Obiettivo
The question of how proteins fold to their unique, compact, and highly organized functional states is a central issue in structural and cellular biology. The folding of a protein involves the search for a unique native structure within a large ensemble of conformations that are accessible to the polypeptide chain. Simple calculations suggested that even a small protein of 100 amino acid residues would take over a billion years to find its native state if folding were occur by a random search of all possible conformations. The fact that folding occurs in a short time (typically in seconds or less), in spite of the length of time needed for a systematic search of all conformations, has become known as "Levinthal Paradox". This led to the view that there must be a specific pathway for folding, with intermediates between native and unfolded states that might represent the stepping-stones to the native state. Nowadays, on the basis of theoretical work, it is believed that a multidimensional energy landscape, or folding funnel, better describes the folding process.
The funnel shape illustrates the fact that the number of accessible conformations decreases as one get closer to the native state. In such representation an intermediate state is an ensemble of conformations that can be accumulated during the folding reaction because of an energy hump on the surface of the energy landscape. At the contrary, with the view of intermediate states as stepping-stones to the native state, the "energy landscape" view assumes that non-native structures might be present within the conformation ensemble that constitutes an intermediate. However, few examples of proteins, which form non-native structures during their folding reaction, are known. Is it because the conformations present within an intermediate state are quite close? Or, is it because the methods commonly used to study the intermediate state structure were not adapted for such observation? Moreover the view of intermediate states as an ensemble of different conformations implies that proteins in such states undergo large conformational exchange. Therefore, the internal dynamics of proteins in such intermediate states must be quite different with that of the native state.
Protein aggregation represents a critical problem in biomedicine and biotechnology. Aggregation of specific proteins results in the development of several disorders such as Alzheimer and Parkinson's diseases, or the prion diseases. The formation of inclusion bodies is a major problem in the over-expression of recombinant proteins. Two kinds of aggregate can be recognized. Amorphous aggregates are commonly found in inclusion bodies. Disorders such as Alzheimer's and prion diseases are associated with the formation of specific aggregates: the amyloid fibrils. It is generally admitted that aggregation is initiated from partially folded states of proteins. Such states can be stabilized under mild denaturant conditions or transiently accumulated during the protein folding reaction. Nowadays, there is no available systematic study that establishes relationships between partially folded state characteristics and the propensity to form aggregates. Moreover the factors that determine the kind of aggregates that is formed: amorphous or fibrils, are completely unknown.
In order to establish general rules about partially folded states structures and their relation to aggregation, it is proposed to perform a systematic studies on a set of proteins with various sizes and topology. These proteins are also able to form various kinds of aggregates. The structure and the internal dynamics of proteins in various states -either soluble or aggregated - will be characterized with a large variety of biophysical methods: fluorescence, phosphorescence, NMR, CD, FTIR and SAXS. Relationships between the internal dynamics of partially folded states and the variety of structures - native-like and non-native - that are present, will be established. Relationships between the characteristics of the partially folded states and the propensity to form aggregates will be investigated. The factors determinant of the formation of amyloid fibrils, instead of amorphous aggregates, will be searched. Beside its fundamental interest for understanding the protein folding process and the molecular mechanisms at the basis of human diseases, the results expected from this project may help for the design of proteins that can be produced by bacteria systems without accumulation within inclusion bodies.
Campo scientifico (EuroSciVoc)
CORDIS classifica i progetti con EuroSciVoc, una tassonomia multilingue dei campi scientifici, attraverso un processo semi-automatico basato su tecniche NLP. Cfr.: Il Vocabolario Scientifico Europeo.
CORDIS classifica i progetti con EuroSciVoc, una tassonomia multilingue dei campi scientifici, attraverso un processo semi-automatico basato su tecniche NLP. Cfr.: Il Vocabolario Scientifico Europeo.
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Programma(i)
Programmi di finanziamento pluriennali che definiscono le priorità dell’UE in materia di ricerca e innovazione.
Programmi di finanziamento pluriennali che definiscono le priorità dell’UE in materia di ricerca e innovazione.
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Gli inviti a presentare proposte sono suddivisi per argomenti. Un argomento definisce un’area o un tema specifico per il quale i candidati possono presentare proposte. La descrizione di un argomento comprende il suo ambito specifico e l’impatto previsto del progetto finanziato.
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Procedura per invitare i candidati a presentare proposte di progetti, con l’obiettivo di ricevere finanziamenti dall’UE.
Meccanismo di finanziamento
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Meccanismo di finanziamento (o «Tipo di azione») all’interno di un programma con caratteristiche comuni. Specifica: l’ambito di ciò che viene finanziato; il tasso di rimborso; i criteri di valutazione specifici per qualificarsi per il finanziamento; l’uso di forme semplificate di costi come gli importi forfettari.
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Coordinatore
38054 Grenoble
Francia
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