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Prion protein remodelling confers an immediate phenotypic switch


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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Figure 1: Mature Sup35 can adopt the prion state.
Figure 3: Phenotypic switching occurs within a single cell cycle after [ PSI + ] transmission by mating.
Figure 2: Existing Sup35 [ psi-] is remodelled after prion transmission by mating.


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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.

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Correspondence to Tricia R. Serio.

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Supplementary information

Supplementary Video S1

Movie of Sup35-GFP in a [psi-] X [PSI+] zygote isolated in Fig. 2a. (MOV 284 kb)

Supplementary Video S2

Movie of Sup35-GFP in a [psi-] X [psi-] zygote isolated in Fig. 2b. (MOV 241 kb)

Supplementary Video S3

Movie of Sup35-GFP in a [psi-] X [PSI+] zygote isolated in Fig. 2c. (MOV 73 kb)

Supplementary Figure Legends

Legends to accompany the below Supplementary Figures. (DOC 71 kb)

Supplementary Figure S1

Unprocessed Gst-Sup35 fusions cannot propagate the prion state. (JPG 79 kb)

Supplementary Figure S2

Sup35[PSI+] and Sup35[psi-] are equally stable and long-lived. (JPG 17 kb)

Supplementary Figure S3

Protein profiles in transient tag strains. (JPG 27 kb)

Supplementary Figure S4

PMFA1 is rapidly repressed in diploids upon mating. (JPG 58 kb)

Supplementary Figure S5

Sup35-GFP functionally replaces Sup35 and acts independently as a prion. (JPG 32 kb)

Supplementary Figure S6

Confirmation of [PSI] state of zygotes. (JPG 76 kb)

Supplementary Figure S7

Sup35-GFP maturation half-time. (JPG 17 kb)

Supplementary Figure S8

Fluorescence pattern confirms mating in phenotypic switch experiments. (JPG 36 kb)

Supplementary Figure S9

Single cell reporter for stop codon read-through. (JPG 22 kb)

Supplementary Figure S10

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).

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