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Prion recognition elements govern nucleation, strain specificity and species barriers

Nature volume 447, pages 556–561 (2007)Cite this article

Abstract

Prions are proteins that can switch to self-perpetuating, infectious conformations. The abilities of prions to replicate, form structurally distinct strains, and establish and overcome transmission barriers between species are poorly understood. We exploit surface-bound peptides to overcome complexities of investigating such problems in solution. For the yeast prion Sup35, we find that the switch to the prion state is controlled with exquisite specificity by small elements of primary sequence. Strikingly, these same sequence elements govern the formation of distinct self-perpetuating conformations (prion strains) and determine species-specific seeding activities. A Sup35 chimaera that traverses the transmission barrier between two yeast species possesses the critical sequence elements from both. Using this chimaera, we show that the influence of environment and mutations on the formation of species-specific strains is driven by selective recognition of either sequence element. Thus, critical aspects of prion conversion are enciphered by subtle differences between small, highly specific recognition elements.

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Figure 1: Identification of recognition sequences within ScNM using peptide arrays.
Figure 2: Analysis of CaNM recognition sequences and the species barrier between S. cerevisiae/C. albicans NM.
Figure 3: Analysis of the conformational preference of the S. cerevisiae/C. albicans NM chimaera.
Figure 4: Analysis of the mutational disruption of the ScNM and CaNM recognition elements.

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Acknowledgements

We thank J. Weissman for providing the CaNM and Sc/Ca NM chimaera plasmids, M. Schutkowski for assistance in designing and preparing the peptide arrays, N. Watson for performing the transmission electron microscope imaging and members of the Lindquist laboratory for helpful discussions. This research was supported by an American Cancer Society Postdoctoral Fellowship (P.M.T.), and grants from the DuPont-MIT Alliance and the NIH. S.L. is an Investigator of the Howard Hughes Medical Institute.

Author Contributions Experimental work was performed by P. Tessier, and the data analysis and writing were conducted by P. Tessier and S. Lindquist.

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  1. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA,

    Peter M. Tessier

  2. Howard Hughes Medical Institute, Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA,

    Susan Lindquist

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Correspondence to Susan Lindquist.

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Tessier, P., Lindquist, S. Prion recognition elements govern nucleation, strain specificity and species barriers. Nature 447, 556–561 (2007). https://doi.org/10.1038/nature05848

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