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Microbiology and Molecular Biology Reviews, December 1999, p. 844-861, Vol. 63, No. 4
Laboratory of Biochemistry and Genetics,
National Institute of Diabetes, Digestive and Kidney Diseases,
National Institutes of Health, Bethesda, Maryland 20892-0830
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
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Copyright © 1999, American Society for Microbiology. All rights reserved.
Prions in Saccharomyces and Podospora
spp.: Protein-Based Inheritance
-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.
*
Corresponding author. Mailing address: Bldg. 8, Rm.
225, N.I.H., 8 Center Dr. MSC 0830, Bethesda, MD 20892-0830. Phone:
(301) 496-3452. Fax: (301) 402-0240. E-mail:
wickner{at}helix.nih.gov.
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