.
H. I. Alanen, R. A. Williamson, M. J. Howard, A.-K. Lappi, H. P. Jantti, S. M. Rautio, S. Kellokumpu, and L. W. Ruddock (2003)
J. Biol. Chem. 278, 28912-28920
   Abstract »    Full Text »    PDF »
Oxidative Folding of Interleukin-2 Is Impaired in Flavin-Deficient Jurkat Cells, Causing Intracellular Accumulation of Interleukin-2 and Increased Expression of Stress Response Genes.
G. Camporeale and J. Zempleni (2003)
J. Nutr. 133, 668-672
   Abstract »    Full Text »    PDF »
An Atypical Protein Disulfide Isomerase from the Protozoan Parasite Leishmania Containing a Single Thioredoxin-like Domain.
A. Padilla, R. Noiva, N. Lee, K. V. K. Mohan, H. L. Nakhasi, and A. Debrabant (2003)
J. Biol. Chem. 278, 1872-1878
   Abstract »    Full Text »    PDF »
ERdj5, an Endoplasmic Reticulum (ER)-resident Protein Containing DnaJ and Thioredoxin Domains, Is Expressed in Secretory Cells or following ER Stress.
P. M. Cunnea, A. Miranda-Vizuete, G. Bertoli, T. Simmen, A. E. Damdimopoulos, S. Hermann, S. Leinonen, M. P. Huikko, J.-A. Gustafsson, R. Sitia, et al. (2003)
J. Biol. Chem. 278, 1059-1066
   Abstract »    Full Text »    PDF »
Unfolded cholera toxin is transferred to the ER membrane and released from protein disulfide isomerase upon oxidation by Ero1.
B. Tsai and T. A. Rapoport (2002)
J. Cell Biol. 159, 207-216
   Abstract »    Full Text »    PDF »
Complete pathway for protein disulfide bond formation encoded by poxviruses.
T. G. Senkevich, C. L. White, E. V. Koonin, and B. Moss (2002)
PNAS 99, 6667-6672
   Abstract »    Full Text »    PDF »
Vaccinia Virus G4L Glutaredoxin Is an Essential Intermediate of a Cytoplasmic Disulfide Bond Pathway Required for Virion Assembly.
C. L. White, T. G. Senkevich, and B. Moss (2002)
J. Virol. 76, 467-472
   Abstract »    Full Text »    PDF »
Yeast Erv2p Is the First Microsomal FAD-linked Sulfhydryl Oxidase of the Erv1p/Alrp Protein Family.
J. Gerber, U. Muhlenhoff, G. Hofhaus, R. Lill, and T. Lisowsky (2001)
J. Biol. Chem. 276, 23486-23491
   Abstract »    Full Text »    PDF »
Reduction of Interchain Disulfide Bonds Precedes the Dislocation of Ig-{micro} Chains from the Endoplasmic Reticulum to the Cytosol for Proteasomal Degradation.
C. Fagioli, A. Mezghrani, and R. Sitia (2001)
J. Biol. Chem. 276, 40962-40967
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)