Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2018 May 1;18(3):foy026.
doi: 10.1093/femsyr/foy026.

[PIN+]ing down the mechanism of prion appearance

Tricia R Serio  1
Affiliations
Review

[PIN+]ing down the mechanism of prion appearance

Tricia R Serio. FEMS Yeast Res. .

Abstract

Prions are conformationally flexible proteins capable of adopting a native state and a spectrum of alternative states associated with a change in the function of the protein. These alternative states are prone to assemble into amyloid aggregates, which provide a structure for self-replication and transmission of the underlying conformer and thereby the emergence of a new phenotype. Amyloid appearance is a rare event in vivo, regulated by both the aggregation propensity of prion proteins and their cellular environment. How these forces normally intersect to suppress amyloid appearance and the ways in which these restrictions can be bypassed to create protein-only phenotypes remain poorly understood. The most widely studied and perhaps most experimentally tractable system to explore the mechanisms regulating amyloid appearance is the [PIN+] prion of Saccharomyces cerevisiae. [PIN+] is required for the appearance of the amyloid state for both native yeast proteins and for human proteins expressed in yeast. These observations suggest that [PIN+] facilitates the bypass of amyloid regulatory mechanisms by other proteins in vivo. Several models of prion appearance are compatible with current observations, highlighting the complexity of the process and the questions that must be resolved to gain greater insight into the mechanisms regulating these events.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Models for the role of [PIN+] in [PSI+] appearance. Two models have been proposed to explain the requirement for [PIN+] in the appearance of [PSI+] in vivo. (A) The most widely accepted model for [PIN+] is that of heterologous nucleus (unfilled pinwheel), stimulating the nucleation of Sup35 (green and blue) by direct interaction. Once nucleated, Sup35 and Rnq1 (the determinant of [PIN+] in laboratory yeast strains) amyloids propagate as separate aggregates. (B) [PIN+] may also promote [PSI+] formation by titrating an inhibitor (green oval) that binds to non-prion state Sup35 and blocks its self-association (step 1). As a variation on the inhibitor model, [PIN+] may titrate the fragmentation machinery (blue hexamer) away from spontaneously forming nascent Sup35 aggregates, allowing them to persist and amplify (step 2). See the text for details on each of the models.
Figure 2.
Figure 2.
Genetic regulation of early steps of [PSI+] appearance (adapted from Sharma et al. 2017). Overexpression of the prion-determining domain of Sup35 fused to GFP in [PIN+] yeast cells leads to the appearance and evolution of microscopically visible protein aggregates of distinct types: rings (pathway 1), single dots (pathway 2), lines (pathway 3) and multiple dots (pathway 4), which all lead to [PSI+] appearance (Sharma et al. 2017). Deletion mutants (red), which reduce [PSI+] appearance, differentially impact the appearance and/or accumulation of these visible aggregates (e.g. Δlas17, Δvps5 or Δsac6) or appear to act downstream of these events (e.g. Δbug1, Δbem1, Δarf1 or Δhog1) (Manogaran et al. ; Sharma et al. ; Wisniewski et al. 2018).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Aguzzi A. Beyond the prion principle. Nature 2009;459:924–5. - PubMed
    1. Alexandrov IM, Vishnevskaya AB, Ter-Avanesyan MD et al. . Appearance and propagation of Polyglutamine-based amyloids in yeast. J Biol Chem 2008;283:15185–92. - PMC - PubMed
    1. Allen KD, Wegrzyn RD, Chernova TA et al. . Hsp70 chaperones as modulators of prion life cycle. Genetics 2005;169:1227–42. - PMC - PubMed
    1. Arslan F, Hong JY, Kanneganti V et al. . Heterologous aggregates promote de novo prion appearance via more than one mechanism. PLoS Genet 2015;11:e1004814. - PMC - PubMed
    1. Bagriantsev S, Liebman SW. Specificity of prion assembly in vivo. [PSI+] and [PIN+] form separate structures in yeast. J Biol Chem 2004;279:51042–8. - PubMed

Publication types

LinkOut - more resources