Yeast Prions: Proteins Templating Conformation and an Anti-prion System

Most yeast prions (infectious proteins) are amyloids, linear β-sheet-rich polymers of a single protein with the β-strands perpendicular to the long axis of the filament. A single prion protein can form any of many different prion variants, differing in structure and biological properties, but with the same amino acid sequence. The folded in-register parallel β-sheet architecture we have shown for several yeast prions explains how a given prion variant can be propagated stably, how a protein can template its conformation, just as DNA can template its sequence. We have found an anti-prion system that sequesters prion seeds, preventing their even distribution to daughter cells. This system involves Btn2p, Cur1p, and Hsp42, and cures most of the [URE3] variants arising. Btn2p is weakly homologous to mammalian HOOK proteins, which include the aggresome-active HOOK2. While mammalian prions (infectious proteins) are rare, many common human amyloid diseases, such as Alzheimer disease, Parkinson disease, and others, have prion aspects, including infectivity in some cases. Most yeast prions are infectious amyloids, filamentous polymers of a single protein. Work on yeast prions was the first to establish the protein-only (prion) hypothesis, and, now, work on the structure of yeast prion infectious amyloid explains how a prion protein can template its conformation, just as DNA can template its sequence. The recent discovery of a cellular anti-prion system that cures most arising prions of the yeast Ure2 protein offers a possible direction to look for treatments of amyloidoses. The yeast non-chromosomal genetic elements [URE3] and [PSI+] were discovered to be prions of Ure2p and Sup35p, respectively, based on their unusual genetic properties [1], and were demonstrated to be based on amyloids of these proteins [2–4]. There are now at least eight amyloid-based prions of Saccharomyces cerevisiae (reviewed in [5,6]) and one of Podospora anserina [7]. In addition to the PrP-related mammalian prion diseases, recent work indicates that Alzheimer disease and other common human amyloidoses have prion-like aspects, including infectivity (reviewed by [8]). This broadens the importance of detailed studies of yeast prions.