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Determination of the structure of the disease-associated, srapie form of the prion protein

Ziel

The proposed work seeks to determine the tertiary structure of the scrappy form of the prion protein. Prion diseases are marked by the conformational transition of the prion protein (PrP) from its cellular, dominantly alfa-helical form (PrPC) to a beta-she et-containing, protease-resistant form (PrPSc). Since PrPSc is insoluble and forms aggregates, most structure-determination methods are unfeasible. A new approach is proposed here for mapping the secondary structure of PrPSc, using mutant analogues of PrP, in which amino acids are systematically replaced by alfa-aminoisobutyric acid (Aib), an unnatural amino acid that cannot adopt backbone dihedral angles in the beta-sheet region of the Ramachandran map.

These analogues can only be converted to the protease-resistant scrapie conformation when the residue replaced by Aib is in an alfa-helix (and not in a beta-strand) in the scrappy form. The tertiary structure of PrPSc than will be determined by computer modelling based on the experimentally determined secondary structure. This model will be validated experimentally by covalent cross-linking the appropriate segments of PrPSc. This structural information will facilitate the development of sensitive diagnostic procedure for early detection and effective treatment of the prion disease.

I have conducted research for 6 years at Cornell University (US) and obtained expertise in protein folding and semi-synthesis as well as on the prion field. I would like now to return to Europe and capitalize my expertise in pursuing a carrier on conformational diseases as a principal investigator in a world-class European research institute.

Aufforderung zur Vorschlagseinreichung

FP6-2002-MOBILITY-5
Andere Projekte für diesen Aufruf anzeigen

Koordinator

BIOLOGICAL RESEARCH CENTER, HUNGARIAN ACADEMY OF SCIENCES
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