Skip to main content

Thank you for visiting 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.

Generation of prion transmission barriers by mutational control of amyloid conformations


Self-propagating β-sheet-rich protein aggregates are implicated in a wide range of protein-misfolding phenomena, including amyloid diseases and prion-based inheritance1. Two properties have emerged as common features of amyloids. Amyloid formation is ubiquitous: many unrelated proteins form such aggregates and even a single polypeptide can misfold into multiple forms2,3,4,5,6 — a process that is thought to underlie prion strain variation7. Despite this promiscuity, amyloid propagation can be highly sequence specific: amyloid fibres often fail to catalyse the aggregation of other amyloidogenic proteins8,9. In prions, this specificity leads to barriers that limit transmission between species7,8,10,11,12. Using the yeast prion [PSI+]13, we show in vitro that point mutations in Sup35p, the protein determinant of [PSI+], alter the range of ‘infectious’ conformations, which in turn changes amyloid seeding specificity. We generate a new transmission barrier in vivo by using these mutations to specifically disfavour subsets of prion strains. The ability of mutations to alter the conformations of amyloid states without preventing amyloid formation altogether provides a general mechanism for the generation of prion transmission barriers and may help to explain how mutations alter toxicity in conformational diseases.

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

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Conformation of chimaeric prion fibres is sensitive to polymerization conditions.
Figure 2: Mutations create a transmission barrier in vitro.
Figure 3: Mutations create a transmission barrier in vivo by shifting strain preference of chimaeric prion.
Figure 4: Effects of mutations on the natural S. cerevisiae Sup35 prion domain.


  1. Dobson, C. M. The structural basis of protein folding and its links with human disease. Phil. Trans. R. Soc. Lond. B 356, 133–145 (2001)

    CAS  Article  Google Scholar 

  2. DePace, A. H. & Weissman, J. S. Origins and kinetic consequences of diversity in Sup35 yeast prion fibers. Nature Struct. Biol. 9, 389–396 (2002)

    CAS  PubMed  Google Scholar 

  3. Baxa, U., Speransky, V., Steven, A. C. & Wickner, R. B. Mechanism of inactivation on prion conversion of the Saccharomyces cerevisiae Ure2 protein. Proc. Natl Acad. Sci. USA 99, 5253–5260 (2002)

    ADS  CAS  Article  Google Scholar 

  4. 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  Article  Google Scholar 

  5. Kad, N. M., Thomson, N. H., Smith, D. P., Smith, D. A. & Radford, S. E. β2-Microglobulin and its deamidated variant, N17D form amyloid fibrils with a range of morphologies in vitro. J. Mol. Biol. 313, 559–571 (2001)

    CAS  Article  Google Scholar 

  6. Lashuel, H. A., Hartley, D., Petre, B. M., Walz, T. & Lansbury, P. T. Jr Neurodegenerative disease: amyloid pores from pathogenic mutations. Nature 418, 291 (2002)

    ADS  CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  9. Come, J. H., Fraser, P. E. & Lansbury, P. T. Jr A kinetic model for amyloid formation in the prion diseases: importance of seeding. Proc. Natl Acad. Sci. USA 90, 5959–5963 (1993)

    ADS  CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  11. 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  Article  Google Scholar 

  12. 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  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  14. 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)

    ADS  CAS  Article  Google Scholar 

  15. 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 

  16. Kushnirov, V. V., Kryndushkin, D. S., Boguta, M., Smirnov, V. N. & Ter-Avanesyan, M. D. Chaperones that cure yeast artificial [PSI+] and their prion-specific effects. Curr. Biol. 10, 1443–1446 (2000)

    CAS  Article  Google Scholar 

  17. Zhou, P. et al. The yeast non-Mendelian factor [ETA+] is a variant of [PSI+], a prion-like form of release factor eRF3. EMBO J. 18, 1182–1191 (1999)

    CAS  Article  Google Scholar 

  18. Kochneva-Pervukhova, N. V. et al. [PSI+] prion generation in yeast: characterization of the ‘strain’ difference. Yeast 18, 489–497 (2001)

    CAS  Article  Google Scholar 

  19. Uptain, S. M., Sawicki, G. J., Caughey, B. & Lindquist, S. Strains of [PSI+] are distinguished by their efficiencies of prion-mediated conformational conversion. EMBO J. 20, 6236–6245 (2001)

    CAS  Article  Google Scholar 

  20. King, C. Y. Supporting the structural basis of prion strains: induction and identification of [PSI] variants. J. Mol. Biol. 307, 1247–1260 (2001)

    CAS  Article  Google Scholar 

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

    ADS  CAS  Article  Google Scholar 

  22. 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  Article  Google Scholar 

  23. Barron, R. M. et al. Changing a single amino acid in the N-terminus of murine PrP alters TSE incubation time across three species barriers. EMBO J. 20, 5070–5078 (2001)

    CAS  Article  Google Scholar 

  24. Mastrianni, J. A. et al. Inherited prion disease caused by the V210I mutation: transmission to transgenic mice. Neurology 57, 2198–2205 (2001)

    CAS  Article  Google Scholar 

  25. Peretz, D. et al. A change in the conformation of prions accompanies the emergence of a new prion strain. Neuron 34, 921–932 (2002)

    CAS  Article  Google Scholar 

  26. Bartz, J. C., Bessen, R. A., McKenzie, D., Marsh, R. F. & Aiken, J. M. Adaptation and selection of prion protein strain conformations following interspecies transmission of transmissible mink encephalopathy. J. Virol. 74, 5542–5547 (2000)

    CAS  Article  Google Scholar 

  27. Hill, A. F., Antoniou, M. & Collinge, J. Protease-resistant prion protein produced in vitro lacks detectable infectivity. J. Gen. Virol. 80, 11–14 (1999)

    CAS  Article  Google Scholar 

  28. 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  Article  Google Scholar 

  29. Post, K., Brown, D. R., Groschup, M., Kretzschmar, H. A. & Riesner, D. Neurotoxicity but not infectivity of prion proteins can be induced reversibly in vitro. Arch. Virol. Suppl. 16, 265–273 (2000)

    Google Scholar 

Download references


We thank H. Wille, J. Hood-DeGrenier and members of the Weissman and Lim lab for discussion and critical reading of the manuscript. P.C. and S.R.C. were supported by National Science Foundation Graduate Fellowships and the ARCS (Achievement Rewards for College Scientists) foundation (P.C.). A.H.D. was supported by a Howard Hughes Medical Institute predoctoral fellowship. Funding was also provided by Howard Hughes Medical Institute, The David and Lucile Packard Foundation and the National Institutes of Health.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Jonathan S. Weissman.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Chien, P., DePace, A., Collins, S. et al. Generation of prion transmission barriers by mutational control of amyloid conformations. Nature 424, 948–951 (2003).

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


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