In a variety of systems, proteins have been linked to processes historically limited to nucleic acids, such as infectivity and inheritance1,2. These atypical proteins, termed prions3, lack sequence homology but are collectively defined by their capacity to adopt multiple physical and therefore functional states in vivo. Newly synthesized prion protein generally adopts the form already present in the cell, and this in vivo folding bias directs the near faithful transmission of the corresponding phenotypic state1,2. Switches between the prion and non-prion phenotypes can occur in vivo2; however, the fate of existing protein during these transitions and its effects on the emergence of new traits remain major unanswered questions. Here, we determine the changes in protein-state that induce phenotypic switching for the yeast prion Sup35/[PSI+]. We show that the prion form does not need to be specified by an alternate misfolding pathway initiated during Sup35 synthesis but instead can be accessed by mature protein. This remodelling of protein from one stable form to another is accompanied by the loss of Sup35 activity, evoking a rapid change in cellular phenotype within a single cell cycle.
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This work is dedicated to the memory of A. Serio, Jr. We thank S. Lindquist, M. Hochstrasser, J. Laney, B. Glick and S. Hanes for reagents and discussions, J. Laney, K. Mowry, A. Jacobson, J. Sedivy, A. Landy, M. McKeown, A. DeLong, M. Strbuncelj, S. Langseth and Z. Zinn for comments on the manuscript, and R. Lesiak and J. Nathanson for graphics assistance. This research was supported by the National Cancer Institute and the Pew Scholars Program in the Biomedical Sciences.
Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.
Movie of Sup35-GFP in a [psi-] X [PSI+] zygote isolated in Fig. 2a. (MOV 284 kb)
Movie of Sup35-GFP in a [psi-] X [psi-] zygote isolated in Fig. 2b. (MOV 241 kb)
Movie of Sup35-GFP in a [psi-] X [PSI+] zygote isolated in Fig. 2c. (MOV 73 kb)
Legends to accompany the below Supplementary Figures. (DOC 71 kb)
Unprocessed Gst-Sup35 fusions cannot propagate the prion state. (JPG 79 kb)
Sup35[PSI+] and Sup35[psi-] are equally stable and long-lived. (JPG 17 kb)
Protein profiles in transient tag strains. (JPG 27 kb)
PMFA1 is rapidly repressed in diploids upon mating. (JPG 58 kb)
Sup35-GFP functionally replaces Sup35 and acts independently as a prion. (JPG 32 kb)
Confirmation of [PSI] state of zygotes. (JPG 76 kb)
Sup35-GFP maturation half-time. (JPG 17 kb)
Fluorescence pattern confirms mating in phenotypic switch experiments. (JPG 36 kb)
Single cell reporter for stop codon read-through. (JPG 22 kb)
Confirmation of [PSI] state of zygotes. (JPG 71 kb)
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Satpute-Krishnan, P., Serio, T. Prion protein remodelling confers an immediate phenotypic switch. Nature 437, 262–265 (2005). https://doi.org/10.1038/nature03981
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