Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Perspective
  • Published:

Unraveling infectious structures, strain variants and species barriers for the yeast prion [PSI+]

Nature Structural & Molecular Biology volume 16, pages 598–605 (2009)Cite this article

Abstract

Prions are proteins that can access multiple conformations, at least one of which is β-sheet rich, infectious and self-perpetuating in nature. These infectious proteins show several remarkable biological activities, including the ability to form multiple infectious prion conformations, also known as strains or variants, encoding unique biological phenotypes, and to establish and overcome prion species (transmission) barriers. In this Perspective, we highlight recent studies of the yeast prion [PSI+], using various biochemical and structural methods, that have begun to illuminate the molecular mechanisms by which self-perpetuating prions encipher such biological activities. We also discuss several aspects of prion conformational change and structure that remain either unknown or controversial, and we propose approaches to accelerate the understanding of these enigmatic, infectious conformers.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Molecular basis of [PSI+] prion propagation.
Figure 2: Amyloid structures of prion peptides and proteins.
Figure 3: Sup35 nucleates into multiple prion strain variants with unique structural attributes.
Figure 4: Steric zipper structural variants of a Sup35 peptide fragment.
Figure 5: Species-specific infectivities of prion strains.

Similar content being viewed by others

References

  1. Selkoe, D.J. Folding proteins in fatal ways. Nature 426, 900–904 (2003).

    CAS  PubMed  Google Scholar 

  2. Fowler, D.M., Koulov, A.V., Balch, W.E. & Kelly, J.W. Functional amyloid—from bacteria to humans. Trends Biochem. Sci. 32, 217–224 (2007).

    CAS  PubMed  Google Scholar 

  3. Shorter, J. & Lindquist, S. Prions as adaptive conduits of memory and inheritance. Nat. Rev. Genet. 6, 435–450 (2005).

    CAS  PubMed  Google Scholar 

  4. Chien, P., Weissman, J.S. & DePace, A.H. Emerging principles of conformation-based prion inheritance. Annu. Rev. Biochem. 73, 617–656 (2004).

    CAS  PubMed  Google Scholar 

  5. Uptain, S.M. & Lindquist, S. Prions as protein-based genetic elements. Annu. Rev. Microbiol. 56, 703–741 (2002).

    CAS  PubMed  Google Scholar 

  6. Tuite, M.F. & Cox, B.S. Propagation of yeast prions. Nat. Rev. Mol. Cell Biol. 4, 878–890 (2003).

    CAS  PubMed  Google Scholar 

  7. Wickner, R.B., Edskes, H.K., Shewmaker, F. & Nakayashiki, T. Prions of fungi: inherited structures and biological roles. Nat. Rev. Microbiol. 5, 611–618 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Prusiner, S.B. Prions. Proc. Natl. Acad. Sci. USA 95, 13363–13383 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Collinge, J. Prion diseases of humans and animals: their causes and molecular basis. Annu. Rev. Neurosci. 24, 519–550 (2001).

    CAS  PubMed  Google Scholar 

  10. Aguzzi, A. & Polymenidou, M. Mammalian prion biology: one century of evolving concepts. Cell 116, 313–327 (2004).

    CAS  PubMed  Google Scholar 

  11. Wickner, R.B. [URE3] as an altered URE2 protein: evidence for a prion analog in Saccharomyces cerevisiae. Science 264, 566–569 (1994).

    CAS  PubMed  Google Scholar 

  12. Patino, M.M., Liu, J.J., Glover, J.R. & Lindquist, S. Support for the prion hypothesis for inheritance of a phenotypic trait in yeast. Science 273, 622–626 (1996).

    CAS  PubMed  Google Scholar 

  13. Paushkin, S.V., Kushnirov, V.V., Smirnov, V.N. & Ter-Avanesyan, M.D. Propagation of the yeast prion-like [PSI+] determinant is mediated by oligomerization of the SUP35-encoded polypeptide chain release factor. EMBO J. 15, 3127–3134 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Si, K., Lindquist, S. & Kandel, E.R. A neuronal isoform of the aplysia CPEB has prion-like properties. Cell 115, 879–891 (2003).

    CAS  PubMed  Google Scholar 

  15. Du, Z., Park, K.W., Yu, H., Fan, Q. & Li, L. Newly identified prion linked to the chromatin-remodeling factor Swi1 in Saccharomyces cerevisiae. Nat. Genet. 40, 460–465 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Alberti, S., Halfmann, R., King, O., Kapila, A. & Lindquist, S. A systematic survey identifies prions and illuminates sequence features of prionogenic proteins. Cell 137, 146–158 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Derkatch, I.L., Chernoff, Y.O., Kushnirov, V.V., Inge-Vechtomov, S.G. & Liebman, S.W. Genesis and variability of [PSI] prion factors in Saccharomyces cerevisiae. Genetics 144, 1375–1386 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. King, C.Y. & Diaz-Avalos, R. Protein-only transmission of three yeast prion strains. Nature 428, 319–323 (2004).

    CAS  PubMed  Google Scholar 

  19. Tanaka, M., Chien, P., Naber, N., Cooke, R. & Weissman, J.S. Conformational variations in an infectious protein determine prion strain differences. Nature 428, 323–328 (2004).

    CAS  PubMed  Google Scholar 

  20. Bruce, M.E., McConnell, I., Fraser, H. & Dickinson, A.G. The disease characteristics of different strains of scrapie in Sinc congenic mouse lines: implications for the nature of the agent and host control of pathogenesis. J. Gen. Virol. 72, 595–603 (1991).

    CAS  PubMed  Google Scholar 

  21. Caughey, B., Raymond, G.J. & Bessen, R.A. Strain-dependent differences in β-sheet conformations of abnormal prion protein. J. Biol. Chem. 273, 32230–32235 (1998).

    CAS  PubMed  Google Scholar 

  22. Kocisko, D.A. et al. Cell-free formation of protease-resistant prion protein. Nature 370, 471–474 (1994).

    CAS  PubMed  Google Scholar 

  23. Safar, J. et al. Eight prion strains have PrPSc molecules with different conformations. Nat. Med. 4, 1157–1165 (1998).

    CAS  PubMed  Google Scholar 

  24. Collinge, J. et al. Unaltered susceptibility to BSE in transgenic mice expressing human prion protein. Nature 378, 779–783 (1995).

    CAS  PubMed  Google Scholar 

  25. Prusiner, S.B. et al. Transgenic studies implicate interactions between homologous PrP isoforms in scrapie prion replication. Cell 63, 673–686 (1990).

    CAS  PubMed  Google Scholar 

  26. Hill, A.F. et al. The same prion strain causes vCJD and BSE. Nature 389, 448–450 (1997).

    CAS  PubMed  Google Scholar 

  27. Collinge, J., Sidle, K.C., Meads, J., Ironside, J. & Hill, A.F. Molecular analysis of prion strain variation and the aetiology of 'new variant' CJD. Nature 383, 685–690 (1996).

    CAS  PubMed  Google Scholar 

  28. Bessen, R.A. & Marsh, R.F. Distinct PrP properties suggest the molecular basis of strain variation in transmissible mink encephalopathy. J. Virol. 68, 7859–7868 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Chien, P., DePace, A.H., Collins, S.R. & Weissman, J.S. Generation of prion transmission barriers by mutational control of amyloid conformations. Nature 424, 948–951 (2003).

    CAS  PubMed  Google Scholar 

  30. Chien, P. & Weissman, J.S. Conformational diversity in a yeast prion dictates its seeding specificity. Nature 410, 223–227 (2001).

    CAS  PubMed  Google Scholar 

  31. Santoso, A., Chien, P., Osherovich, L.Z. & Weissman, J.S. Molecular basis of a yeast prion species barrier. Cell 100, 277–288 (2000).

    CAS  PubMed  Google Scholar 

  32. Chernoff, Y.O. et al. Evolutionary conservation of prion-forming abilities of the yeast Sup35 protein. Mol. Microbiol. 35, 865–876 (2000).

    CAS  PubMed  Google Scholar 

  33. Kushnirov, V.V., Kochneva-Pervukhova, N.V., Chechenova, M.B., Frolova, N.S. & Ter-Avanesyan, M.D. Prion properties of the Sup35 protein of yeast Pichia methanolica . EMBO J. 19, 324–331 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Resende, C. et al. The Candida albicans Sup35p protein (CaSup35p): function, prion-like behaviour and an associated polyglutamine length polymorphism. Microbiology 148, 1049–1060 (2002).

    CAS  PubMed  Google Scholar 

  35. Nakayashiki, T., Ebihara, K., Bannai, H. & Nakamura, Y. Yeast [PSI+] “prions” that are crosstransmissible and susceptible beyond a species barrier through a quasi-prion state. Mol. Cell 7, 1121–1130 (2001).

    CAS  PubMed  Google Scholar 

  36. Scott, M. et al. Transgenic mice expressing hamster prion protein produce species-specific scrapie infectivity and amyloid plaques. Cell 59, 847–857 (1989).

    CAS  PubMed  Google Scholar 

  37. Bruce, M. et al. Transmission of bovine spongiform encephalopathy and scrapie to mice: strain variation and the species barrier. Phil. Trans. R. Soc. Lond. B 343, 405–411 (1994).

    CAS  Google Scholar 

  38. Supattapone, S. et al. Prion protein of 106 residues creates an artificial transmission barrier for prion replication in transgenic mice. Cell 96, 869–878 (1999).

    CAS  PubMed  Google Scholar 

  39. Chen, B., Newnam, G.P. & Chernoff, Y.O. Prion species barrier between the closely related yeast proteins is detected despite coaggregation. Proc. Natl. Acad. Sci. USA 104, 2791–2796 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Tanaka, M., Chien, P., Yonekura, K. & Weissman, J.S. Mechanism of cross-species prion transmission: an infectious conformation compatible with two highly divergent yeast prion proteins. Cell 121, 49–62 (2005).

    CAS  PubMed  Google Scholar 

  41. Tessier, P.M. & Lindquist, S. Prion recognition elements govern nucleation, strain specificity and species barriers. Nature 447, 556–561 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Legname, G. et al. Synthetic mammalian prions. Science 305, 673–676 (2004).

    CAS  PubMed  Google Scholar 

  43. Deleault, N.R., Harris, B.T., Rees, J.R. & Supattapone, S. Formation of native prions from minimal components in vitro . Proc. Natl. Acad. Sci. USA 104, 9741–9746 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Maddelein, M.L., Dos Reis, S., Duvezin-Caubet, S., Coulary-Salin, B. & Saupe, S.J. Amyloid aggregates of the HET-s prion protein are infectious. Proc. Natl. Acad. Sci. USA 99, 7402–7407 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Patel, B.K. & Liebman, S.W. “Prion-proof” for [PIN+]: infection with in vitro-made amyloid aggregates of Rnq1p-(132–405) induces [PIN+]. J. Mol. Biol. 365, 773–782 (2007).

    CAS  PubMed  Google Scholar 

  46. Brachmann, A., Baxa, U. & Wickner, R.B. Prion generation in vitro: amyloid of Ure2p is infectious. EMBO J. 24, 3082–3092 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Wickner, R.B., Masison, D.C. & Edskes, H.K. [PSI] and [URE3] as yeast prions. Yeast 11, 1671–1685 (1995).

    CAS  PubMed  Google Scholar 

  48. Chernoff, Y.O., Lindquist, S.L., Ono, B., Ingevechtomov, S.G. & Liebman, S.W. Role of the chaperone protein Hsp104 in propagation of the yeast prion-like factor. Science 268, 880–884 (1995).

    CAS  PubMed  Google Scholar 

  49. Eaglestone, S.S., Cox, B.S. & Tuite, M.F. Translation termination efficiency can be regulated in Saccharomyces cerevisiae by environmental stress through a prion-mediated mechanism. EMBO J. 18, 1974–1981 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. True, H.L., Berlin, I. & Lindquist, S.L. Epigenetic regulation of translation reveals hidden genetic variation to produce complex traits. Nature 431, 184–187 (2004).

    CAS  PubMed  Google Scholar 

  51. True, H.L. & Lindquist, S.L. A yeast prion provides a mechanism for genetic variation and phenotypic diversity. Nature 407, 477–483 (2000).

    CAS  PubMed  Google Scholar 

  52. Lian, H.Y., Jiang, Y., Zhang, H., Jones, G.W. & Perrett, S. The yeast prion protein Ure2: structure, function and folding. Biochim. Biophys. Acta 1764, 535–545 (2006).

    CAS  PubMed  Google Scholar 

  53. Sondheimer, N., Lopez, N., Craig, E.A. & Lindquist, S. The role of Sis1 in the maintenance of the [RNQ+] prion. EMBO J. 20, 2435–2442 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Derkatch, I.L. et al. Dependence and independence of [PSI+] and [PIN+]: a two-prion system in yeast? EMBO J. 19, 1942–1952 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Derkatch, I.L., Bradley, M.E., Hong, J.Y. & Liebman, S.W. Prions affect the appearance of other prions: the story of. Cell 106, 171–182 (2001).

    CAS  PubMed  Google Scholar 

  56. Osherovich, L.Z. & Weissman, J.S. Multiple Gln/Asn-rich prion domains confer susceptibility to induction of the yeast [PSI+] prion. Cell 106, 183–194 (2001).

    CAS  PubMed  Google Scholar 

  57. Wickner, R.B. et al. Prions beget prions: the [PIN+] mystery! Trends Biochem. Sci. 26, 697–699 (2001).

    CAS  PubMed  Google Scholar 

  58. Coustou, V., Deleu, C., Saupe, S. & Begueret, J. The protein product of the het-s heterokaryon incompatibility gene of the fungus Podospora anserina behaves as a prion analog. Proc. Natl. Acad. Sci. USA 94, 9773–9778 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Coustou, V., Deleu, C., Saupe, S.J. & Begueret, J. Mutational analysis of the [Het-s] prion analog of Podospora anserina. A short N-terminal peptide allows prion propagation. Genetics 153, 1629–1640 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Nemecek, J., Nakayashiki, T. & Wickner, R.B. A prion of yeast metacaspase homolog (Mca1p) detected by a genetic screen. Proc. Natl. Acad. Sci. USA 106, 1892–1896 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Patel, B.K., Gavin-Smyth, J. & Liebman, S.W. The yeast global transcriptional co-repressor protein Cyc8 can propagate as a prion. Nat. Cell Biol. 11, 344–349 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Ball, A.J., Wong, D.K. & Elliott, J.J. Glucosamine resistance in yeast. I. A preliminary genetic analysis. Genetics 84, 311–317 (1976).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Volkov, K.V. et al. Novel non-Mendelian determinant involved in the control of translation accuracy in Saccharomyces cerevisiae. Genetics 160, 25–36 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Tallóczy, Z., Menon, S., Neigeborn, L. & Leibowitz, M.J. The [KIL-d] cytoplasmic genetic element of yeast results in epigenetic regulation of viral M double-stranded RNA gene expression. Genetics 150, 21–30 (1998).

    PubMed  PubMed Central  Google Scholar 

  65. Collin, P., Beauregard, P.B., Elagoz, A. & Rokeach, L.A. A non-chromosomal factor allows viability of Schizosaccharomyces pombe lacking the essential chaperone calnexin. J. Cell Sci. 117, 907–918 (2004).

    CAS  PubMed  Google Scholar 

  66. Silar, P., Haedens, V., Rossignol, M. & Lalucque, H. Propagation of a novel cytoplasmic, infectious and deleterious determinant is controlled by translational accuracy in Podospora anserina . Genetics 151, 87–95 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Michelitsch, M.D. & Weissman, J.S. A census of glutamine/asparagine-rich regions: implications for their conserved function and the prediction of novel prions. Proc. Natl. Acad. Sci. USA 97, 11910–11915 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Liu, J.J. & Lindquist, S. Oligopeptide-repeat expansions modulate 'protein-only' inheritance in yeast. Nature 400, 573–576 (1999).

    CAS  PubMed  Google Scholar 

  69. Parham, S.N., Resende, C.G. & Tuite, M.F. Oligopeptide repeats in the yeast protein Sup35p stabilize intermolecular prion interactions. EMBO J. 20, 2111–2119 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Vital, C. et al. Prion encephalopathy with insertion of octapeptide repeats: the number of repeats determines the type of cerebellar deposits. Neuropathol. Appl. Neurobiol. 24, 125–130 (1998).

    CAS  PubMed  Google Scholar 

  71. Ter-Avanesyan, M.D., Dagkesamanskaya, A.R., Kushnirov, V.V. & Smirnov, V.N. The SUP35 omnipotent suppressor gene is involved in the maintenance of the non-Mendelian determinant [PSI+] in the yeast Saccharomyces cerevisiae. Genetics 137, 671–676 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Glover, J.R. et al. Self-seeded fibers formed by Sup35, the protein determinant of [PSI+], a heritable prion-like factor of S. cerevisiae. Cell 89, 811–819 (1997).

    CAS  PubMed  Google Scholar 

  73. Lindquist, S. et al. The role of Hsp104 in stress tolerance and [PSI+] propagation in Saccharomyces cerevisiae. Cold Spring Harb. Symp. Quant. Biol. 60, 451–460 (1995).

    CAS  PubMed  Google Scholar 

  74. Patino, M.M., Liu, J.J., Glover, J.R. & Lindquist, S. Support for the prion hypothesis for inheritance of a phenotypic trait in yeast. Science 273, 622–626 (1996).

    CAS  PubMed  Google Scholar 

  75. Paushkin, S.V., Kushnirov, V.V., Smirnov, V.N. & Ter-Avanesyan, M.D. In vitro propagation of the prion-like state of yeast Sup35 protein. Science 277, 381–383 (1997).

    CAS  PubMed  Google Scholar 

  76. Glover, J.R. & Lindquist, S. Hsp104, Hsp70, and Hsp40: a novel chaperone system that rescues previously aggregated proteins. Cell 94, 73–82 (1998).

    CAS  PubMed  Google Scholar 

  77. King, C.Y. et al. Prion-inducing domain 2–114 of yeast Sup35 protein transforms in vitro into amyloid-like filaments. Proc. Natl. Acad. Sci. USA 94, 6618–6622 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. DePace, A.H., Santoso, A., Hillner, P. & Weissman, J.S. A critical role for amino-terminal glutamine/asparagine repeats in the formation and propagation of a yeast prion. Cell 93, 1241–1252 (1998).

    CAS  PubMed  Google Scholar 

  79. Li, L. & Lindquist, S. Creating a protein-based element of inheritance. Science 287, 661–664 (2000).

    CAS  PubMed  Google Scholar 

  80. Nelson, R. & Eisenberg, D. Recent atomic models of amyloid fibril structure. Curr. Opin. Struct. Biol. 16, 260–265 (2006).

    CAS  PubMed  Google Scholar 

  81. Serpell, L.C. Alzheimer's amyloid fibrils: structure and assembly. Biochim. Biophys. Acta 1502, 16–30 (2000).

    CAS  PubMed  Google Scholar 

  82. Wetzel, R. Ideas of order for amyloid fibril structure. Structure 10, 1031–1036 (2002).

    CAS  PubMed  Google Scholar 

  83. Nelson, R. et al. Structure of the cross-β spine of amyloid-like fibrils. Nature 435, 773–778 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. van der Wel, P.C., Lewandowski, J.R. & Griffin, R.G. Solid-state NMR study of amyloid nanocrystals and fibrils formed by the peptide GNNQQNY from yeast prion protein Sup35p. J. Am. Chem. Soc. 129, 5117–5130 (2007).

    CAS  PubMed  Google Scholar 

  85. Sawaya, M.R. et al. Atomic structures of amyloid cross-β spines reveal varied steric zippers. Nature 447, 453–457 (2007).

    CAS  PubMed  Google Scholar 

  86. Krishnan, R. & Lindquist, S.L. Structural insights into a yeast prion illuminate nucleation and strain diversity. Nature 435, 765–772 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Shewmaker, F., Wickner, R.B. & Tycko, R. Amyloid of the prion domain of Sup35p has an in-register parallel β-sheet structure. Proc. Natl. Acad. Sci. USA 103, 19754–19759 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Kajava, A.V., Baxa, U., Wickner, R.B. & Steven, A.C. A model for Ure2p prion filaments and other amyloids: the parallel superpleated β-structure. Proc. Natl. Acad. Sci. USA 101, 7885–7890 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Diaz-Avalos, R., King, C.Y., Wall, J., Simon, M. & Caspar, D.L. Strain-specific morphologies of yeast prion amyloid fibrils. Proc. Natl. Acad. Sci. USA 102, 10165–10170 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Ross, E.D., Edskes, H.K., Terry, M.J. & Wickner, R.B. Primary sequence independence for prion formation. Proc. Natl. Acad. Sci. USA 102, 12825–12830 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Yoder, M.D. & Jurnak, F. Protein motifs. 3. The parallel β helix and other coiled folds. FASEB J. 9, 335–342 (1995).

    CAS  PubMed  Google Scholar 

  92. Kishimoto, A. et al. β-helix is a likely core structure of yeast prion Sup35 amyloid fibers. Biochem. Biophys. Res. Commun. 315, 739–745 (2004).

    CAS  PubMed  Google Scholar 

  93. Makin, O.S., Sikorski, P. & Serpell, L.C. Diffraction to study protein and peptide assemblies. Curr. Opin. Chem. Biol. 10, 417–422 (2006).

    CAS  PubMed  Google Scholar 

  94. Toyama, B.H., Kelly, M.J., Gross, J.D. & Weissman, J.S. The structural basis of yeast prion strain variants. Nature 449, 233–237 (2007).

    CAS  PubMed  Google Scholar 

  95. Romanelli, A., Shekhtman, A., Cowburn, D. & Muir, T.W. Semisynthesis of a segmental isotopically labeled protein splicing precursor: NMR evidence for an unusual peptide bond at the N-extein-intein junction. Proc. Natl. Acad. Sci. USA 101, 6397–6402 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Muir, T.W. Semisynthesis of proteins by expressed protein ligation. Annu. Rev. Biochem. 72, 249–289 (2003).

    CAS  PubMed  Google Scholar 

  97. Shivaprasad, S. & Wetzel, R. Analysis of amyloid fibril structure by scanning cysteine mutagenesis. Methods Enzymol. 413, 182–198 (2006).

    CAS  PubMed  Google Scholar 

  98. Iwata, K., Eyles, S.J. & Lee, J.P. Exposing asymmetry between monomers in Alzheimer's amyloid fibrils via reductive alkylation of lysine residues. J. Am. Chem. Soc. 123, 6728–6729 (2001).

    CAS  PubMed  Google Scholar 

  99. Prusiner, S.B. Molecular biology of prion diseases. Science 252, 1515–1522 (1991).

    CAS  PubMed  Google Scholar 

  100. Tanaka, M., Collins, S.R., Toyama, B.H. & Weissman, J.S. The physical basis of how prion conformations determine strain phenotypes. Nature 442, 585–589 (2006).

    CAS  PubMed  Google Scholar 

  101. Scheibel, T., Kowal, A.S., Bloom, J.D. & Lindquist, S.L. Bidirectional amyloid fiber growth for a yeast prion determinant. Curr. Biol. 11, 366–369 (2001).

    CAS  PubMed  Google Scholar 

  102. Chang, H.Y., Lin, J.Y., Lee, H.C., Wang, H.L. & King, C.Y. Strain-specific sequences required for yeast [PSI+] prion propagation. Proc. Natl. Acad. Sci. USA 105, 13345–13350 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Serio, T.R. et al. Nucleated conformational conversion and the replication of conformational information by a prion determinant. Science 289, 1317–1321 (2000).

    CAS  PubMed  Google Scholar 

  104. Scheibel, T. & Lindquist, S.L. The role of conformational flexibility in prion propagation and maintenance for Sup35p. Nat. Struct. Biol. 8, 958–962 (2001).

    CAS  PubMed  Google Scholar 

  105. Shorter, J. & Lindquist, S. Destruction or potentiation of different prions catalyzed by similar Hsp104 remodeling activities. Mol. Cell 23, 425–438 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Collins, S.R., Douglass, A., Vale, R.D. & Weissman, J.S. Mechanism of prion propagation: amyloid growth occurs by monomer addition. PLoS Biol. 2, e321 (2004).

    PubMed  PubMed Central  Google Scholar 

  107. Voter, W.A. & Erickson, H.P. The kinetics of microtubule assembly. Evidence for a two-stage nucleation mechanism. J. Biol. Chem. 259, 10430–10438 (1984).

    CAS  PubMed  Google Scholar 

  108. Dill, K.A. & Chan, H.S. From Levinthal to pathways to funnels. Nat. Struct. Biol. 4, 10–19 (1997).

    CAS  PubMed  Google Scholar 

  109. Catharino, S., Buchner, J. & Walter, S. Characterization of oligomeric species in the fibrillization pathway of the yeast prion Ure2p. Biol. Chem. 386, 633–641 (2005).

    CAS  PubMed  Google Scholar 

  110. Cleary, J.P. et al. Natural oligomers of the amyloid-β protein specifically disrupt cognitive function. Nat. Neurosci. 8, 79–84 (2005).

    CAS  PubMed  Google Scholar 

  111. Kayed, R. et al. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 300, 486–489 (2003).

    CAS  PubMed  Google Scholar 

  112. Krzewska, J. & Melki, R. Molecular chaperones and the assembly of the prion Sup35p, an in vitro study. EMBO J. 25, 822–833 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Shankar, G.M. et al. Amyloid-β protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat. Med. 14, 837–842 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Baskakov, I.V., Legname, G., Baldwin, M.A., Prusiner, S.B. & Cohen, F.E. Pathway complexity of prion protein assembly into amyloid. J. Biol. Chem. 277, 21140–21148 (2002).

    CAS  PubMed  Google Scholar 

  115. Walsh, D.M. & Selkoe, D.J. Aβ oligomers—a decade of discovery. J. Neurochem. 101, 1172–1184 (2007).

    CAS  PubMed  Google Scholar 

  116. Lesné, S. et al. A specific amyloid-β protein assembly in the brain impairs memory. Nature 440, 352–357 (2006).

    PubMed  Google Scholar 

  117. Shorter, J. & Lindquist, S. Hsp104 catalyzes formation and elimination of self-replicating Sup35 prion conformers. Science 304, 1793–1797 (2004).

    CAS  PubMed  Google Scholar 

  118. Mukhopadhyay, S., Krishnan, R., Lemke, E.A., Lindquist, S. & Deniz, A.A. A natively unfolded yeast prion monomer adopts an ensemble of collapsed and rapidly fluctuating structures. Proc. Natl. Acad. Sci. USA 104, 2649–2654 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Crick, S.L., Jayaraman, M., Frieden, C., Wetzel, R. & Pappu, R.V. Fluorescence correlation spectroscopy shows that monomeric polyglutamine molecules form collapsed structures in aqueous solutions. Proc. Natl. Acad. Sci. USA 103, 16764–16769 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Cohen, E., Bieschke, J., Perciavalle, R.M., Kelly, J.W. & Dillin, A. Opposing activities protect against age-onset proteotoxicity. Science 313, 1604–1610 (2006)

    CAS  PubMed  Google Scholar 

  121. Fowler, D.M. et al. Functional amyloid formation within mammalian tissue. PLoS Biol. 4, e6 (2006).

    PubMed  Google Scholar 

  122. Chapman, M.R. et al. Role of Escherichia coli curli operons in directing amyloid fiber formation. Science 295, 851–855 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Tyedmers, J., Madariaga, M.L. & Linquist, S. Prion switching in response to environmental stress. PLoS Biol. 6, e294 (2008).

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank members of the Tessier and Lindquist laboratories for critical reading of this manuscript. P.M.T. acknowledges financial support from the Alzheimer's Association (NIRG-08-90967). S.L. acknowledges funding from the US National Institutes of Health (GM25874) and the Howard Hughes Medical Institute.

Author information

Authors and Affiliations

  1. Department of Chemical & Biological Engineering, Peter M Tessier is at the Center of Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York, USA.,

    Peter M Tessier

  2. Department of Biology, Susan Lindquist is at the Howard Hughes Medical Institute, Massachusetts Institute of Technology, Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts, USA.,

    Susan Lindquist

Authors
  1. Peter M Tessier
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Susan Lindquist
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Peter M Tessier or Susan Lindquist.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tessier, P., Lindquist, S. Unraveling infectious structures, strain variants and species barriers for the yeast prion [PSI+]. Nat Struct Mol Biol 16, 598–605 (2009). https://doi.org/10.1038/nsmb.1617

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nsmb.1617

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing