Impact of Amyloid Polymorphism on Prion-Chaperone Interactions in Yeast

Abstract

Yeast prions are protein-based genetic elements found in the baker’s yeast Saccharomyces cerevisiae, most of which are amyloid aggregates that propagate by fragmentation and spreading of small, self-templating pieces called propagons. Fragmentation is carried out by molecular chaperones, specifically Hsp104, Hsp70, and Hsp40. Like other amyloid-forming proteins, amyloid-based yeast prions exhibit structural polymorphisms, termed “strains” in mammalian systems and “variants” in yeast, which demonstrate diverse phenotypes and chaperone requirements for propagation. Here, the known differential interactions between chaperone proteins and yeast prion variants are reviewed, specifically those of the yeast prions [PSI+], [RNQ+]/[PIN+], and [URE3]. For these prions, differences in variant-chaperone interactions (where known) with Hsp104, Hsp70s, Hsp40s, Sse1, and Hsp90 are summarized, as well as some interactions with chaperones of other species expressed in yeast. As amyloid structural differences greatly impact chaperone interactions, understanding and accounting for these variations may be crucial to the study of chaperones and both prion and non-prion amyloids.

Three J-proteins impact Hsp104-mediated variant-specific prion elimination: a new critical role for a low-complexity domain

“…One of these J-proteins, Sis1, is essential for both cell survival and propagation of the four best-studied yeast prions: [PSI + ], [RNQ + ], [URE3], and [SWI + ] (Luke et al 1991;Sondheimer et al 2001;Aron et al 2007;Higurashi et al 2008;Hines et al 2011b). Specific chaperone requirements for propagation are largely differentiable among different prions and prion variants, particularly with respect to domain requirements of J-proteins (Derkatch et al 1996;Hines et al 2011a;Prusiner 2013;Stein and True 2014;Sporn and Hines 2015;Schilke et al 2017;Killian and Hines 2018;Killian et al 2019). In addition to Sis1, three other J-proteins-Ydj1, Swa2, and Apj1-have been previously implicated in prion biology.…”

Client processing is altered by novel myopathy-causing mutations in the HSP40 J domain

“…Defects in chaperone function disrupt this process and, therefore, prion propagation (27, 33-36, 47, 48). In order to ask whether these disease variants disrupt client processing, we studied two known Sis1 substrates: the translation termination factor Sup35, which forms the [PSI + ] prion, and Rnq1, which forms the [RNQ + ] prion (14,29).…”

“…Somewhat counterintuitively, chaperones not only promote prion propagation in yeast, but are essential for it (14,(23)(24)(25)(26). At the heart of this chaperone-mediated process is the Hsp40 Sis1, with the interaction between Hsp40 and Hsp70 chaperones being crucial for prion propagation in yeast (24,(27)(28)(29)(30)(31)(32). When chaperone function is defective, prion propagation is impaired (17,(33)(34)(35)(36).…”

Molecular Chaperones: A Double-Edged Sword in Neurodegenerative Diseases

“…These observations raise the question of whether differences in the proteostasis capacity of these cells could be the reason for this selective susceptibility (Jackson, 2014 ; Labbadia and Morimoto, 2015 ). In yeast, chaperone activity helps to maintain the conformational diversity of prion strains (Stein and True, 2014 ; Killian et al, 2019 ). Thus, it is tempting to speculate that mammalian chaperones could as well promote the structural identity of amyloid conformers and contribute to the amplification of disease-specific strains by generating distinct seeding-competent propagons.…”