Academic journal article Genetics

Investigating the Interactions of Yeast Prions: [SWI^sup +^], [PSI^sup +^], and [PIN^sup +^]

Academic journal article Genetics

Investigating the Interactions of Yeast Prions: [SWI^sup +^], [PSI^sup +^], and [PIN^sup +^]

Article excerpt

PRIONS are host proteins with altered and infectious con- formations. In mammals, all subtypes of prion diseases are associated with conformational changes of a single protein, prion protein (PrP) (Prusiner 1998). One unique property of PrP is its ability to exist as multiple stable conformations: a normal cellular conformation (PrPc) and abnormal patho- genic conformations (PrPSc) that manifest as a group of fatal neurodegenerative diseases known as transmissible spongi- form encephalopathies or prion diseases (Prusiner 1998; Collinge and Clarke 2007; Weissmann 2009). Interestingly, a number of prions have also been discovered in Saccharomy- ces cerevisiae,amongwhichare[PSI+] (Cox 1965), [URE3] (Lacroute 1971; Wickner 1994), [PIN+](or[RNQ+]) (Derkatch et al. 1997; Sondheimer and Lindquist 2000), [SWI+](Du et al. 2008), [OCT+](Patelet al. 2009), [MOT3](Alberti et al. 2009), [ISP+](Rogozaet al. 2010), [MOD+](Suzuki et al. 2012), and [NUP100+] (Halfmann et al. 2012), and their corresponding protein determinants are Sup35, Ure2, Rnq1, Swi1, Cyc8, Mot3, Sfp1, Mod5,andNup100, respec- tively. Similar to PrPSc, these yeast prions are transmitted as altered protein conformations. Importantly, yeast prion pro- teins have diverse cellular functions and do not share signif- icant sequence similarities with PrP (Crow and Li 2011; Li and Kowal 2012). Except for the newly identified Mod5, all of the above-mentioned yeast prion proteins contain a region that is highly rich in glutamine (Q) and/or asparagine (N) residues and is essential for prion formation and propagation (Alberti et al. 2009; Crow and Li 2011). These Q/N-rich re- gions are referred to as prion domains (PrD). Similar to PrPSc, yeast PrDs purified from an Escherichea coli recombinant source can form amyloid fibrils in vitro. Upon incubation with naïve cells, these test-tube assembled amyloid fibrils can be incorporated into yeast cells and serve as seeds for prion propagation (King and Diaz-Avalos 2004; Tanaka et al. 2004; Brachmann et al. 2005; Patel and Liebman 2007; Alberti et al. 2009; Du et al. 2010). Collectively, these data provide convincing evidence supporting the protein-only prion concept and demonstrating that amyloid architecture is the structural basis of prion-mediated infectivity.

The existence of multiple prion elements in yeast has made this unicellular organism an ideal system to study prion-prion interactions. The earliest work in this line of research is an investigation identifying the cellular factors required for [PSI+] de novo formation (Derkatch et al. 1997). The spontaneous conversion from [psi2]to[PSI+] is a rare event with an approximate frequency of ^5.8 3 1027 (Lund and Cox 1981; Chernoff et al. 1999; Allen et al. 2007; Lancaster et al. 2010). However, overproduction of Sup35 in the presence of [PIN+] dramatically increases [PSI+] de novo formation (Chernoff et al. 1993; Derkatch et al. 1996, 1997). Intriguingly, [PIN+] is required only for the de novo formation of [PSI+] but not for its propagation (Derkatch et al. 2000, 2001). Once [PSI+] is established, it can stably propagate in the absence of [PIN+]. In addition to [PIN+], presence of [URE3] or [NU+]-a prion form of the fusion protein New1PrD-Sup35MC-can also promote [PSI+] formation (Derkatch et al. 2001; Osherovich and Weissman 2001). In addition to prions, other events, for example, overproduction of one of several Q/N-rich yeast prion proteins, such as Ure2, Swi1, Cyc8,orNew1, can also enhance [PSI+] de novo when Sup35 or its PrD is co-over- produced (Derkatch et al. 2001). Intriguingly, overproduc- tion of Mod5, a non-Q/N-rich protein, can also substitute [PIN+] to facilitate [PSI+] conversion (Suzuki et al. 2012). In addition, such a [PSI+]-promoting phenotype (termed Pin+) can also be achieved by overproduction of some non-prion Q-rich proteins, such as the poly(Q)-containing domain of huntingtin (Q74 and Q103) (Derkatch et al. 2004). Although most reported prion-prion interactions are mutually promoting, antagonistic prion-prion interac- tions have also been reported. …

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