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.

The physical basis of how prion conformations determine strain phenotypes

Nature volume 442, pages 585–589 (2006)Cite this article

Abstract

A principle that has emerged from studies of protein aggregation is that proteins typically can misfold into a range of different aggregated forms. Moreover, the phenotypic and pathological consequences of protein aggregation depend critically on the specific misfolded form1,2. A striking example of this is the prion strain phenomenon, in which prion particles composed of the same protein cause distinct heritable states3. Accumulating evidence from yeast prions such as [PSI+] and mammalian prions argues that differences in the prion conformation underlie prion strain variants3,4,5,6,7. Nonetheless, it remains poorly understood why changes in the conformation of misfolded proteins alter their physiological effects. Here we present and experimentally validate an analytical model describing how [PSI+] strain phenotypes arise from the dynamic interaction among the effects of prion dilution, competition for a limited pool of soluble protein, and conformation-dependent differences in prion growth and division rates. Analysis of three distinct prion conformations of yeast Sup35 (the [PSI+] protein determinant) and their in vivo phenotypes reveals that the Sup35 amyloid causing the strongest phenotype surprisingly shows the slowest growth. This slow growth, however, is more than compensated for by an increased brittleness that promotes prion division. The propensity of aggregates to undergo breakage, thereby generating new seeds, probably represents a key determinant of their physiological impact for both infectious (prion) and non-infectious amyloids.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

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

Figure 1: An analytical model describing prion strains.
Figure 2: Effects of strain conformation on fibre growth rate.
Figure 3: Effects of strain conformation on fibre fragmentation.
Figure 4: Analysis of distinct [ PSI + ] strain phenotypes.

References

  1. Caughey, B. & Lansbury, P. T. Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. Annu. Rev. Neurosci. 26, 267–298 (2003)

    Article  CAS  Google Scholar 

  2. Dobson, C. M. Protein folding and misfolding. Nature 426, 884–890 (2003)

    Article  ADS  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  5. 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)

    Article  ADS  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  9. Tuite, M. F. & Koloteva-Levin, N. Propagating prions in fungi and mammals. Mol. Cell 14, 541–552 (2004)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  11. 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 

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

    Article  CAS  Google Scholar 

  13. Kushnirov, V. V. & Ter-Avanesyan, M. D. Structure and replication of yeast prions. Cell 94, 13–16 (1998)

    Article  CAS  Google Scholar 

  14. Bradley, M. E., Edskes, H. K., Hong, J. Y., Wickner, R. B. & Liebman, S. W. Interactions among prions and prion “strains” in yeast. Proc. Natl Acad. Sci. USA 99 (suppl. 4), 16392–16399 (2002)

    Article  ADS  CAS  Google Scholar 

  15. Kryndushkin, D. S., Alexandrov, I. M., Ter-Avanesyan, M. D. & Kushnirov, V. V. Yeast [PSI+] prion aggregates are formed by small Sup35 polymers fragmented by Hsp104. J. Biol. Chem. 278, 49636–49643 (2003)

    Article  CAS  Google Scholar 

  16. Castilla, J., Saa, P., Hetz, C. & Soto, C. In vitro generation of infectious scrapie prions. Cell 121, 195–206 (2005)

    Article  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  18. Cox, B., Ness, F. & Tuite, M. Analysis of the generation and segregation of propagons: entities that propagate the [PSI+] prion in yeast. Genetics 165, 23–33 (2003)

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 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)

    Article  Google Scholar 

  20. Satpute-Krishnan, P. & Serio, T. R. Prion protein remodelling confers an immediate phenotypic switch. Nature 437, 262–265 (2005)

    Article  ADS  CAS  Google Scholar 

  21. 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 

  22. Ness, F., Ferreira, P., Cox, B. S. & Tuite, M. F. Guanidine hydrochloride inhibits the generation of prion “seeds” but not prion protein aggregation in yeast. Mol. Cell. Biol. 22, 5593–5605 (2002)

    Article  CAS  Google Scholar 

  23. Masel, J., Jansen, V. A. & Nowak, M. A. Quantifying the kinetic parameters of prion replication. Biophys. Chem. 77, 139–152 (1999)

    Article  CAS  Google Scholar 

  24. Weissmann, C. The state of the prion. Nature Rev. Microbiol. 2, 861–871 (2004)

    Article  CAS  Google Scholar 

  25. Hall, D. & Edskes, H. Silent prions lying in wait: a two-hit model of prion/amyloid formation and infection. J. Mol. Biol. 336, 775–786 (2004)

    Article  CAS  Google Scholar 

  26. 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)

    Article  CAS  Google Scholar 

  27. Ferreira, P. C., Ness, F., Edwards, S. R., Cox, B. S. & Tuite, M. F. The elimination of the yeast [PSI+] prion by guanidine hydrochloride is the result of Hsp104 inactivation. Mol. Microbiol. 40, 1357–1369 (2001)

    Article  CAS  Google Scholar 

  28. Jung, G. & Masison, D. C. Guanidine hydrochloride inhibits Hsp104 activity in vivo: a possible explanation for its effect in curing yeast prions. Curr. Microbiol. 43, 7–10 (2001)

    Article  CAS  Google Scholar 

  29. Silveira, J. R. et al. The most infectious prion protein particles. Nature 437, 257–261 (2005)

    Article  ADS  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank G. Legname and S. Prusiner for communicating their results before publication, B. Cox and T. Serio for personal communication, and T. C. Keller III for providing us with chicken pectoralis extracts. We also thank C. Cunningham, J. Newman, L. Osherovich, M. Schuldiner, K. Tipton and members of the Weissman laboratory for helpful discussion and critical reading of the manuscript. M.T. was partly supported by JSPS and Uehara Memorial postdoctoral fellowships for research abroad. S.R.C. was supported by predoctoral fellowships from the Burroughs Wellcome Fund. Funding was also provided by the Howard Hughes Medical Institute, The David and Lucile Packard Foundation and the National Institutes of Health (J.S.W.). Author Contributions S.R.C. led the development of the analytical model. M.T. was responsible for the execution of the experiments, with the exception of the fibre growth studies, which were conducted by B.H.T. and M.T. M.T., S.R.C. and J.S.W. were primarily responsible for the design, interpretation and written description of the results.

Author information

Authors and Affiliations

  1. Howard Hughes Medical Institute, Department of Cellular and Molecular Pharmacology, University of California–San Francisco and California Institute for Quantitative Biomedical Research, California, 94143, San Francisco, USA

    Motomasa Tanaka, Sean R. Collins, Brandon H. Toyama & Jonathan S. Weissman

  2. PRESTO, Japan Science and Technology Agency, 4-1-8 Honcho Kawaguchi, 332-0012, Saitama, Japan

    Motomasa Tanaka

Authors
  1. Motomasa Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sean R. Collins
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Brandon H. Toyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jonathan S. Weissman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jonathan S. Weissman.

Ethics declarations

Competing interests

Reprints and permission information is available at npg.nature.com/reprintsandpermisions. The authors declare no competing financial interests.

Supplementary information

Supplementary Data

This file contains additional Methods, data and references. (DOC 295 kb)

Supplementary Figure 1

Supplementary Figure 1 nature04922-s2.pdf Introduction of a single prion fibre is sufficient to allow induction of a stable [PSI+] state. (PDF 47 kb)

Supplementary Figure 2

Ade1-14 read-through phenotype of typical [PSI+] strains produced by infection of [psi−] with in vitro produced Sc4, Sc37 and SCS Sup-NM amyloid fibres as well as a [psi−] control. (PDF 430 kb)

Supplementary Figure 3

Supplementary Figure 3 nature04922-s4.pdf Frequency of Sup-NM fibre length after physical shearing of fibres for 60 minutes. (PDF 32 kb)

Supplementary Figure 4

Effects of strains conformation on prion growth and division in vivo. (PDF 76 kb)

Supplementary Figure 5

Separation of in vivo prion particles of distinct strains by sucrose gradient. (PDF 111 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Tanaka, M., Collins, S., Toyama, B. et al. The physical basis of how prion conformations determine strain phenotypes. Nature 442, 585–589 (2006). https://doi.org/10.1038/nature04922

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature04922

This article is cited by

Comments

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.

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