title: Prions in Saccharomyces and Podospora spp.: protein-based inheritance.
abstract: Genetic evidence showed two non-Mendelian genetic elements of Saccharomyces cerevisiae, called [URE3] and [PSI], to be prions of Ure2p and Sup35p, respectively. [URE3] makes cells derepressed for nitrogen catabolism, while [PSI] elevates the efficiency of weak suppressor tRNAs. The same approach led to identification of the non-Mendelian element [Het-s] of the filamentous fungus Podospora anserina, as a prion of the het-s protein. The prion form of the het-s protein is required for heterokaryon incompatibility, a normal fungal function, suggesting that other normal cellular functions may be controlled by prions. [URE3] and [PSI] involve a self-propagating aggregation of Ure2p and Sup35p, respectively. In vitro, Ure2p and Sup35p form amyloid, a filamentous protein structure, high in beta-sheet with a characteristic green birefringent staining by the dye Congo Red. Amyloid deposits are a cardinal feature of Alzheimer's disease, non-insulin-dependent diabetes mellitus, the transmissible spongiform encephalopathies, and many other diseases. The prion domain of Ure2p consists of Asn-rich residues 1 to 80, but two nonoverlapping fragments of the molecule can, when overproduced, induce the de nova appearance of [URE3]. The prion domain of Sup35 consists of residues 1 to 114, also rich in Asn and Gln residues. While runs of Asn and Gln are important for [URE3] and [PSI], no such structures are found in PrP or the Het-s protein. Either elevated or depressed levels of the chaperone Hsp104 interfere with propagation of [PSI]. Both [URE3] and [PSI] are cured by growth of cells in millimolar guanidine HCl. [URE3] is also cured by overexpression of fragments of Ure2p or fusion proteins including parts of Ure2p.
authors.affiliation: Laboratory of Biochemistry and Genetics, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0830, USA. wickner@helix.nih.gov
authors.forename: R B
authors.initials: RB
authors.lastname: Wickner
authors.forename: K L
authors.initials: KL
authors.lastname: Taylor
authors.forename: H K
authors.initials: HK
authors.lastname: Edskes
authors.forename: M L
authors.initials: ML
authors.lastname: Maddelein
authors.forename: H
authors.initials: H
authors.lastname: Moriyama
authors.forename: B T
authors.initials: BT
authors.lastname: Roberts
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000378:metabolism / Q000648:ultrastructure; D000818:Animals; D016798:Ciliophora / Q000235:genetics; D005656:Fungal Proteins; D005979:Glutathione Peroxidase; D008957:Models, Genetic; D008969:Molecular Sequence Data; D010454:Peptide Termination Factors; D011328:Prions / Q000235:genetics*; D012098:Reproduction; D012440:Saccharomyces / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins; D020037:Sordariales / Q000235:genetics*
chemical_list: D000682:Amyloid; D005656:Fungal Proteins; D010454:Peptide Termination Factors; D011328:Prions; C068068:SUP35 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D005979:Glutathione Peroxidase; C067020:URE2 protein, S cerevisiae