PRION PROTEIN · Determination of the structure of the disease-associated, srapie form of the prion protein
6РП — Действия „Мария Кюри“
- Период
- 2004-12-01 → 2006-11-30
- Финансиране от ЕС
- 152 569 €
- Участници
- 1
- Схема
- EIF
Линиите свързват координатора с партньорите. За проекти отпреди 2014 г. CORDIS не винаги дава точни координати. Тези точки са на ниво град или държава.
Накратко на български
Структурата на патогенните приони, които се различават от нормалните протеини само по своята форма, е обект на анализ. По-доброто познаване на тези промени помага за разработването на чувствителни методи за откриване на заболяването.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Final Activity Report Summary - PRION PROTEIN (Determination of the structure of the disease-associated, srapie form of the prion protein)
Although the exact nature of the infectious agents, the prions, is not known, the presence of the abnormal form is a generally accepted indication for the on-going progression of the disease process. It constitutes the best surrogate marker so far. One of the major problems in developing a method based on the detection of the abnormal form is that very little structural information is available about the abnormal form which would facilitate the generation of monoclonal antibodies with high sensitivity. The difference between the two forms is conformational only, no alteration in the covalent structure of the forms has been revealed. The abnormal form has an elevated b-sheet content indicating a dramatic conformational change. It has a high tendency for aggregation and soluble only in detergents and denaturants. However, these treatments also destroy the structure of the abnormal form as indicated by the loss of the b-sheet content and most importantly, the loss of the infectivity in the sample. The most characteristic feature of the abnormal form is its elevated protease resistance and digestion pattern that is used most frequently for its identification. Our purpose was here to gain more structural information about the abnormal form that would facilitate the development of a sensitive detection. We found regions in the N-terminal part of the protease-resistant core of the abnormal form that are exposed for antibody detection in accord with the literature. By contrast, the C-terminal long helixes that are depicted as exposed parts in the most recent models of the abnormal form were not available for antibody detection. Using antibodies against the rather N-terminal part of the protease-resistant core of the protein, we managed to detect disease-associated forms of the protein in the blood plasma of TSE-affected hamsters.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
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.
Оригинален текст от CORDIS (на английски).
Участници
- BIOLOGICAL RESEARCH CENTER HUNGARIAN ACADEMY OF SCIENCES · SZEGEDКоординаторНиво градУнгария
Връзки
Данни: CORDIS, © Европейски съюз