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Study of the prion phenomenon using the Sup35p-[PSI+] system of yeast Saccharomyces cerevisiae

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The main objective of the project is to find and study novel proteins with prion properties. This task also involves the development of a universal experimental system for detection of the prion properties of proteins. Such system will be based on the Sup35 prion-like protein of Saccharomyces cerevisiae and an appropriate set of yeast genetic markers used for the detection of prion state of Sup35. This system will be used for identification of novel prion-like proteins of different organisms including man. The methods developed earlier in the course of characterization of the Sup35 prion-like protein will be used to characterize the prion state of these proteins. The research activities will include the creation and study of artificial prions, chimeric proteins combining potentially prionogenic amino acid sequences of different origin with the C-terminal domain of Sup35p.

This approach is based
(a) on the principal possibility to transfer the prion-forming domains from one protein to another;
(b) on the possibility to monitor the prion conversion of hybrid proteins by the nonsense suppressor phenotype resulting from the prion inactivation of the Sup35p C domain.

The N-terminal regions of Sup35p homologues from some fungi species, frog Xenopus laevis and man will be tested in these experiments. The demonstration of prion potential of these proteins would indicate that prion properties are conserved in the Sup35p protein family and may have adaptive functions. Another group of potentially prionogenic proteins, which will be studied in the project, are glutamine/asparagine rich polypeptides of different origin: human protein huntingtin related to Huntington disease, artificial polyGln sequences, Gln/Asn rich regions of some yeast proteins. The Huntington disease was shown to result from amyloid-forming properties of the polyglutamine fragment of huntingtin. The demonstration of the prion properties of polyglutamine sequences would strongly support the close relation between the two fundamentally important phenomena, the prions and amyloids.

Identification of new prion-like determinants in yeast and filamentous fungi is the second main goal of the project. This goal is based on the preliminary data indicating the prion-like nature of some recently described or known for a long time cytoplasmically inherited determinants in Saccharomyces cerevisiae, Podospora anserina and Nectria haematococca. The general strategy used in this part of the project will be the identification of prion proteins defining these determinants by gene cloning or by protein microsequencing. Then genes corresponding to these proteins will be used for construction and subsequent study of hybrid proteins with the Sup35p C domain.
The study proposed could substantially extend the knowledge of the occurrence of the prion phenomenon in nature and of the structural variability of the prionogenic proteins.

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UNIVERSITY OF KENT
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CANTERBURY
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Letzte Aktualisierung: 30 Oktober 2002

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Permalink: https://cordis.europa.eu/project/id/INTAS-1999-00491/de

European Union, 2024