Protein Folding in the Endoplasmic Reticulum

  • Ari Helenius
  • Utpal Tatu
  • Thorsten Marquardt
  • Ineke Braakman
Conference paper
Part of the Serono Symposia, USA book series (SERONOSYMP)


The endoplasmic reticulum (ER) is the first and usually the largest compartment of the secretory pathway. It is a highly specialized organelle primarily devoted to biosynthetic functions. In addition to lipid synthesis, it is responsible for protein translation, translocation, folding, assembly, and covalent modifications. The majority of the proteins made are for secretion into the extracellular space, for export to the plasma membrane, or for membranes and internal compartments that constitute the vacuolar system. Thus, the ER is responsible for generating an extensive palette of important receptors, hormones, enzymes, antibodies, inhibitors, extra-cellular matrix components, and the like. Most of these proteins are glycoproteins, many are oligomeric in their final mature form, and a majority contain intra- and/or interchain disulfide bonds.


Endoplasmic Reticulum Disulfide Bond Protein Disulfide Isomerase Vesicular Stomatitis Virus Disulfide Bond Formation 
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  1. 1.
    Dill KA. Dominant forces in protein folding. Biochemistry 1990; 29: 7133–52.PubMedCrossRefGoogle Scholar
  2. 2.
    Jaenicke R. Protein folding: local structures, domains, subunits and assemblies. Biochemistry 1991; 30: 3147–61.PubMedCrossRefGoogle Scholar
  3. 3.
    Kim PS, Baldwin RL. Specific intermediates in the folding reactions of small proteins and the mechanism of protein folding. Annu Rev Biochem 1982; 51: 459–89.PubMedCrossRefGoogle Scholar
  4. 4.
    Creighton TE. Experimental studies of protein folding and unfolding. Prog Biophys Mol Biol 1978; 33: 231–97.PubMedCrossRefGoogle Scholar
  5. 5.
    Hubbard TJP, Sander C. Heat-shock and chaperone proteins: evidence for a role in protein folding. Protein Eng (in press).Google Scholar
  6. 6.
    Ellis RJ, van der Vies SM. Molecular chaperones. Annu Rev Biochem 1991; 60: 321–47.PubMedCrossRefGoogle Scholar
  7. 7.
    Creighton TE. Disulfide bonds as probes of protein folding pathways. Methods Enzymol 1986; 131: 83–106.PubMedCrossRefGoogle Scholar
  8. 8.
    Gething M-J, Sambrook J. Protein folding and intracellular transport: studies on influenza virus haemagglutinin. Biochem Soc Symp 1990; 55: 155–66.Google Scholar
  9. 9.
    Rothman JE. Polypeptide chain binding proteins: catalysts of protein folding and related processes in cells. Cell 1989; 59: 591–601.PubMedCrossRefGoogle Scholar
  10. 10.
    Schlesinger MJ. Heat shock proteins. J Biol Chem 1990; 265: 12111–4.PubMedGoogle Scholar
  11. 11.
    Gething M-J, Sambrook J. Protein folding in the cell. Nature 1992; 355: 33–45.PubMedCrossRefGoogle Scholar
  12. 12.
    Bergman LW, Kuehl WM. Formation of an intrachain disulfide bond on nascent immunoglobulin light chains. J Biol Chem 1979; 254: 8869–76.PubMedGoogle Scholar
  13. 13.
    Bergman LW, Kuehl WM. Formation of intermolecular disulfide bonds on nascent immunoglobulin polypeptides. J Biol Chem 1979; 254: 5690–4.PubMedGoogle Scholar
  14. 14.
    Hurtley SM, Helenius A. Protein oligomerization in the endoplasmic reticulum. Annu Rev Cell Biol 1989; 5: 277–307.PubMedCrossRefGoogle Scholar
  15. 15.
    Klausner RD. Architectural editing: determining the fate of newly synthesized membrane proteins. New Biologist 1989; 1: 3–8.PubMedGoogle Scholar
  16. 16.
    Sitia R, Neuberger M, Alberini C, et al. Developmental regulation of IgM secretion: the role of the carboxy-terminal cysteine. Cell 1990; 60: 781–90.PubMedCrossRefGoogle Scholar
  17. 17.
    Hurtley SM, Bole DG, Hoover-Litty H, et al. Interactions of misfolded influenza hemagglutinin with binding protein (BiP). J Cell Biol 1989; 108: 2117–26.PubMedCrossRefGoogle Scholar
  18. 18.
    Jaenicke R. Folding and association of proteins. Prog Biophys Mol Biol 1987; 49: 117–237.PubMedCrossRefGoogle Scholar
  19. 19.
    Ceriotti A, Colman A. Trimer formation determines the rate of influenza haemagglutinin transport in the early stages of secretion in Xenopus oocytes. J Cell Biol 1990; 111: 409–20.PubMedCrossRefGoogle Scholar
  20. 20.
    Braakman I, Hoover-Litty H, Wagner KR, Helenius A. Folding of influenza hemagglutinin in the endoplasmic reticulum. J Cell Biol 1991; 114: 401–11.PubMedCrossRefGoogle Scholar
  21. 21.
    Fahey RC, Hunt JS, Windham GC. On the cysteine and cystein content of proteins. Differences between intracellular and extracellular proteins. J Mol Evol 1977; 10: 155–60.PubMedCrossRefGoogle Scholar
  22. 22.
    Creighton TE. Disulfide bonds and protein stablility. Bioessays 1988; 8: 57–62.PubMedCrossRefGoogle Scholar
  23. 23.
    Pace CN, Grimsley GR, Thomson JA, Barnett BJ. Conformational stability and activity of ribonuclease T1 with zero, one, and two intact disulfide bonds. J Biol Chem 1988; 263: 11820–5.PubMedGoogle Scholar
  24. 24.
    Bulleid NJ, Freedman RB. Defective co-translational formation of disulphide bonds in protein disulfide-isomerase-deficient microsomes. Nature 1988; 335: 649–51.PubMedCrossRefGoogle Scholar
  25. 25.
    Freedman RB. Protein disulfide isomerase: multiple roles in the modification of nascent secretory proteins. Cell 1989; 57: 1069–72.PubMedCrossRefGoogle Scholar
  26. 26.
    Edman JC, Ellis L, Blacher RW, et al. Sequence of protein disulfide isomerase and implications of its relationship to thioredoxin. Nature 1985; 317: 276–80.CrossRefGoogle Scholar
  27. 27.
    Kivirikko KI, Myllylä R. Post-translational processing of procollagens. Ann NY Acad Sci 1986; 460: 187–201.CrossRefGoogle Scholar
  28. 28.
    Wetterau JR, Combs KA, Spinner SN, Joiner BJ. Protein disulfide isomerase is a component of the microsomal triglyceride transfer protein complex. J Biol Chem 1990; 265: 9800–7.PubMedGoogle Scholar
  29. 29.
    Creighton TE, D-A H, Freedman RB. Catalysis by protein-disulphide isomerase of the unfolding and refolding of proteins with disulphide bonds. J Mol Biol 1980; 142: 43–62.PubMedCrossRefGoogle Scholar
  30. 30.
    Lambert N, Freedman RB. Structural properties of homogeneous protein disulphide-isomerase from bovine liver purified by a rapid high-yielding procedure. Biochem J 1983; 213: 225–34.PubMedGoogle Scholar
  31. 31.
    Lambert N, Freedman RB. Kinetics and specificity of homogeneous protein disulphide-isomerase in protein disulphide isomerization and in thiol-proteindisulphide oxidoreduction. Biochem J 1983; 213: 235–43.PubMedGoogle Scholar
  32. 32.
    Freedman RB. Native disulfide bond formation in protein biosynthesis: evidence for the role of protein disulphide isomerase. Trends Biochem Sci 1984; 438–41.Google Scholar
  33. 33.
    Mazzarella RA, Srinivasan M, Haugejorden SM, Green M. ERp72, an abundant luminal endoplasmic reticulum protein, contains three copies of the active site sequence of protein disulfide isomerase. J Biol Chem 1990; 265: 1094–101.PubMedGoogle Scholar
  34. 34.
    Lewis MJ, Mazzarella RA, Green M. Structure and assembly of the endoplasmic reticulum: the synthesis of three major endoplasmic reticulum proteins during lipopolysaccharide-induced differentiation of murine lymphocytes. J Biol Chem 1985; 260: 3050–7.PubMedGoogle Scholar
  35. 35.
    Saxena VP, Wetlaufer DB. Formation of three-dimensional structure in proteins, I. Rapid nonenzymic reactivation of reduced lysozyme. Biochemistry 1970; 9: 5015–22.PubMedCrossRefGoogle Scholar
  36. 36.
    Scheele G, Jacoby R. Conformational changes associated with proteolytic processing of presecretory proteins allow glutathione-catalyzed formation of native disulfide bonds. J Biol Chem 1982; 257: 12277–82.PubMedGoogle Scholar
  37. 37.
    Olden K, Parent JB, White SL. Carbohydrate moieties of glycoproteins. A re-evaluation of their function. Biochim Biophys Acta 1982; 650: 209–32.PubMedGoogle Scholar
  38. 38.
    Paulson JC. Glycoproteins: what are the sugar chains for? Trends Biochem Sci 1989; 14: 272–5.PubMedCrossRefGoogle Scholar
  39. 39.
    Schälke N, Schmidt FX. The stability of yeast invertase is not significantly influenced by glycosylation. J Biol Chem 1988; 263: 8827–31.Google Scholar
  40. 40.
    Gibson R, Schlesinger S, Kornfeld S. The nonglycosylated glycoprotein of vesicular stomatitis virus is temperature sensitive and undergoes intracellular aggregation at elevated temperatures. J Biol Chem 1979; 254: 3600.PubMedGoogle Scholar
  41. 41.
    Machamer CE, Florkiewicz RZ, Rose JK. A single N-linked oligosaccharide at either of the two normal sites is sufficient for transport of vesicular stomatitis virus G protein to the cell surface. Mol Cell Biol 1985; 5: 3074–83.PubMedGoogle Scholar
  42. 42.
    Singh I, Doms RW, Wagner KR, Helenius A. Intracellular transport of soluble and membrane-bound glycoproteins: folding, assembly and secretion of anchor-free influenza hemagglutinin. EMBO J 1990; 9: 631–9.PubMedGoogle Scholar
  43. 43.
    Rothman JE, Lodish HF. Synchronised transmembrane insertion and glycosylation of a nascent membrane protein. Nature 1977; 269: 775–80.PubMedCrossRefGoogle Scholar
  44. 44.
    Evans EA, Gilmore R, Blobel G. Purification of microsomal signal peptidase as a complex. Proc Natl Acad Sci USA 1986; 83: 581–5.PubMedCrossRefGoogle Scholar
  45. 45.
    Rottier PJM, Florkiewicz RZ, Shaw AS, Rose JK. An internalized amino-terminal signal sequence retains full acitivity in vivo but not in vitro. J Biol Chem 1987; 262: 8889–95.PubMedGoogle Scholar
  46. 46.
    Kassenbrock CK, Garcia PD, Walter P, Kelly RB. Heavy-chain binding protein recognizes aberrant polypeptides in vitro. Nature 1988; 333: 90–3.PubMedCrossRefGoogle Scholar
  47. 47.
    Ng DTW, Randall RE, Lamb RA. Intracellular maturation and transport of the SV5 type II glycoprotein hemagglutinin-neuraminidase: specific and transient association with GRP78-BiP in the endoplasmic reticulum and extensive internalization from the cell surface. J Cell Biol 1989; 109: 3273–89.PubMedCrossRefGoogle Scholar
  48. 48.
    Bole DG, Hendershot LM, Kearney JF. Posttranslational association of immunoglobulin heavy chain binding protein with nascent heavy chains in nonsecreting and secreting hybridomas. J Cell Biol 1986; 102: 1558–66.PubMedCrossRefGoogle Scholar
  49. 49.
    Machamer CE, Doms RW, Bole DG, et al. Heavy chain binding protein recognizes incompletely disulfide-bonded forms of vesicular stomatitis virus G protein. J Biol Chem 1990; 265: 6879–83.PubMedGoogle Scholar
  50. 50.
    Vogel JP, Misra LM, Rose MD. Loss of BiP/GRP78 function blocks translocation of secretory proteins in yeast. J Cell Biol 1990; 110: 1885–95.PubMedCrossRefGoogle Scholar
  51. 51.
    Lee AS, Bell J, Ting J. Biochemical characterization of the 94 and 78kilodalton glucose regulated proteins in hamster fibroblasts. J Biol Chem 1984; 259: 4616–21.PubMedGoogle Scholar
  52. 52.
    Melnick JR, Aviel S, Argon Y. A 100kD protein is associated in the endoplasmic reticulum with both BiP/GRP78 and newly synthesized proteins. J Cell Biol 1991; 115: 1a.Google Scholar
  53. 53.
    Price ER, Zudowsky LD, Baker CH, et al. Human cyclophilin B: a second cyclophilin gene encodes a paptidyl-prolyl isomerase with a signal sequence. Proc Natl Acad Sci USA 1991; 88: 1903–7.PubMedCrossRefGoogle Scholar
  54. 54.
    Bergsma DJ, Eder C, Gross M, et al. The cyclophilin multigene family of peptidyl-prolyl isomerases: characterization of three separate human isoforms. J Biol Chem 1991; 266: 23204–14.PubMedGoogle Scholar
  55. 55.
    Stamnes MA, Shieh B-H, Chuman L, et al. The cyclophilin homolog ninaA is a tissue-specific integral membrane protein required for the proper synthesis of a subset of Drosophila rhodopsins. Cell 1991; 65: 219–27.PubMedCrossRefGoogle Scholar
  56. 56.
    Sadler I, Chiang A, Kurihara T, et al. A yeast gene important for protein assembly into the endoplasmic reticulum and the nucleus has homology to DnaJ, an Escherichia coli heat shock protein. J Cell Biol 1989; 109: 2665–75.PubMedCrossRefGoogle Scholar
  57. 57.
    Sambrook JF. The involvement of calcium in the transport of secretory proteins from the endoplasmic reticulum. Cell 1990; 61: 197–9.PubMedCrossRefGoogle Scholar
  58. 58.
    Suzuki CK, Bonafacino JS, Lin AY, et al. Regulating the retention of T-Cell receptor alpha chain within the endoplasmic reticulum: Ca’-dependent association with BiP. J Cell Biol 1991; 114: 189–205.PubMedCrossRefGoogle Scholar
  59. 59.
    Booth C, Koch LE. Perturbation of cellular calcium induces secretion of luminal ER proteins. Cell 1990; 59: 729–37.CrossRefGoogle Scholar
  60. 60.
    Braakman I, Helenius J, Helenius A. The role of ATP and disulfide bonds during protein folding in the endoplasmic reticulum. Nature (in press).Google Scholar
  61. 61.
    Braakman I, Helenius J, Helenius A. Manipulating disulfide bond formation and protein folding in the endoplasmic reticulum. EMBO J (in press).Google Scholar
  62. 62.
    Martin J, Langer T, Boteva R, et al. Chaperonin-mediated protein folding at the surface of groEL through a molten globule’-like intermediate. Nature 1991; 352: 36–42.PubMedCrossRefGoogle Scholar
  63. 63.
    Clairmont CA, De Maio A, Hirschberg CB. Translocation of ATP into the lumen of rough endoplasmic reticulum derived vesicles and its binding to lumenal proteins including BiP(GRP78) and GRP94. J Biol Chem (in press).Google Scholar

Copyright information

© Springer-Verlag New York, Inc. 1993

Authors and Affiliations

  • Ari Helenius
  • Utpal Tatu
  • Thorsten Marquardt
  • Ineke Braakman

There are no affiliations available

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