Advertisement

Protein Aggregation: Opposing Effects of Chaperones and Crowding

  • R. John Ellis
Chapter

Abstract

Each molecule of every protein runs the risk that at any time between its synthesis and its degradation, it will bind to one or more identical molecules to form a nonfunctional aggregate. Some protein aggregates are toxic to cells, including neurones, and are thus factors in the development of neurodegenerative and other human diseases. The incidence of such diseases is increasing, together with human longevity and obesity. The probability of protein aggregation is increased by the crowded state of most intracellular compartments, but is reduced by the activities of a diverse range of proteins acting as molecular chaperones. These chaperones use a variety of mechanisms to combat aggregation during the folding of newly synthesized protein chains, their transport into and across membranes, and their assembly into functional oligomers. This article discusses some of the key concepts and basic evidence underlying these conclusions.

Keywords

Protein Aggregation Molecular Chaperone Amyloid Fibril Trigger Factor Protein Chain 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Akey CW, Luger K (2003) Histone chaperones and nucleosome assembly. Curr Opin Struct Biol 13: 6–14PubMedCrossRefGoogle Scholar
  2. Anfinsen CB (1973) Principles that govern the folding of protein chains. Science 181: 223–230PubMedCrossRefGoogle Scholar
  3. Balch WE, Morimoto RI, Dillin A, Kelly JW (2008) Adapting proteostasis for disease intervention. Science 319: 916–919PubMedCrossRefGoogle Scholar
  4. Barral JM, Broadley SA, Schaffar G, Hartl FU (2004) Roles of molecular chaperones in protein misfolding diseases. Semin Cell Dev Biol 15: 17–29PubMedCrossRefGoogle Scholar
  5. Bousset L, Redeker V, Decottignies P, Dubois S, Marechal PL, Melki R (2004) Structural characterisation of th fibrillar form of the yeast Saccharomyces cerevisiae prion Ure2p. Biochemistry 43: 5022–5032PubMedCrossRefGoogle Scholar
  6. Bukau B, Horwich AL (1998) The Hsp70 and Hsp60 chaperone machines. Cell 92: 351–366PubMedCrossRefGoogle Scholar
  7. Caspar DLD, Klug A (1962) Physical principles in the construction of regular virsuses. Cold Spring Harbor Symp Quant Biol 27:1–24PubMedCrossRefGoogle Scholar
  8. Chakraborty K, Georgeacauld F, Hayer-Hartl M, Hartl FU (2010) Roles of molecular chaperones in protein folding. In: Ramirez-Alvarado M, Kelly JW, Dobson CM (eds) Protein Misfolding Diseases, Wiley pp. 42–72Google Scholar
  9. Chiti F, Stefani M, Taddei N, Ramponi G, Dobson CM (2003) Rationalization of the effects of mutations on peptide and protein aggregation rates. Nature 424: 805–808PubMedCrossRefGoogle Scholar
  10. Chiti F, Dobson CM (2006) Protein misfolding, functional amyloid and disease. Annu Rev Biochem 75: 333–366PubMedCrossRefGoogle Scholar
  11. Cohen E, Bieschke J, Perciavalle RM, Kelly JW, Dillin A (2006) Opposing activities protect against age-onset proteotoxicity. Science 313: 1604–1610PubMedCrossRefGoogle Scholar
  12. Cowen LE, Lindquist S (2005) Hsp90 potentiates the rapid evolution of new traits: drug resistance in diverse fungi. Science 309: 2185–2189PubMedCrossRefGoogle Scholar
  13. Crick FHC (1958) On protein synthesis. Symp Soc Exp Biol 13: 138–163Google Scholar
  14. Deuerling E, Schulze-Specking A, Tomoyasu A, Mogk A, Bukau B. (1999) Trigger factors and DnaK cooperate in the folding of newly synthesized proteins. Nature 400: 693–696PubMedCrossRefGoogle Scholar
  15. Dinner AR et al (2000) Understanding protein Folding via Free-energy Surfaces from theory and experiment. Trends Biochem Sc. 25 331–339Google Scholar
  16. Dobson CM (1999) Protein misfolding, evolution and disease. Trends Biochem Sci 24: 329–332PubMedCrossRefGoogle Scholar
  17. Dobson CM, Ellis RJ, Fersht AR (eds) (2001) Protein Misfolding and Disease. Phil Trans R Soc B: 356: 129–131Google Scholar
  18. Ellis RJ (1987) Proteins as molecular chaperones. Nature 328: 378–379PubMedCrossRefGoogle Scholar
  19. Ellis RJ (2000) Macromolecular crowding: obvious but underappreciated. Trends Biochem Sci 26: 597–604CrossRefGoogle Scholar
  20. Ellis RJ (2003) The importance of the Anfinsen cage. Current Biol 13: R881–R883CrossRefGoogle Scholar
  21. Ellis RJ (2004) From chloroplasts to chaperones: how one thing led to another. Photosyn Res 80: 333–343CrossRefGoogle Scholar
  22. Ellis RJ (2006) Molecular chaperones: assisting assembly in addition to folding. Trends Biochem Sci 31: 395–401PubMedCrossRefGoogle Scholar
  23. Ellis RJ, Hemmingsen SM (1989) Molecular chaperones: proteins essential for the biogenesis of some macromolecular structures. Trends Biochem Sci 14: 339–342PubMedCrossRefGoogle Scholar
  24. Ellis RJ, Minton AP (2006) Protein aggregation in crowded environments. Biol Chem 387: 485–497PubMedCrossRefGoogle Scholar
  25. Farr GW, Fenton WA, Rospert S, Horwich AR. Folding with and without encapsulation by cis and trans-only GroEL-GroES complexes (2001) EMBO J 22: 3220–3230CrossRefGoogle Scholar
  26. Freedman RB (2008) Eukaryotic protein disulfide-isomerases and their potential in the production of disulfide-bonded protein products: what we need to know but do not! In: Buchner J, Moroder L (eds) Oxidative folding of peptides and proteins, Royal Society of Chemistry pp. 121–157Google Scholar
  27. Frydman J (2001) Folding of newly translated proteins in vivo: the role of molecular chaperones. Annu Rev Biochem 70: 603–647PubMedCrossRefGoogle Scholar
  28. Goodsell DS (1992) The Machinery of Life. Springer Varlaa New York Inc.Google Scholar
  29. Hartl FU, Hayer-Hartl M (2002) Molecular chaperones in the cytosol: from nascent chain to folded protein. Science 295: 1852–1858PubMedCrossRefGoogle Scholar
  30. Hatters DM, Minton AP, Howlett GJ (2002) Macromolecular crowding accelerates amyloid formation by human apolipoprotein C-II. J Biol Chem 277: 7824–7830PubMedCrossRefGoogle Scholar
  31. Hemmingsen SM, Woolford C, van der Vies SM, Tilly K, Dennis DT, Georgopoulos GC, Hendrix RW, Ellis RJ (1988) Homologous plant and bacterial proteins chaperone oligomeric protein assembly. Nature 333: 330–334PubMedCrossRefGoogle Scholar
  32. Henderson B, Pockley AG (eds) (2005) Molecular chaperones and cell signalling. Cambridge University Press, New YorkGoogle Scholar
  33. Horwich AL, Fenton WA, Chapman E, Farr GW (2007) Two families of chaperonin: physiology and mechanism. Annu Rev Cell Dev Biol 23: 115–145PubMedCrossRefGoogle Scholar
  34. Horwitz J (2000) The function of alpha-crystallin in vision. Semin Cell Develop Biol 11: 53–60CrossRefGoogle Scholar
  35. Idicula-Thomas S, Balaji PV (2007) Protein aggregation: a perspective from amyloid and inclusion-body formation. Current Science 92: 758–767Google Scholar
  36. Kota J, Ljungdahl PO (2005) Specialized membrane-localized chaperones prevent aggregation of polytopic proteins in the ER. J Cell Biol 168: 79–88PubMedCrossRefGoogle Scholar
  37. Kusmierczyk AR, Hochstrasser M (2008) Some assembly required: dedicated chaperones in eukaryotic proteasome biogenesis, Biol Chem 389: 1143–1151PubMedCrossRefGoogle Scholar
  38. Laskey RA, Honda BM, Mills AD, Finch JT (1978) Nucleosomes are assembled by an acidic protein which binds histones and transfers them to DNA. Nature 275: 416–420PubMedCrossRefGoogle Scholar
  39. Lazardis T, Karplus M (1997) ‘New view’ of protein folding reconciled with the old through multiple unfolding simulations. Science 278: 1928–1931CrossRefGoogle Scholar
  40. London J, Skrzynia C, Goldberg M (1975) Renaturation of Escherichia coli tryptophanase in aqueous urea solutions. Eur J Biochem 47: 409–415CrossRefGoogle Scholar
  41. Luhrs T, Ritter C, Adrian M., Riek-Loher D, Bohrmann B, Dobeli H, Schubert D, Riel R (2005) 3D structure of Alzheimer’s amyloid-ß(1–42) fibrils. Proc Nat Acad Sci 102: 17342–17347PubMedCrossRefGoogle Scholar
  42. Martin J, Hartl FU (1997) The effect of macromolecular crowding on chaperonin-mediated protein folding. Proc Nat Acad Sci 94: 1107–1112PubMedCrossRefGoogle Scholar
  43. Merz F, Hoffmann A, Rutkowska A, Zachmann-Brand B, Bukau B, Deuerling E (2006) The C-terminal domain of Escherichia coli trigger factor represents the central module of its chaperone activity. J Biol Chem 272: 21865–21871Google Scholar
  44. Minton AP (1983) The effect of volume occupancy upon the thermodynamic activity of proteins: some biochemical consequences. Mol Cell Biochem 55: 119–140PubMedCrossRefGoogle Scholar
  45. Minton AP, (1992) Confinement as a determinant of macromolecular structure. Biophys J 63: 1090–1100PubMedCrossRefGoogle Scholar
  46. Musgrove JE, Ellis RJ (1986) The rubisco large subunit binding protein. Phil Trans. Roy Soc Lond B 313: 419–428CrossRefGoogle Scholar
  47. Nelson R, Sawaya MR, Balbirnie M, Madsen AO, Riekel C, Grothe R, Eisenberg D (2005) Structure of the cross-β spine of amyloid-like fibrils. Nature 435: 773–778PubMedCrossRefGoogle Scholar
  48. Petkova AT, Ishii Y, Balbach JJ, Antzutkin ON, Leapman RD, Delaglio F, Tycko R (2002) A structural model for Alzheimer’s β-amyloid fibrils based on experimental constraints from solid state NMR. Proc Natl Acad Sci 99: 16742–16753PubMedCrossRefGoogle Scholar
  49. Philpott A, Krude T, Lasker RA (2000) Nuclear chaperones. Semin Cell Dev Biol 11: 7–14PubMedCrossRefGoogle Scholar
  50. Puig A, Gilbert HF (1994) Protein disulfide isomerase exhibits chaperone and antichaperone activities in the oxidative folding of lysozyme. J Biol Chem 269: 7764–7771PubMedGoogle Scholar
  51. Queitsch C, Sangster TA, Lindquist S (2002) Hsp90 as a capacitor of phenotypic variation. Nature 417: 618–624PubMedCrossRefGoogle Scholar
  52. Raviol H, Sadlish H, Rodrigvez F, Mayer MP, Bukau B (2006) Chaperone network in the yeast cytosol=Hsp 110 is revealed as an Hsp 70 nucleotide exchange Factor. EMBO J. 2510–2518Google Scholar
  53. Rousseau F, Schymkowitz J, Serrano L (2006) Protein aggregation and amyloidosis: confusion of the kinds? Curr Opin Struct Biol 16: 118–126PubMedCrossRefGoogle Scholar
  54. Rudiger S, Germeroth L, Schneider-Mergener J, Bukau B, (1997) Substrate specificity of the DnaK chaperone determined by screening cellulose-bound peptide libraries. EMBO J 16: 1501–1507PubMedCrossRefGoogle Scholar
  55. Schaffar G, Breuer P, Boteva R, Behrends C, Tzvetkov N, Strippel N, Sakahira H, Siegers K, Hayer-hartl M, Hartl FU (2004) Cellular toxicity of polyglutamine expansion proteins: mechanism of transcription factor inactivation. Molecular Cell 15: 95–105PubMedCrossRefGoogle Scholar
  56. Serpell LC, Sunde M, Benson MD, Tennent GA, Pepys MB, Fraser PE (2000) The protofilament substructure of amyloid fibrils. J Mol Biol 300: 1033–1039PubMedCrossRefGoogle Scholar
  57. Sharma S, Chakraborty K, Muller BK, Astola N, Tang YC, Lamb DC, Hayer-Hartl M, Hartl FU (2008) Monitoring protein conformation along the pathway of chaperonin-assisted folding. Cell 133: 142–153PubMedCrossRefGoogle Scholar
  58. Tam S, Geller R, Spiess C, Frydman J (2006) The chaperonin TriC controls polyglutamine aggregation and toxicity through subunit-specific interactions. Nature Cell Biology 8: 1155–1162PubMedCrossRefGoogle Scholar
  59. Tang Y-C, Chang H-C, Roeben A, Wischnewski D, Wischnewski N, Kerner MJ, Hartl FU, ­Hayer-Hartl M (2006) Structural features of the GroEL-GroES nanocage required for rapid folding of encapsulated protein. Cell 125: 903–914PubMedCrossRefGoogle Scholar
  60. Teter SA, Houry WA, Ang D, Tradler T, Rockabrand D, Fischer G, Blum P, Georgopoulos C, Hartl FU (1999) Polypeptide flux through bacterial hsp70: DnaK cooperates with trigger factor in chaperoning nascent chains. Cell 97: 755–765PubMedCrossRefGoogle Scholar
  61. Uversky VN, Cooper EM, Bower JI, Fink AL (2002) Accelerated α-synuclein fibrillation in crowded mileu. FEBS Lett 515: 99–103PubMedCrossRefGoogle Scholar
  62. Wegrzyn RD, Hofmann D, Merz F, Nikolay R, Rauch T, Graf C, Deuerling E (2006) A conserved motif is prerequisite for the interaction of NAC with ribosomal protein L23 and nascent chains. J Biol Chem 281: 2847–2857PubMedCrossRefGoogle Scholar
  63. Wright CF, Teichmann SA, Clarke J, Dodson CM (2005) Specificity in aggregation and the evolution of modular proteins. Nature 438: 878–881PubMedCrossRefGoogle Scholar
  64. Xu Z, Horwich AL, Sigler, P.(1997) The crystal structure of the asymmetric GroEL-GroES-(ADP)7 chaperonin complex. Nature 388:741–750PubMedCrossRefGoogle Scholar
  65. Young JC, Agashe VR, Siegers K, Hartl FU (2004) Pathways of chaperone-mediated protein folding in the cytosol. Nature Revs Cell Biol 5:781–790CrossRefGoogle Scholar
  66. Zhou HX, Rivas G, Minton AP (2008) Macromolecular crowding and confinement: biochemical, biophysical and potential physiological consequences. Annu Rev Biophys 37: 375–397PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Biological SciencesUniversity of WarwickCoventryUK

Personalised recommendations