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Strain conformation, primary structure and the propagation of the yeast prion [PSI+]

Nature Structural & Molecular Biology volume 18, pages 493–499 (2011)Cite this article

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Abstract

Prion proteins can adopt multiple infectious strain conformations. Here we investigate how the sequence of a prion protein affects its capacity to propagate specific conformations by exploiting our ability to create two distinct infectious conformations of the yeast [PSI+] prion protein Sup35, termed Sc4 and Sc37. PNM2, a G58D point mutant of Sup35 that was originally identified for its dominant interference with prion propagation, leads to rapid, recessive loss of Sc4 but does not interfere with propagation of Sc37. PNM2 destabilizes the amyloid core of Sc37 and causes compensatory effects that slow prion growth but aid prion division and result in robust propagation of Sc37. By contrast, PNM2 does not affect the structure or chaperone-mediated division of Sc4 but interferes with its delivery to daughter cells. Thus, effective delivery of infectious particles during cell division is a crucial and conformation-dependent step in prion inheritance.

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Figure 1: Characterization of in vivo prion phenotypes.
Figure 2: Schematic of the prion propagation cycle.
Figure 3: Characterization of the physical properties of fibers formed in vitro.
Figure 4: H/D exchange of wild-type (WT) and PNM2 SupNM fibers.
Figure 5: PNM2 fibers in the Sc4 conformation interact with the in vivo chaperone machinery.
Figure 6: PNM2 in the Sc4 conformation shows a defect in partitioning.

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Acknowledgements

We thank B. Bukau, A. Mogk and P. Tessarz for reagents; M. Kelly for NMR assistance; D. Cameron, S. Collins, C. Gross, D. Mullins, G. Narlikar, M. Tanaka and K. Tipton for discussions; and O. Brandman, C. Foo, A. Frost, N. Ingolia, E. Oh, E. Quan and E. Rodriguez for critical reading of the manuscript. This work was funded by the Howard Hughes Medical Institute (J.S.W.), the National Science Foundation Graduate Research Fellowship program (K.J.V.), the Hertz Foundation Peter Strauss Fellowship (M.H.S.) and the US National Institutes of Health.

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Author notes

  1. Brandon H Toyama

    Present address: Present address: The Salk Institute for Biological Studies, La Jolla, California, USA.,

  2. Katherine J Verges and Melanie H Smith: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California, USA

    Katherine J Verges, Melanie H Smith, Brandon H Toyama & Jonathan S Weissman

  2. Howard Hughes Medical Institute, University of California, San Francisco, California, USA

    Katherine J Verges, Melanie H Smith, Brandon H Toyama & Jonathan S Weissman

  3. Graduate Group in Biophysics, University of California, San Francisco, California, USA

    Melanie H Smith

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  1. Katherine J Verges
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Contributions

K.J.V., M.H.S. and J.S.W. designed this study and wrote the manuscript. J.S.W. supervised this work. K.J.V. and M.H.S. conducted the majority of the experiments. B.H.T. designed the H/X NMR experiments and acquired and analyzed the NMR data.

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Correspondence to Jonathan S Weissman.

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Verges, K., Smith, M., Toyama, B. et al. Strain conformation, primary structure and the propagation of the yeast prion [PSI+]. Nat Struct Mol Biol 18, 493–499 (2011). https://doi.org/10.1038/nsmb.2030

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