Cellular and Molecular Life Sciences

, Volume 67, Issue 22, pp 3797–3814 | Cite as

Multiple catalytically active thioredoxin folds: a winning strategy for many functions

  • Emilia Pedone
  • Danila Limauro
  • Katia D’Ambrosio
  • Giuseppina De Simone
  • Simonetta BartolucciEmail author


The Thioredoxin (Trx) fold is a versatile protein scaffold consisting of a four-stranded β-sheet surrounded by three α-helices. Various insertions are possible on this structural theme originating different proteins, which show a variety of functions and specificities. During evolution, the assembly of different Trx fold domains has been used many times to build new multi-domain proteins able to perform a large number of catalytic functions. To clarify the interaction mode of the different Trx domains within a multi-domain structure and how their combination can affect catalytic performances, in this review, we report on a structural and functional analysis of the most representative proteins containing more than one catalytically active Trx domain: the eukaryotic protein disulfide isomerases (PDIs), the thermophilic protein disulfide oxidoreductases (PDOs) and the hybrid peroxiredoxins (Prxs).


Trx fold Disulfide bond Redox sites Protein disulfide oxidoreductase Protein disulfide isomerase Hybrid peroxiredoxin 


  1. 1.
    Berndt C, Lillig CH, Holmgren A (2008) Thioredoxins and glutaredoxins as facilitators of protein folding. Biochim Biophys Acta 1783:641–650PubMedCrossRefGoogle Scholar
  2. 2.
    Kinch LN, Baker D, Grishin NV (2003) Deciphering a novel thioredoxin-like fold family. Proteins 52:323–331PubMedCrossRefGoogle Scholar
  3. 3.
    Martin JL (1995) Thioredoxin—a fold for all reasons. Structure 3:245–250PubMedCrossRefGoogle Scholar
  4. 4.
    Eklund H, Cambillau C, Sjöberg BM, Holmgren A, Jörnvall H, Höög JO, Brändén CI (1984) Conformational and functional similarities between glutaredoxin and thioredoxins. EMBO J 3:1443–1449PubMedGoogle Scholar
  5. 5.
    Meyer Y, Buchanan BB, Vignols F, Reichheld JP (2009) Thioredoxins and glutaredoxins: unifying elements in redox biology. Annu Rev Genet 43:335–367PubMedCrossRefGoogle Scholar
  6. 6.
    Inaba K (2009) Disulfide bond formation system in Escherichia coli. J Biochem 146:591–597PubMedCrossRefGoogle Scholar
  7. 7.
    Appenzeller-Herzog C, Ellgaard L (2008) The human PDI family: versatility packed into a single fold. Biochim Biophys Acta 1783:535–548PubMedCrossRefGoogle Scholar
  8. 8.
    Pedone E, Limauro D, Bartolucci S (2008) The machinery for oxidative protein folding in thermophiles. Antioxid Redox Signal 10:157–169PubMedCrossRefGoogle Scholar
  9. 9.
    Heckler EJ, Rancy PC, Kodali VK, Thorpe C (2008) Generating disulfides with the Quiescin-sulfhydryl oxidases. Biochim Biophys Acta 1783:567–577PubMedCrossRefGoogle Scholar
  10. 10.
    Thorpe C, Coppock DL (2007) Generating disulfides in multicellular organisms: emerging roles for a new flavoprotein family. J Biol Chem 282:13929–13933PubMedCrossRefGoogle Scholar
  11. 11.
    Messens J, Martins JC, Van Belle K, Brosens E, Desmyter A, De Gieter M, Wieruszeski J, Willem R, Wyns L, Zegers I (2002) All intermediates of the arsenate reductase mechanism, including an intramolecular dynamic disulfide cascade. Proc Natl Acad Sci USA 99:8506–8511PubMedCrossRefGoogle Scholar
  12. 12.
    Copley SD, Novak WR, Babbitt PC (2004) Divergence of function in the thioredoxin fold suprafamily: evidence for evolution of peroxiredoxins from a thioredoxin-like ancestor. Biochemistry 43:13981–13995PubMedCrossRefGoogle Scholar
  13. 13.
    Carvalho AP, Fernandes PA, Ramos MJ (2006) Similarities and differences in the thioredoxin superfamily. Prog Biophys Mol Biol 91:229–248PubMedCrossRefGoogle Scholar
  14. 14.
    Atkinson HJ, Babbitt PC (2009) An atlas of the thioredoxin fold class reveals the complexity of function-enabling adaptations. PLoS Comput Biol 5:e1000541PubMedCrossRefGoogle Scholar
  15. 15.
    Atkinson HJ, Babbitt PC (2009) Glutathione transferases are structural and functional outliers in the thioredoxin fold. Biochemistry 48:11108–11116PubMedCrossRefGoogle Scholar
  16. 16.
    Doublié S, Tabor S, Long AM, Richardson CC, Ellenberger T (1998) Crystal structure of a bacteriophage T7 DNA replication complex at 2.2 Å resolution. Nature 391:251–258PubMedCrossRefGoogle Scholar
  17. 17.
    Guddat LW, Bardwell JC, Zander T, Martin JL (1997) The uncharged surface features surrounding the active site of Escherichia coli DsbA are conserved and are implicated in peptide binding. Protein Sci 6:1148–1156PubMedCrossRefGoogle Scholar
  18. 18.
    Ellgaard L, Ruddock LW (2005) The human protein disulphide isomerase family: substrate interactions and functional properties. EMBO Rep 6:28–32PubMedCrossRefGoogle Scholar
  19. 19.
    Dyson HJ, Jeng MF, Tennant LL, Slaby I, Lindell M, Cui DS, Kuprin S, Holmgren A (1997) Effects of buried charged groups on cysteine thiol ionization and reactivity in Escherichia coli thioredoxin: structural and functional characterization of mutants of Asp 26 and Lys 57. Biochemistry 36:2622–2636PubMedCrossRefGoogle Scholar
  20. 20.
    Fomenko DE, Gladyshev VN (2002) CxxS: fold-independent redox motif revealed by genome-wide searches for thiol/disulfide oxidoreductase function. Protein Sci 11:2285–2296PubMedCrossRefGoogle Scholar
  21. 21.
    Ito K, Inaba K (2008) The disulfide bond formation (Dsb) system. Curr Opin Struct Biol 18:450–458PubMedCrossRefGoogle Scholar
  22. 22.
    Grimshaw JPA, Stirnimann CU, Brozzo MS, Malojcic G, Grütter MG, Capitani G, Glockshuber R (2008) DsbL and DsbI form a specific dithiol oxidase system for periplasmic arylsulfate sulfotransferase in uropathogenic Escherichia coli. J Mol Biol 380:667–680PubMedCrossRefGoogle Scholar
  23. 23.
    Ren G, Stephan D, Xu Z, Zheng Y, Tang D, Harrison RS, Kurz M, Jarrott R, Shouldice SR, Hiniker A, Martin JL, Heras B, Bardwell JC (2009) Properties of the thioredoxin fold superfamily are modulated by a single amino acid residue. J Biol Chem 284:10150–10159PubMedCrossRefGoogle Scholar
  24. 24.
    Banci L, Bertini I, Ciofi-Baffoni S, Hadjiloi T, Martinelli M, Palumaa P (2008) Mitochondrial copper(I) transfer from Cox17 to Sco1 is coupled to electron transfer. Proc Natl Acad Sci USA 105:6803–6808PubMedCrossRefGoogle Scholar
  25. 25.
    Wang S, Trumble WR, Liao H, Wesson CR, Dunker AK, Kang CH (1998) Crystal structure of calsequestrin from rabbit skeletal muscle sarcoplasmic reticulum. Nat Struct Biol 5:476–483PubMedCrossRefGoogle Scholar
  26. 26.
    Alanen HI, Williamson RA, Howard MJ, Hatahet FS, Salo KE, Kauppila A, Kellokumpu S, Ruddock LW (2006) ERp27, a new non-catalytic endoplasmic reticulum-located human protein disulfide isomerase family member, interacts with ERp57. J Biol Chem 281:33727–33738PubMedCrossRefGoogle Scholar
  27. 27.
    Pan JL, Bardwell JC (2006) The origami of thioredoxin-like folds. Protein Sci 15:2217–2227PubMedCrossRefGoogle Scholar
  28. 28.
    Hatahet F, Ruddock LW (2009) Protein disulfide isomerase: a critical evaluation of its function in disulfide bond formation. Antioxid Redox Signal 11:2807–2850PubMedCrossRefGoogle Scholar
  29. 29.
    Freedman RB (1998) Novel disulfide oxidoreductase in search of a function. Nat Struct Biol 5:531–532PubMedCrossRefGoogle Scholar
  30. 30.
    Rouhier N, Gama F, Wingsle G, Gelhaye E, Gans P, Jacquot JP (2006) Engineering functional artificial hybrid proteins between poplar peroxiredoxin II and glutaredoxin or thioredoxin. Biochem Biophys Res Commun 341:1300–1308PubMedCrossRefGoogle Scholar
  31. 31.
    Kemmink J, Darby N, Dijkstra K, Nilges M, Creighton TE (1996) Structure determination of the N-terminal thioredoxin-like domain of protein disulfide isomerase using multidimensional heteronuclear 13C/15N NMR spectroscopy. Biochemistry 35:7684–7691PubMedCrossRefGoogle Scholar
  32. 32.
    Kemmink J, Dijkstra K, Mariani M, Scheek RM, Penka E, Nilges M, Darby NJ (1999) The structure in solution of the b domain of protein disulfide isomerase. J Biomol NMR 13:357–368PubMedCrossRefGoogle Scholar
  33. 33.
    Denisov AY, Maattanen P, Dabrowski C, Kozlov G, Thomas DY, Gehring K (2009) Solution structure of the bb′ domains of human protein disulfide isomerase. FEBS J 276:1440–1449PubMedCrossRefGoogle Scholar
  34. 34.
    Serve O, Kamiya Y, Maeno A, Nakano M, Murakami C, Sasakawa H, Yamaguchi Y, Harada T, Kurimoto E, Yagi-Utsumi M, Iguchi T, Inaba K, Kikuchi J, Asami O, Kajino T, Oka T, Nakasako M, Kato K (2010) Redox-dependent domain rearrangement of protein disulfide isomerase coupled with exposure of its substrate-binding hydrophobic surface. J Mol Biol 396:361–374PubMedCrossRefGoogle Scholar
  35. 35.
    Wang LK, Wang L, Vavassori S, Li SJ, Ke H, Anelli T, Degano M, Ronzoni R, Sitia R, Sun F, Wang CC (2008) Crystal structure of human ERp44 shows a dynamic functional modulation by its carboxy-terminal tail. Embo Rep 9:642–647PubMedCrossRefGoogle Scholar
  36. 36.
    Barak NN, Neumann P, Sevvana M, Schutkowski M, Naumann K, Malesevic M, Reichardt H, Fischer G, Stubbs MT, Ferrari DM (2009) Crystal structure and functional analysis of the protein disulfide isomerase-related protein ERp29. J Mol Biol 385:1630–1642PubMedCrossRefGoogle Scholar
  37. 37.
    Liepinsh E, Baryshev M, Sharipo A, Ingelman-Sundberg M, Otting G, Mkrtchian S (2001) Thioredoxin fold as homodimerization module in the putative chaperone ERp29: NMR structures of the domains and experimental model of the 51-kDa dimer. Structure 9:457–471PubMedCrossRefGoogle Scholar
  38. 38.
    Rowe ML, Ruddock LW, Kelly G, Schmidt JM, Williamson RA, Howard MJ (2009) Solution structure and dynamics of ERp18, a small endoplasmic reticulum resident oxidoreductase. Biochemistry 48:4596–4606PubMedCrossRefGoogle Scholar
  39. 39.
    Jessop CE, Tavender TJ, Watkins RH, Chambers JE, Bulleid NJ (2009) Substrate specificity of the oxidoreductase ERp57 is determined primarily by its interaction with calnexin and calreticulin. J Biol Chem 284:2194–2202PubMedCrossRefGoogle Scholar
  40. 40.
    Maattanen P, Kozlov G, Gehring K, Thomas DY (2006) ERp57 and PDI: multifunctional protein disulfide isomerases with similar domain architectures but differing substrate-partner associations. Biochem Cell Biol 84:881–889PubMedCrossRefGoogle Scholar
  41. 41.
    Gruber CW, Cemazar M, Heras B, Martin JL, Craik DJ (2006) Protein disulfide isomerase: the structure of oxidative folding. Trends Biochem Sci 31:455–464PubMedCrossRefGoogle Scholar
  42. 42.
    Wang CC, Tsou CL (1993) Protein disulfide isomerase is both an enzyme and a chaperone. FASEB J 7:1515–1517PubMedGoogle Scholar
  43. 43.
    Koivu J, Myllyla R, Helaakoski T, Pihlajaniemi T, Tasanen K, Kivirikko KI (1987) A single polypeptide acts both as the β subunit of prolyl 4-hydroxylase and as a protein disulfide-isomerase. J Biol Chem 262:6447–6449PubMedGoogle Scholar
  44. 44.
    Wetterau JR, Combs KA, McLean LR, Spinner SN, Aggerbeck LP (1991) Protein disulfide isomerase appears necessary to maintain the catalytically active structure of the microsomal triglyceride transfer protein. Biochemistry 30:9728–97235PubMedCrossRefGoogle Scholar
  45. 45.
    Janiszewski M, Lopes LR, Carmo AO, Pedro MA, Brandes RP, Santos CXC, Laurindo FRM (2005) Regulation of NAD(P)H oxidase by associated protein disufide isomerase in vascular smooth muscle cells. J Biol Chem 280:40813–40819PubMedCrossRefGoogle Scholar
  46. 46.
    Creighton TE (1997) Protein folding coupled to disulphide bond formation. Biol Chem 378:731–744PubMedCrossRefGoogle Scholar
  47. 47.
    Ruddon RW, Bedows E (1997) Assisted protein folding. J Biol Chem 272:3125–3128PubMedCrossRefGoogle Scholar
  48. 48.
    Satoh M, Shimada A, Kashiwai A, Saga S, Hosokawa M (2005) Differential cooperative enzymatic activities of protein disulfide isomerase family in protein folding. Cell Stress Chaperones 10:211–220PubMedCrossRefGoogle Scholar
  49. 49.
    Pagani M, Fabbri M, Benedetti C, Fassio A, Pilati S, Bulleid NJ, Cabibbo A, Sitia R (2000) Endoplasmic reticulum oxidoreductin 1-lβ (ERO1-Lβ), a human gene induced in the course of the unfolded protein response. J Biol Chem 275:23685–236292PubMedCrossRefGoogle Scholar
  50. 50.
    Cabibbo A, Pagani M, Fabbri M, Rocchi M, Farmery MR, Bulleid NJ, Sitia R (2000) ERO1-L, a human protein that favors disulfide bond formation in the endoplasmic reticulum. J Biol Chem 275:4827–4833PubMedCrossRefGoogle Scholar
  51. 51.
    Gross E, Kastner DB, Kaiser CA, Fass D (2004) Structure of Ero1p, source of disulfide bonds for oxidative protein folding in the cell. Cell 117:601–610PubMedCrossRefGoogle Scholar
  52. 52.
    Gross E, Sevier CS, Heldman N, Vitu E, Bentzur M, Kaiser CA, Thorpe C, Fass D (2006) Generating disulfides enzymatically: reaction products and electron acceptors of the endoplasmic reticulum thiol oxidase Ero1p. Proc Natl Acad Sci USA 103:299–304PubMedCrossRefGoogle Scholar
  53. 53.
    Sevier CS, Kaiser CA (2006) Disulfide transfer between two conserved cysteine pairs imparts selectivity to protein oxidation by Ero1. Mol Biol Cell 17:2256–22566PubMedCrossRefGoogle Scholar
  54. 54.
    Sevier CS, Cuozzo JW, Vala A, Aslund F, Kaiser CA (2001) A flavoprotein oxidase defines a new endoplasmic reticulum pathway for biosynthetic disulphide bond formation. Nat Cell Biol 3:874–882PubMedCrossRefGoogle Scholar
  55. 55.
    Vala A, Sevier CS, Kaiser CA (2005) Structural determinants of substrate access to the disulfide oxidase Erv2p. J Mol Biol 354:952–966PubMedCrossRefGoogle Scholar
  56. 56.
    Gross E, Sevier CS, Vala A, Kaiser CA, Fass D (2002) A new FAD-binding fold and intersubunit disulfide shuttle in the thiol oxidase Erv2p. Nat Struct Biol 9:61–67PubMedCrossRefGoogle Scholar
  57. 57.
    Chakravarthi S, Jessop CE, Bulleid NJ (2006) The role of glutathione in disulphide bond formation and endoplasmic-reticulum-generated oxidative stress. EMBO Rep 7:271–275PubMedCrossRefGoogle Scholar
  58. 58.
    Ashworth JL, Kelly V, Wilson R, Shuttleworth CA, Kielty CM (1999) Fibrillin assembly: dimer formation mediated by amino-terminal sequences. J Cell Sci 112:3549–3558PubMedGoogle Scholar
  59. 59.
    Di Jeso B, Park YN, Ulianich L, Treglia AS, Urbanas ML, High S, Arvan P (2005) Mixed-disulfide folding intermediates between thyroglobulin and endoplasmic reticulum resident oxidoreductases ERp57 and protein disulfide isomerase. Mol Cell Biol 25:9793–9805PubMedCrossRefGoogle Scholar
  60. 60.
    Molinari M, Helenius A (1999) Glycoproteins form mixed disulfides with oxidoreductases during folding in living cells. Nature 402:90–93PubMedCrossRefGoogle Scholar
  61. 61.
    Roth RA, Pierce SB (1987) In vivo cross-linking of protein disulfide isomerase to immunoglobulins. Biochemistry 26:4179–4182PubMedCrossRefGoogle Scholar
  62. 62.
    Vandenbroeck K, Martens E, Alloza I (2006) Multi-chaperone complexes regulate the folding of interferon-gamma in the endoplasmic reticulum. Cytokine 33:264–273PubMedCrossRefGoogle Scholar
  63. 63.
    Vuori K, Myllylä R, Pihlajaniemi T, Kivirikko KI (1992) Expression and site-directed mutagenesis of human protein disulfide isomerase in Escherichia coli. This multifunctional polypeptide has two independently acting catalytic sites for the isomerase activity. J Biol Chem 267:7211–7214PubMedGoogle Scholar
  64. 64.
    LaMantia ML, Lennarz WJ (1993) The essential function of yeast protein disulfide isomerase does not reside in its isomerase activity. Cell 74:899–908PubMedCrossRefGoogle Scholar
  65. 65.
    Lyles MM, Gilbert HF (1994) Mutations in the thioredoxin sites of protein disulfide isomerase reveal functional nonequivalence of the N- and C-terminal domains. J Biol Chem 269:30946–30952PubMedGoogle Scholar
  66. 66.
    Laboissiere MC, Sturley SL, Raines RT (1995) The essential function of protein-disulfide isomerase is to unscramble non-native disulfide bonds. J Biol Chem 270:28006–28009PubMedCrossRefGoogle Scholar
  67. 67.
    Darby NJ, Creighton TE (1995) Characterization of the active site cysteine residues of the thioredoxin-like domains of protein disulfide isomerase. Biochemistry 34:16770–16780PubMedCrossRefGoogle Scholar
  68. 68.
    Walker KW, Lyles MM, Gilbert HF (1996) Catalysis of oxidative protein folding by mutants of protein disulfide isomerase with a single active-site cysteine. Biochemistry 35:1972–1980PubMedCrossRefGoogle Scholar
  69. 69.
    Westphal V, Darby NJ, Winther JR (1999) Functional properties of the two redox-active sites in yeast protein disulphide isomerase in vitro and in vivo. J Mol Biol 286:1229–1239PubMedCrossRefGoogle Scholar
  70. 70.
    Kulp MS, Frickel EM, Ellgaard L, Weissman JS (2006) Domain architecture of protein-disulfide isomerase facilitates its dual role as an oxidase and an isomerase in Ero1p-mediated disulfide formation. J Biol Chem 281:876–884PubMedCrossRefGoogle Scholar
  71. 71.
    Holst B, Tachibana C, Winther JR (1997) Active site mutations in yeast protein disulfide isomerase cause dithiothreitol sensitivity and a reduced rate of protein folding in the endoplasmic reticulum. J Cell Biol 138:1229–1238PubMedCrossRefGoogle Scholar
  72. 72.
    Wang L, Li SJ, Sidhu A, Zhu L, Liang Y, Freedman RB, Wang CC (2009) Reconstitution of human Ero1-Lα/protein-disulfide isomerase oxidative folding pathway in vitro. Position-dependent differences in role between the a and a′ domains of protein-disulfide isomerase. J Biol Chem 284:199–206PubMedCrossRefGoogle Scholar
  73. 73.
    Klappa P, Ruddock LW, Darby NJ, Freedman RB (1998) The b′ domain provides the principal peptide-binding site of protein disulfide isomerase but all domains contribute to binding of misfolded proteins. EMBO J 17:927–935PubMedCrossRefGoogle Scholar
  74. 74.
    Pirneskoski A, Klappa P, Lobell M, Williamson RA, Byrne L, Alanen HI, Salo KE, Kivirikko KI, Freedman RB, Ruddock LW (2004) Molecular characterization of the principal substrate binding site of the ubiquitous folding catalyst protein disulfide isomerase. J Biol Chem 279:10374–10381PubMedCrossRefGoogle Scholar
  75. 75.
    Darby NJ, Penka E, Vincentelli R (1998) The multi-domain structure of protein disulfide isomerase is essential for high catalytic efficiency. J Mol Biol 276:239–247PubMedCrossRefGoogle Scholar
  76. 76.
    Tian G, Xiang S, Noiva R, Lennarz WJ, Schindelin H (2006) The crystal structure of yeast protein disulfide isomerase suggests cooperativity between its active sites. Cell 124:61–73PubMedCrossRefGoogle Scholar
  77. 77.
    Karala AR, Lappi AK, Ruddock LW (2010) Modulation of an active-site cysteine pKa allows PDI to act as a catalyst of both disulfide bond formation and isomerization. J Mol Biol 396:883–892PubMedCrossRefGoogle Scholar
  78. 78.
    Lappi AK, Lensink MF, Alanen HI, Salo KE, Lobell M, Juffer AH, Ruddock LW (2004) A conserved arginine plays a role in the catalytic cycle of the protein disulphide isomerases. J Mol Biol 335:283–295PubMedCrossRefGoogle Scholar
  79. 79.
    D’Ambrosio K, Pedone E, Langella E, De Simone G, Rossi M, Pedone C, Bartolucci S (2006) A novel member of the protein disulfide oxidoreductase family from Aeropyrum pernix K1: structure, function and electrostatics. J Mol Biol 362:743–752PubMedCrossRefGoogle Scholar
  80. 80.
    Tian G, Kober FX, Lewandrowski U, Sickmann A, Lennarz WJ, Schindelin H (2008) The catalytic activity of protein-disulfide isomerase requires a conformationally flexible molecule. J Biol Chem 283:33630–33640PubMedCrossRefGoogle Scholar
  81. 81.
    Nguyen VD, Wallis K, Howard MJ, Haapalainen AM, Salo KE, Saaranen MJ, Sidhu A, Wierenga RK, Freedman RB, Ruddock LW, Williamson RA (2008) Alternative conformations of the x region of human protein disulphide-isomerase modulate exposure of the substrate binding b′ domain. J Mol Biol 383:1144–1155PubMedCrossRefGoogle Scholar
  82. 82.
    Byrne LJ, Sidhu A, Wallis AK, Ruddock LW, Freedman RB, Howard MJ, Williamson RA (2009) Mapping of the ligand-binding site on the b′ domain of human PDI: interaction with peptide ligands and the x-linker region. Biochem J 423:209–217PubMedCrossRefGoogle Scholar
  83. 83.
    Wallis AK, Sidhu A, Byrne LJ, Howard MJ, Ruddock LW, Williamson RA, Freedman RB (2009) The ligand-binding b′ domain of human protein disulphide-isomerase mediates homodimerization. Protein Sci 18:2569–2577PubMedCrossRefGoogle Scholar
  84. 84.
    Soldà T, Garbi N, Hämmerling GJ, Molinari M (2006) Consequences of ERp57 deletion on oxidative folding of obligate and facultative clients of the calnexin cycle. J Biol Chem 281:6219–6226PubMedCrossRefGoogle Scholar
  85. 85.
    Jessop CE, Chakravarthi S, Garbi N, Hämmerling GJ, Lovell S, Bulleid NJ (2007) ERp57 is essential for efficient folding of glycoproteins sharing common structural domains. EMBO J 26:28–40PubMedCrossRefGoogle Scholar
  86. 86.
    Frickel EM, Frei P, Bouvier M, Stafford WF, Helenius A, Glockshuber R, Ellgaard L (2004) ERp57 is a multifunctional thiol-disulfide oxidoreductase. J Biol Chem 279:18277–18287PubMedCrossRefGoogle Scholar
  87. 87.
    Zapun A, Darby NJ, Tessier DC, Michalak M, Bergeron JJ, Thomas DY (1998) Enhanced catalysis of ribonuclease B folding by the interaction of calnexin or calreticulin with ERp57. J Biol Chem 273:6009–6012PubMedCrossRefGoogle Scholar
  88. 88.
    Oliver JD, van der Wal FJ, Bulleid NJ, High S (1997) Interaction of the thiol-dependent reductase ERp57 with nascent glycoproteins. Science 275:86–88PubMedCrossRefGoogle Scholar
  89. 89.
    Ellgaard L, Helenius A (2001) ER quality control: towards an understanding at the molecular level. Curr Opin Cell Biol 13:431–437PubMedCrossRefGoogle Scholar
  90. 90.
    Oliver JD, Roderick HL, Llewellyn DH, High S (1999) ERp57 functions as a subunit of specific complexes formed with the ER lectins calreticulin and calnexin. Mol Biol Cell 10:2573–2582PubMedGoogle Scholar
  91. 91.
    Ellgaard L, Frickel EM (2003) Calnexin, calreticulin, and ERp57: teammates in glycoprotein folding. Cell Biochem Biophys 39:223–247PubMedCrossRefGoogle Scholar
  92. 92.
    Frickel EM, Riek R, Jelesarov I, Helenius A, Wuthrich K, Ellgaard L (2002) TROSY-NMR reveals interaction between ERp57 and the tip of the calreticulin P-domain. Proc Natl Acad Sci USA 99:1954–1959PubMedCrossRefGoogle Scholar
  93. 93.
    Kozlov G, Maattanen P, Schrag JD, Pollock S, Cygler M, Nagar B, Thomas DY, Gehring K (2006) Crystal structure of the bb′ domains of the protein disulfide isomerase ERp57. Structure 14:1331–1339PubMedCrossRefGoogle Scholar
  94. 94.
    Ellgaard L, Bettendorff P, Braun D, Herrmann T, Fiorito F, Jelesarov I, Güntert P, Helenius A, Wüthrich K (2002) NMR structures of 36 and 73-residue fragments of the calreticulin P-domain. J Mol Biol 322:773–784PubMedCrossRefGoogle Scholar
  95. 95.
    Leach MR, Cohen-Doyle MF, Thomas DY, Williams DB (2002) Localization of the lectin, ERp57 binding, and polypeptide binding sites of calnexin and calreticulin. J Biol Chem 277:29686–29697PubMedCrossRefGoogle Scholar
  96. 96.
    Russell SJ, Ruddock LW, Salo KE, Oliver JD, Roebuck QP, Llewellyn DH, Roderick HL, Koivunen P, Myllyharju J, High S (2004) The primary substrate binding site in the b′ domain of ERp57 is adapted for endoplasmic reticulum lectin association. J Biol Chem 279:18861–18869PubMedCrossRefGoogle Scholar
  97. 97.
    Dick TP, Bangia N, Peaper DR, Cresswell P (2002) Disulfide bond isomerization and the assembly of MHC class I-peptide complexes. Immunity 16:87–98PubMedCrossRefGoogle Scholar
  98. 98.
    Peaper DR, Wearsch PA, Cresswell P (2005) Tapasin and ERp57 form a stable disulfide-linked dimer within the MHC class I peptide-loading complex. EMBO J 24:3613–3623PubMedCrossRefGoogle Scholar
  99. 99.
    Hirano N, Shibasaki F, Sakai R, Tanaka T, Nishida J, Yazaki Y, Takenawa T, Hirai H (1995) Molecular cloning of the human glucose-regulated protein ERp57/GRP58, a thiol-dependent reductase. Identification of its secretory form and inducible expression by the oncogenic transformation. Eur J Biochem 234:336–342PubMedCrossRefGoogle Scholar
  100. 100.
    Antoniou AN, Ford S, Alphey M, Osborne A, Elliott T, Powis SJ (2002) The oxidoreductase ERp57 efficiently reduces partially folded in preference to fully folded MHC class I molecules. EMBO J 21:2655–2663PubMedCrossRefGoogle Scholar
  101. 101.
    Beynon-Jones SM, Antoniou AN, Powis SJ (2006) Mutational analysis of the oxidoreductase ERp57 reveals the importance of the two central residues in the redox motif. FEBS Lett 580:1897–1902PubMedCrossRefGoogle Scholar
  102. 102.
    Lundström J, Holmgren A (1993) Determination of the reduction-oxidation potential of the thioredoxin-like domains of protein disulfide-isomerase from the equilibrium with glutathione and thioredoxin. Biochemistry 32:6649–6655PubMedCrossRefGoogle Scholar
  103. 103.
    Silvennoinen L, Karvonen P, Koivunen P, Myllyharju J, Kivirikko K, Kilpeläinen I (2001) Assignment of 1H, 13C and 15N resonances of the a′ domain of ERp57. J Biomol NMR 20:385–386PubMedCrossRefGoogle Scholar
  104. 104.
    Silvennoinen L, Koivunen P, Myllyharju J, Kilpeläinen I, Permi P (2005) NMR assignment of the N-terminal domain a of the glycoprotein chaperone ERp57. J Biomol NMR 33:136PubMedCrossRefGoogle Scholar
  105. 105.
    Pollock S, Kozlov G, Pelletier MF, Trempe JF, Jansen G, Sitnikov D, Bergeron JJ, Gehring K, Ekiel I, Thomas DY (2004) Specific interaction of ERp57 and calnexin determined by NMR spectroscopy and an ER two-hybrid system. EMBO J 23:1020–1029PubMedCrossRefGoogle Scholar
  106. 106.
    Dong G, Wearsch PA, Peaper DR, Cresswell P, Reinisch KM (2009) Insights into MHC class I peptide loading from the structure of the tapasin-ERp57 thiol oxidoreductase heterodimer. Immunity 30:21–32PubMedCrossRefGoogle Scholar
  107. 107.
    Mazzarella RA, Srinivasan M, Haugejorden SM, Green M (1990) ERp72, an abundant luminal endoplasmic reticulum protein, contains three copies of the active site sequences of protein disulfide isomerase. J Biol Chem 265:1094–1101PubMedGoogle Scholar
  108. 108.
    Kozlov G, Määttänen P, Schrag JD, Hura GL, Gabrielli L, Cygler M, Thomas DY, Gehring K (2009) Structure of the noncatalytic domains and global fold of the protein disulfide isomerase ERp72. Structure 17:651–659PubMedCrossRefGoogle Scholar
  109. 109.
    Van PN, Rupp K, Lampen A, Söling HD (1993) CaBP2 is a rat homolog of ERp72 with protein disulfide isomerase activity. Eur J Biochem 213:789–795PubMedCrossRefGoogle Scholar
  110. 110.
    Kramer B, Ferrari DM, Klappa P, Pöhlmann N, Söling HD (2001) Functional roles and efficiencies of the thioredoxin boxes of calcium-binding proteins 1 and 2 in protein folding. Biochem J 357:83–95PubMedCrossRefGoogle Scholar
  111. 111.
    Lundström-Ljung J, Birnbach U, Rupp K, Söling HD, Holmgren A (1995) Two resident ER-proteins, CaBP1 and CaBP2, with thioredoxin domains, are substrates for thioredoxin reductase: comparison with protein disulfide isomerase. FEBS Lett 357:305–358PubMedCrossRefGoogle Scholar
  112. 112.
    Rupp K, Birnbach U, Lundström J, Van PN, Söling HD (1994) Effects of CaBP2, the rat analog of ERp72, and of CaBP1 on the refolding of denatured reduced proteins. Comparison with protein disulfide isomerase. J Biol Chem 269:2501–2507PubMedGoogle Scholar
  113. 113.
    Miyaishi O, Kozaki K, Iida K, Isobe K, Hashizume Y, Saga S (1998) Elevated expression of PDI family proteins during differentiation of mouse F9 teratocarcinoma cells. J Cell Biochem 68:436–445PubMedCrossRefGoogle Scholar
  114. 114.
    Cotterill SL, Jackson GC, Leighton MP, Wagener R, Mäkitie O, Cole WG, Briggs MD (2005) Multiple epiphyseal dysplasia mutations in MATN3 cause misfolding of the A-domain and prevent secretion of mutant matrilin-3. Hum Mutat 26:557–565PubMedCrossRefGoogle Scholar
  115. 115.
    Sørensen S, Ranheim T, Bakken KS, Leren TP, Kulseth MA (2006) Retention of mutant low density lipoprotein receptor in endoplasmic reticulum (ER) leads to ER stress. J Biol Chem 281:468–476PubMedCrossRefGoogle Scholar
  116. 116.
    Menon S, Lee J, Abplanalp WA, Yoo SE, Agui T, Furudate S, Kim PS, Arvan P (2007) Oxidoreductase interactions include a role for ERp72 engagement with mutant thyroglobulin from the rdw/rdw rat dwarf. J Biol Chem 282:6183–6191PubMedCrossRefGoogle Scholar
  117. 117.
    Satoh M, Shimada A, Keino H, Kashiwai A, Nagai N, Saga S, Hosokawa M (2005) Functional characterization of 3 thioredoxin homology domains of ERp72. Cell Stress Chaperones 10:278–284PubMedCrossRefGoogle Scholar
  118. 118.
    Mallick P, Boutz DR, Eisenberg D, Yeates TO (2002) Genomic evidence that the intracellular proteins of archaeal microbes contain disulfide bonds. Proc Natl Acad Sci USA 99:9679–9684PubMedCrossRefGoogle Scholar
  119. 119.
    O’Connor B, Yeates TO (2004) GDAP: a web tool for structural disulfide bond prediction. Nucleic Acids Res 32:360–364CrossRefGoogle Scholar
  120. 120.
    Beeby M, O’Connor BD, Ryttersgaard C, Boutz DR, Perry LJ, Yeates TO (2005) The genomics of disulfide bonding and protein stabilization in thermophiles. PLoS Biol 3:1549–1558CrossRefGoogle Scholar
  121. 121.
    Pedone E, Ren B, Ladenstein R, Rossi M, Bartolucci S (2004) Functional properties of the protein disulfide oxidoreductase from the archaeon Pyrococcus furiosus. Eur J Biochem 271:3437–3448PubMedCrossRefGoogle Scholar
  122. 122.
    Limauro D, Saviano M, Galdi I, Rossi M, Bartolucci S, Pedone E (2009) Sulfolobus solfataricus protein disulphide oxidoreductase: insight into the roles of its redox sites. Protein Eng Des Sel 22:19–26PubMedCrossRefGoogle Scholar
  123. 123.
    Becerra A, Delaye L, Lazcano A, Orgel LE (2007) Protein disulfide oxidoreductases and the evolution of thermophily: was the last common ancestor a heat-loving microbe? J Mol Evol 65:296–303PubMedCrossRefGoogle Scholar
  124. 124.
    Ladenstein R, Ren B (2006) Protein disulfides and protein disulfide oxidoreductases in hyperthermophiles. FEBS J 273:4170–4185PubMedCrossRefGoogle Scholar
  125. 125.
    Guagliardi A, de Pascale D, Cannio R, Nobile V, Bartolucci S, Rossi M (1995) The purification, cloning, and high level expression of a glutaredoxin-like protein from the hyperthermophilic archaeon Pyrococcus furiosus. J Biol Chem 270:5748–5755PubMedCrossRefGoogle Scholar
  126. 126.
    Bartolucci S, de Pascale D, Rossi M (2001) Protein disulfide oxidoreductase from Pyrococcus furiosus: biochemical properties. Methods Enzymol 334:62–73PubMedCrossRefGoogle Scholar
  127. 127.
    Ren B, Tibbelin G, de Pascale D, Rossi M, Bartolucci S, Ladenstein R (1998) A protein disulfide oxidoreductase from the archaeon Pyrococcus furiosus contains two thioredoxin fold units. Nat Struct Biol 5:602–611PubMedCrossRefGoogle Scholar
  128. 128.
    Ren B, Ladenstein R (2001) Protein disulfide oxidoreductase from Pyrococcus furiosus: structural properties. Methods Enzymol 334:74–88PubMedCrossRefGoogle Scholar
  129. 129.
    Pedone E, D’Ambrosio K, De Simone G, Rossi M, Pedone C, Bartolucci S (2006) Insights on a new PDI-like family: structural and functional analysis of a protein disulfide oxidoreductase from the bacterium Aquifex aeolicus. J Mol Biol 356:155–164PubMedCrossRefGoogle Scholar
  130. 130.
    Kashima Y, Ishikawa K (2003) A hyperthermostable novel protein-disulfide oxidoreductase is reduced by thioredoxin reductase from hyperthermophilic archaeon Pyrococcus horikoshii. Arch Biochem Biophys 418:179–185PubMedCrossRefGoogle Scholar
  131. 131.
    Pedone E, Limauro D, D’Alterio R, Rossi M, Bartolucci S (2006) Characterization of a multifunctional protein disulfide oxidoreductase from Sulfolobus solfataricus. FEBS J 273:5407–5420PubMedCrossRefGoogle Scholar
  132. 132.
    Quemeneur E, Guthapfel R, Gueguen P (1994) A major phosphoprotein of the endoplasmic reticulum is protein disulfide isomerase. J Biol Chem 269:5485–5488PubMedGoogle Scholar
  133. 133.
    Zapun A, Creighton TE, Rowling PJ, Freedman RB (1992) Folding in vitro of bovine pancreatic trypsin inhibitor in the presence of proteins of the endoplasmic reticulum. Proteins 14:10–15PubMedCrossRefGoogle Scholar
  134. 134.
    Pedone E, Saviano M, Bartolucci S, Rossi M, Ausili A, Scirè A, Bertoli E, Tanfani F (2005) Temperature-, SDS-, and pH-induced conformational changes in protein disulfide oxidoreductase from the archaeon Pyrococcus furiosus: a dynamic simulation and Fourier transform infrared spectroscopic study. J Proteome Res 4:1972–1980PubMedCrossRefGoogle Scholar
  135. 135.
    Hisabori T, Hara S, Fujii T, Yamazaki D, Hosoya-Matsuda N, Motohashi K (2005) Thioredoxin affinity chromatography: a useful method for further understanding the thioredoxin network. J Exp Bot 56:1463–1468PubMedCrossRefGoogle Scholar
  136. 136.
    Goyer A, Haslekås C, Miginiac-Maslow M, Klein U, Le Marechal P, Jacquot JP, Decottignies P (2002) Isolation and characterization of a thioredoxin-dependent peroxidase from Chlamydomonas reinhardtii. Eur J Biochem 269:272–282PubMedCrossRefGoogle Scholar
  137. 137.
    Broin M, Cuiné S, Eymery F, Rey P (2002) The plastidic 2-cysteine peroxiredoxin is a target for a thioredoxin involved in the protection of the photosynthetic apparatus against oxidative damage. Plant Cell 14:1417–1432PubMedCrossRefGoogle Scholar
  138. 138.
    Limauro D, Pedone E, Galdi I, Bartolucci S (2008) Peroxiredoxins as cellular guardians in Sulfolobus solfataricus—characterization of Bcp1, Bcp3 and Bcp4. FEBS J 275:2067–2077PubMedCrossRefGoogle Scholar
  139. 139.
    Holmgren A, Johansson C, Berndt C, Lonn ME, Hudemann C, Lillig CH (2005) Thiol redox control via thioredoxin and glutaredoxin systems. Biochem Soc Trans 33:1375–1377PubMedCrossRefGoogle Scholar
  140. 140.
    Maaty WS, Wiedenheft B, Tarlykov P, Schaff N, Heinemann J, Robison-Cox J, Valenzuela J, Dougherty A, Blum P, Lawrence CM, Douglas T, Young MJ, Bothner B (2009) Something old, something new, something borrowed; how the thermoacidophilic archaeon Sulfolobus solfataricus responds to oxidative stress. PLoS One 4:e6964PubMedCrossRefGoogle Scholar
  141. 141.
    Vivancos AP, Jara M, Zuin A, Sanso M, Hidalgo E (2006) Oxidative stress in Schizosaccharomyces pombe: different H2O2 levels, different response pathways. Mol Genet Genomics 276:495–502PubMedCrossRefGoogle Scholar
  142. 142.
    Rabilloud T, Chevallet M, Luche S, Leize-Wagner E (2005) Oxidative stress response: a proteomic view. Expert Rev Proteomics 2:949–956PubMedCrossRefGoogle Scholar
  143. 143.
    Vandenbroucke K, Robbens S, Vandepoele K, Inze D, de Peer YV, Van Breusegem F (2008) Hydrogen peroxide-induced gene expression across kingdoms: a comparative analysis. Mol Biol Evol 25:507–516PubMedCrossRefGoogle Scholar
  144. 144.
    Trauger SA, Kalisak E, Kalisiak J, Morita H, Weinberg MV, Menon AL, Poole FL 2nd, Adams MW, Siuzdak G (2008) Correlating the transcriptome, proteome, and metabolome in the environmental adaptation of a hyperthermophile. J Proteome Res 7:1027–1035PubMedCrossRefGoogle Scholar
  145. 145.
    Schut GJ, Bridger SL, Adams MW (2007) Insights into the metabolism of elemental sulfur by the hyperthermophilic archaeon Pyrococcus furiosus: characterization of a coenzyme A-dependent NAD(P)H sulfur oxidoreductase. J Bacteriol 189:4431–4441PubMedCrossRefGoogle Scholar
  146. 146.
    Lipscomb GL, Keese AM, Cowart DM, Schut GJ, Thomm M, Adams MW, Scott RA (2009) SurR: a transcriptional activator and repressor controlling hydrogen and elemental sulphur metabolism in Pyrococcus furiosus. Mol Microbiol 71:332–349PubMedCrossRefGoogle Scholar
  147. 147.
    Grauschopf U, Winther JR, Korber P, Zander T, Dallinger P, Bardwell JC (1995) Why is DsbA such an oxidizing disulfide catalyst? Cell 83:947–955PubMedCrossRefGoogle Scholar
  148. 148.
    Kortemme T, Darby NJ, Creighton TE (1996) Electrostatic interactions in the active site of the N-terminal thioredoxin-like domain of protein disulfide isomerase. Biochemistry 35:14503–14511PubMedCrossRefGoogle Scholar
  149. 149.
    Qin J, Clore GM, Kennedy WMP, Kuszewski J, Gronenborn AM (1996) The solution structure of human thioredoxin complexed with its target from Ref-1 reveals peptide chain reversal. Structure 4:613–620PubMedCrossRefGoogle Scholar
  150. 150.
    Qin J, Clore GM, Kennedy WMP, Huth JR, Gronenborn AM (1995) Solution structure of human thioredoxin in a mixed disulfide intermediate complex with its target peptide from the transcription factor NFκB. Structure 3:289–297PubMedCrossRefGoogle Scholar
  151. 151.
    D’Ambrosio K, Limauro D, Pedone E, Galdi I, Pedone C, Bartolucci S, De Simone G (2009) Insights into the catalytic mechanism of the Bcp family: functional and structural analysis of Bcp1 from Sulfolobus solfataricus. Proteins 76:995–1006PubMedCrossRefGoogle Scholar
  152. 152.
    Vergauwen B, Pauwels F, Jacquemotte F, Meyer TE, Cusanovich MA, Bartsch RG, Van Beeumen JJ (2001) Characterization of glutathione amide reductase from Chromatium gracile. Identification of a novel thiol peroxidase (Prx/Grx) fueled by glutathione amide redox cycling. J Biol Chem 276:20890–20897PubMedCrossRefGoogle Scholar
  153. 153.
    Kim SJ, Woo JR, Hwang YS, Jeong DG, Shin DH, Kim K, Ryu SE (2003) The tetrameric structure of Haemophilus influenza hybrid Prx5 reveals interactions between electron donor and acceptor proteins. J Biol Chem 278:10790–10798PubMedCrossRefGoogle Scholar
  154. 154.
    Pauwels F, Vergauwen B, Vanrobaeys F, Devreese B, Van Beeumen JJ (2003) Purification and characterization of a chimeric enzyme from Haemophilus influenzae Rd that exhibits glutathione-dependent peroxidase activity. J Biol Chem 278:16658–16666PubMedCrossRefGoogle Scholar
  155. 155.
    Cha MK, Hong SK, Lee DS, Kim IH (2004) Vibrio cholerae thiol peroxidase-glutaredoxin fusion is a 2-Cys TSA/AhpC subfamily acting as a lipid hydroperoxide reductase. J Biol Chem 279:11035–11041PubMedCrossRefGoogle Scholar
  156. 156.
    Rouhier N, Jacquot JP (2003) Molecular and catalytic properties of a peroxiredoxin-glutaredoxin hybrid from Neisseria meningitidis. FEBS Lett 554:149–153PubMedCrossRefGoogle Scholar
  157. 157.
    Wood ZA, Schröder E, Robin Harris J, Poole LB (2003) Structure, mechanism and regulation of peroxiredoxins. Trends Biochem Sc 28:32–40CrossRefGoogle Scholar
  158. 158.
    Hall A, Karplus PA, Poole LB (2009) Typical 2-Cys peroxiredoxins—structures, mechanisms and functions. FEBS J 276:2469–2477PubMedCrossRefGoogle Scholar
  159. 159.
    Castro H, Tomás AM (2008) Peroxidases of trypanosomatids. Antioxid Redox Signal 10:1593–1606PubMedCrossRefGoogle Scholar
  160. 160.
    Lee SP, Hwang YS, Kim YJ, Kwon KS, Kim HJ, Kim K, Chae HZ (2001) Cyclophilin a binds to peroxiredoxins and activates its peroxidase activity. J Biol Chem 276:29826–29832PubMedCrossRefGoogle Scholar
  161. 161.
    Poole LB (2005) Bacterial defenses against oxidants: mechanistic features of cysteine-based peroxidases and their flavoprotein reductases. Arch Biochem Biophys 433:240–254PubMedCrossRefGoogle Scholar
  162. 162.
    Hall A, Parsonage D, Horita D, Karplus PA, Poole LB, Barbar E (2009) Redox-dependent dynamics of a dual thioredoxin fold protein: evolution of specialized folds. Biochemistry 48:5984–5993PubMedCrossRefGoogle Scholar
  163. 163.
    Rouhier N, Gelhaye E, Jacquot JP (2002) Glutaredoxin-dependent peroxiredoxin from poplar: protein–protein interaction and catalytic mechanism. J Biol Chem 277:13609–13614PubMedCrossRefGoogle Scholar
  164. 164.
    Fernandes AP, Holmgren A (2004) Glutaredoxins: glutathione-dependent redox enzymes with functions far beyond a simple thioredoxin backup system. Antioxid Redox Signal 6:63–74PubMedCrossRefGoogle Scholar
  165. 165.
    Lillig CH, Berndt C, Holmgren A (2008) Glutaredoxin systems. Biochim Biophys Acta 1780:1304–1317PubMedGoogle Scholar
  166. 166.
    Aslund F, Nordstrand K, Berndt KD, Nikkola M, Bergman T, Ponstingl H, Jörnvall H, Otting G, Holmgren A (1996) Glutaredoxin-3 from Escherichia coli. Amino acid sequence, 1H AND 15N NMR assignments, and structural analysis. J Biol Chem 271:6736–6745PubMedCrossRefGoogle Scholar

Copyright information

© Springer Basel AG 2010

Authors and Affiliations

  • Emilia Pedone
    • 1
  • Danila Limauro
    • 2
  • Katia D’Ambrosio
    • 1
  • Giuseppina De Simone
    • 1
  • Simonetta Bartolucci
    • 2
    Email author
  1. 1.Istituto di Biostrutture e Bioimmagini-CNRNaplesItaly
  2. 2.Dipartimento di Biologia Strutturale e FunzionaleUniversità degli Studi di Napoli “Federico II”, Complesso Universitario Monte S. AngeloNaplesItaly

Personalised recommendations