Yeast and Fungal Prions

Abstract

Yeast and fungal prions are infectious proteins, most being self-propagating amyloids of normally soluble proteins. Their effects range from a very mild detriment to lethal, with specific effects dependent on the prion protein and the specific prion variant ("prion strain"). The prion amyloids of Sup35p, Ure2p, and Rnq1p are in-register, parallel, folded β-sheets, an architecture that naturally suggests a mechanism by which a protein can template its conformation, just as DNA or RNA templates its sequence. Prion propagation is critically affected by an array of chaperone systems, most notably the Hsp104/Hsp70/Hsp40 combination, which is responsible for generating new prion seeds from old filaments. The Btn2/Cur1 antiprion system cures most [URE3] prions that develop, and the Ssb antiprion system blocks [PSI+] generation.

Figure 1.

The yeast and fungal prions [URE3], [PSI+], [PIN+], and [Het-s]. Formation of amyloid by Ure2p, Sup35p, Rnq1p, and HET-s results in either the loss of their normal functions (for Ure2p and Sup35p) or the appearance of novel activity (in Rnq1p and HET-s), all of which are heritable because the amyloid catalyzes the conversion of the nonamyloid to the amyloid form. Most variants of [URE3] are also toxic to the cell, and most [PSI+] prions are lethal or severely impair growth because the essential function of Sup35p is impaired or lost (McGlinchey et al. 2011). The prion domains of Ure2p and Sup35p that form the amyloid cores also have normal nonprion functions (see text).

Figure 2.

The prion cloud model. A cell with a single predominant prion variant is generally a mixture of variants as a result of occasional mistemplating, and these variants will gradually be purified from each other by random segregation during growth. This model was proven for the yeast prion [PSI+] (Bateman and Wickner 2013) but was first hypothesized to explain the properties of mammalian prions (Collinge and Clarke 2007).

Figure 3.

Protein templating mechanism of prions. Solid-state nuclear magnetic resonance (NMR) experiments show that the infectious amyloids of the prion domains of Sup35p, Ure2p, and Rnq1p have an in-register parallel β-sheet conformation with the sheets folded along the filament long axis as shown (Shewmaker et al. 2006; Baxa et al. 2007; Wickner et al. 2008; Gorkovskiy et al. 2014). The energetically favorable interactions between identical hydrophobic or hydrophilic (H-bonding) side chains keep the structure in-register. The same interactions ensure that a new monomer joining the end of the filament will assume the same conformation as molecules already in the filament. This ensures that the location of the folds/turns in the newly joining molecule will be the same as the previous molecules. We have suggested that prion variants differ in the location of the folds/turns in the β-sheet, and by this mechanism (Wickner et al. 2007, 2010, 2013), a protein can template its own conformation, just as DNA templates its own sequence.

Figure 4.

Prion-handling systems. Prion protein monomers are synthesized and are soon incorporated into amyloid fibers (see Fig. 2). These fibers grow and are split by the ability of the Hsp104–Hsp70–Hsp40 machine to remove a monomer from the middle of the fiber. This ensures sufficient prion seeds to distribute to daughter cells, allowing prion propagation. Some filaments are sequestered by the Btn2p–Hsp42 system. If the seed number is sufficiently low, this results in curing the prion from progeny cells. The Ssb1/2 Hsp70s act to inhibit conversion of the normal form (of Sup35p) to the prion form, an inhibition of prion generation not of propagation (Chernoff et al. 1999).