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Oligopeptide-repeat expansions modulate ‘protein-only’ inheritance in yeast

Abstract

The yeast [PSI +] element represents a new type of genetic inheritance, in which changes in phenotype are transmitted by a ‘protein only’ mechanism1,2,3 reminiscent of the ‘protein-only’ transmission of mammalian prion diseases1,4. The underlying molecular mechanisms for both are poorly understood and it isnot clear how similar they might be. Sup35, the [PSI +] protein determinant, and PrP, the mammalian prion determinant, have different functions, different cellular locations and no sequence similarity; however, each contains five imperfect oligopeptide repeats—PQGGYQQYN in Sup35 and PHGGGWGQ in PrP5,6. Repeat expansions in PrP produce spontaneous prion diseases7,8. Here we show that replacing the wild-type SUP35 gene with a repeat-expansion mutation induces new [PSI +] elements, the first mutation of its type among these newly described elements of inheritance. In vitro, fully denatured repeat-expansion peptides can adopt conformations rich in β-sheets and form higher-order structures much more rapidly than wild-type peptides. Our results provide insight into the nature of the conformational changes underlying protein-based mechanisms of inheritance and suggest a link between this process and those producing neurodegenerative prion diseases in mammals.

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Figure 1: Effect of the R2E2 and RΔ2–5 mutations on spontaneous conversion from [psi ] to [PSI +].
Figure 2: Visualization of [PSI +] conversions.
Figure 3: Interactions between endogenous full-length Sup35 and GFP-fusion proteins.
Figure 4: Kinetics of fibre formation of NM repeat mutants in vitro.

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References

  1. 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 

  2. 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).

    Article  ADS  CAS  Google Scholar 

  3. 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).

    Article  CAS  Google Scholar 

  4. Lindquist, S. Mad cows meet psi-chotic yeast: the expansion of the prion hypothesis. Cell 89, 495–498 (1997).

    Article  CAS  Google Scholar 

  5. Kretzschmar, H. A. et al. Molecular cloning of a human prion protein cDNA. DNA 5, 315–324 (1986).

    Article  CAS  Google Scholar 

  6. Kushnirov, V. V. et al. Nucleotide sequence of the SUP2 (SUP35) gene of Saccharomyces cerevisiae. Gene 66, 45–54 (1988).

    Article  CAS  Google Scholar 

  7. Prusiner, S. B. & Scott, M. R. Genetics of prions. Annu. Rev. Genet. 31, 139–175 (1997).

    Article  CAS  Google Scholar 

  8. Chiesa, R., Piccardo, P., Ghetti, B. & Harris, D. A. Neurological illness in transgenic mice expressing a prion protein with an insertional mutation. Neuron 21, 1339–1351 (1998).

    Article  CAS  Google Scholar 

  9. Zhouravleva, G. et al. Termination of translation in eukaryotes is governed by two interacting polypeptide chain release factors, eRF1 and eRF3. EMBO J. 14, 4065–4072 (1995).

    Article  CAS  Google Scholar 

  10. Stansfield, I. et al. The products of the SUP45 (eRF1) and SUP35 genes interact to mediate translation termination in Saccharomyces cerevisiae. EMBO J. 14, 4365–4373 (1995).

    Article  CAS  Google Scholar 

  11. Ter-Avanesyan, M. D. et al. Deletion analysis of the SUP35 gene of the yeast Saccharomyces cerevisiae reveals two non-overlapping functional regions in the encoded protein. Mol. Microbiol. 7, 683–692 (1993).

    Article  CAS  Google Scholar 

  12. 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 

  13. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  15. Chernoff, Y. O., Lindquist, S. L., Ono, B., Inge-Vechtomov, S. G. & Liebman, S. W. Role of the chaperone protein Hsp104 in propagation of the yeast prion-like factorpsi+]. Science 268, 880–884 (1995).

    Article  ADS  CAS  Google Scholar 

  16. Tuite, M. F., Mundy, C. R. & Cox, B. S. Agents that cause a high frequency of genetic change from [psi+] to [psi] in Saccharomyces cerevisiae. Genetics 98, 691–711 (1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Chernoff, Y. O., Derkach, I. L. & Inge-Vechtomov, S. G. Multicopy SUP35 gene induces de-novo appearance of psi -like factors in the yeast Saccharomyces cerevisiae. Curr. Genet. 24, 268–270 (1993).

    Article  CAS  Google Scholar 

  18. 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).

    Article  CAS  Google Scholar 

  19. Goldmann, W., Chong, A., Foster, J., Hope, J. & Hunter, N. The shortest known prion protein gene allele occurs in goats, has only three octapeptide repeats and is non-pathogenic. J. Gen. Virol. 79, 3173–3176 (1998).

    Article  CAS  Google Scholar 

  20. McCutchen, S. L., Lai, Z., Miroy, G. J., Kelly, J. W. & Colon, W. Comparison of lethal and nonlethal transthyretin variants and their relationship to amyloid disease. Biochemistry 34, 13527–13536 (1995).

    Article  CAS  Google Scholar 

  21. Booth, D. R. et al. Instability, unfolding and aggregation of human lysozyme variants underlying amyloid fibrillogenesis. Nature 385, 787–793 (1997).

    Article  ADS  CAS  Google Scholar 

  22. Swietnicki, W., Petersen, R. B., Gambetti, P. & Surewicz, W. K. Familial mutations and the thermodynamic stability of the recombinant human prion protein. J. Biol. Chem. 273, 31048–31052 (1998).

    Article  CAS  Google Scholar 

  23. Liemann, S. & Glockshuber, R. Influence of amino acid substitutions related to inherited human prion diseases of the thermodynamical stability of the cellular prion protein. Biochemistry 38, 3258–3267 (1999).

    Article  CAS  Google Scholar 

  24. Thiele, D. J. ACE1 regulates expression of the Saccharomyces cerevisiae metallothionein gene. Mol. Cell. Biol. 8, 2745–2752 (1988).

    Article  CAS  Google Scholar 

  25. Sikorski, R. S. & Hieter, P. Asystem of shuttle vectors and yeast host strains designed for efficient manipulation of DNA in Saccharomyces cerevisiae. Genetics 122, 19–27 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Serio, T. R., Cashikar, A. G., Moslehi, J. J., Kowal, A. S. & Lindquist, S. L. The yeast prion [PSI+] and its determinant, Sup35p. Methods Enzymol.(in the press).

  27. Ausubel, F. M. et al. Current Protocols in Molecular Biology (Greene Publishing Associates/Wiley Interscience, New York, (1991).

    Google Scholar 

  28. Derkatch, I. L., Bradley, M. E., Zhou, P., Chernoff, Y. O. & Liebman, S. W. Genetic and environmental factors affecting the de novo appearance of the [PSI+] prion in Saccharomyces cerevisiae. Genetics 147, 507–519 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Klunk, W. E., Pettegrew, J. W. & Abraham, D. J. Two simple methods for quantifying low-affinity dye-substrating binding. J. Histochem. Cytochem. 37, 1293–1297 (1989).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank A. Kowal for technical assistance on electron microscopy, A. Cashikar for assistance with the circular dichroism study, and H. True, T. Serio, S. Uptain, T. Scheibel, L. Li and J. Ma for comments on the manuscript. This work was supported by a grant from the National Institutes of Health and the Howard Hughes Medical Institute.

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Correspondence to Susan Lindquist.

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Liu, JJ., Lindquist, S. Oligopeptide-repeat expansions modulate ‘protein-only’ inheritance in yeast. Nature 400, 573–576 (1999). https://doi.org/10.1038/23048

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