The protein product of the
            <i>het-s</i>
            heterokaryon incompatibility gene of the fungus
            <i>Podospora anserina</i>
            behaves as a prion analog

Coustou, Virginie; Deleu, Carole; Saupe, Sven J.; Bégueret, Joël

doi:10.1073/pnas.94.18.9773

Cited by 442 publications

(356 citation statements)

References 19 publications

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“…To date, there are at least two other proteins in S. cerevisiae that also satisfy the biochemical and genetic criteria to be classed as prions [8,9], namely Sup35/[PSI + ] [10][11][12] and Rnq1/[RNQ/PIN + ] [13,14], and a number of other candidate prions have been identified by searching for prion domain-like sequence regions [15]. In addition, [Het-s] has been identified as a prion of the filamentous fungus Podospora anserina [16,17]. The relative simplicity and tractability of yeast and other fungal systems has allowed convincing proof of the protein-only hypothesis for Het-s [18], Sup35 [19,20] and Ure2 [21].…”

Section: Overviewmentioning

confidence: 99%

The yeast prion protein Ure2: Structure, function and folding

Lian

Jiang

Zhang

et al. 2006

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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The Saccharomyces cerevisiae protein Ure2 functions as a regulator of nitrogen metabolism and as a glutathione-dependent peroxidase. Ure2 also has the characteristics of a prion, in that it can undergo a heritable conformational change to an aggregated state; the prion form of Ure2 loses the regulatory function, but the enzymatic function appears to be maintained. A number of factors are found to affect the prion properties of Ure2, including mutation and expression levels of molecular chaperones, and the effect of these factors on structure and stability are being investigated. The relationship between structure, function and folding for the yeast prion Ure2 are discussed.

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Section: Overviewmentioning

confidence: 99%

The yeast prion protein Ure2: Structure, function and folding

Lian

Jiang

Zhang

et al. 2006

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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“…The molecular events at the origin of propagation are not yet elucidated. In the lower eukaryotes Saccharomyces cerevisiae and Podospora anserina prion proteins have been identified taking advantage of traits they confer (3)(4)(5)(6)(7). These proteins are harmless for humans and constitute valuable model systems to characterize prion propagation.…”

mentioning

confidence: 99%

Assembly of the Yeast Prion Ure2p into Protein Fibrils

Fay

Inoue

Bousset

et al. 2003

Journal of Biological Chemistry

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The [URE3] phenotype in Saccharomyces cerevisiaepropagates by a prion mechanism, involving the aggregation of the normally soluble and highly helical protein Ure2. Previous data have shown that the protein spontaneously forms in vitro long, straight, insoluble fibrils at neutral pH that are similar to amyloids in that they bind Congo red and show green-yellow birefringence and have an increased resistance to proteolysis. These fibrils are not amyloids as they are devoid of a cross-␤ core. Here we further document the mechanism of assembly of Ure2p into fibrils. The critical concentration for Ure2p assembly is measured, and the minimal size of the nuclei that are the precursors of Ure2p fibrils is determined. Our data indicate that the assembly process is irreversible. As a consequence, the critical concentration is very low. By analyzing the elongation rates of preformed fibrils and combining the results with singlefiber imaging experiments of a variant Ure2p labeled by fluorescent dyes, we reveal the polarity of the fibrils and differences in the elongation rates at their ends. These results bring novel insight in the process of Ure2p assembly into fibrils and the mechanism of propagation of yeast prions.Creutzfeldt-Jacob disease, bovine spongiform encephalopathy, and sheep scrapie are transmissible spongiform encephalopathies. They are believed to be caused by a constitutive protein called prion protein (PrP) in an altered conformation (1). This rare form of the protein is thought to convert the normal form to the infectious conformation in a catalytic manner (for review, see Ref.2). The molecular events at the origin of propagation are not yet elucidated. In the lower eukaryotes Saccharomyces cerevisiae and Podospora anserina prion proteins have been identified taking advantage of traits they confer (3-7). These proteins are harmless for humans and constitute valuable model systems to characterize prion propagation.The [URE3] phenotype in S. cerevisiae is caused by a disorder in a signal transduction cascade that regulates nitrogen catabolism (8). Yeast cells exhibiting the [URE3] phenotype have the ability to take up ureidosuccinate, the structural analogue of allantoate, a poor nitrogen source in the presence of a good nitrogen source such as ammonium ions. This is believed to be because of the loss of the function of the protein determinant of [URE3], Ure2p, whose function is unknown although reported to be involved in yeast heavy metal and strong oxidant detoxification (9). Importantly, Ure2p [URE3] promotes the conversion of the newly synthesized active Ure2p into an inactive form. Thus, the Ure2p [URE3] state is heritable, independent of any nucleic acid (10).Native soluble Ure2p assembles in vitro into fibrils that exhibit the characteristics of amyloids in that they are about 20 nm wide and more than 1 m long, bind thioflavin T and Congo Red, show yellow-green birefringence in polarized light upon Congo Red binding, and exhibit an increased resistance to proteolysis (11-13). The assembly reaction fo...

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“…Interestingly, the [Het-s] prion of Podospora may underlie an important adaptive mechanism that prevents the spread of viruses (Coustou et al 1997). It is possible, therefore, that prions provide an important and evolving mechanism for cellular control in fungi and other organisms.…”

Section: Identification Of New Prionsmentioning

confidence: 99%

Investigating protein conformation–based inheritance and disease in yeast

Lindquist

Krobitsch

et al. 2001

Phil. Trans. R. Soc. Lond. B

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Our work supports the hypothesis that a protein can serve as an element of genetic inheritance. This protein-only mechanism of inheritance is propagated in much the same way as hypothesized for the transmission of the protein-only infectious agent in the spongiform encephalopathies; hence these protein factors have been called yeast prions. Our work has focused on [PSI + ], a dominant cytoplasmically inherited factor that alters translational ¢delity.This change in translation is produced by a self-perpetuating change in the conformation of the translation-termination factor, Sup35. Most recently, we have determined that new elements of genetic inheritance can be created by deliberate genetic engineering, opening prospects for new methods of manipulating heredity. We have also uncovered evidence that other previously unknown elements of protein-based inheritance are encoded in the yeast genome. Finally, we have begun to use yeast as a model system for studying human protein folding diseases, such as Huntington's disease. Proteins responsible for some of these diseases have properties uncannily similar to those that produce protein-based mechanisms of inheritance.

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The protein product of the het-s heterokaryon incompatibility gene of the fungus Podospora anserina behaves as a prion analog

Cited by 442 publications

References 19 publications

The yeast prion protein Ure2: Structure, function and folding

The yeast prion protein Ure2: Structure, function and folding

Assembly of the Yeast Prion Ure2p into Protein Fibrils

Investigating protein conformation–based inheritance and disease in yeast

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