Descrizione del progetto
L’impatto delle mutazioni nell’assembaggio delle proteine
La comprensione del modo in cui le mutazioni pregiudicano la struttura e la funzione delle proteine è fondamentale per la comprensione delle malattie. Secondo l’ipotesi su cui lavora il progetto Agglomerates, finanziato dall’UE, le mutazioni potrebbero esercitare un altro impatto: sono in grado, infatti, di cambiare la chimica superficiale di una proteina e di alterarne l’autoassemblaggio supramolecolare, portando alla generazione di grandi strutture polimeriche. I ricercatori studieranno questo fenomeno, noto come agglomerazione proteica, avvalendosi del lievito come sistema modello. Inoltre, il gruppo di ricerca prevedrà i polimorfismi che innescano l’agglomerazione e approfondirà ulteriormente le potenzialità di traduzione di tale effetto nella progettazione di farmaci. I risultati del progetto forniranno importanti spunti riguardo alle ripercussioni dell’agglomerazione sulla fisiologia cellulare.
Obiettivo
Understanding how proteins respond to mutations is of paramount importance to biology and disease. While protein stability and misfolding have been instrumental in rationalizing the impact of mutations, we recently discovered that an alternative route is also frequent, where mutations at the surface of symmetric proteins trigger novel self-interactions that lead to infinite self-assembly. This mechanism can be involved in disease, as in sickle-cell anemia, but may also serve in adaptation. Importantly, it differs fundamentally from aggregation, because misfolding does not drive it. Thus, we term it “agglomeration”. The ease with which agglomeration can occur, even by single point mutations, shifts the paradigm of how quickly new protein assemblies can emerge, both in health and disease. This prompts us to determine the basic principles of protein agglomeration and explore its implications in cell physiology and human disease.
We propose an interdisciplinary research program bridging atomic and cellular scales to explore agglomeration in three aims: (i) Map the landscape of protein agglomeration in response to mutation in endogenous yeast proteins; (ii) Characterize how yeast physiology impacts agglomeration by changes in gene expression or cell state, and, conversely, how protein agglomerates impact yeast fitness. (iii) Analyze agglomeration in relation to human disease via two approaches. First, by predicting single nucleotide polymorphisms that trigger agglomeration, prioritizing them using knowledge from Aims 1 & 2, and characterizing them experimentally. Second, by providing a proof-of-concept that agglomeration can be exploited in drug design, whereby drugs induce its formation, like mutations can do.
Overall, through this research, we aim to establish agglomeration as a paradigm for protein assembly, with implications for our understanding of evolution, physiology, and disease.
Campo scientifico
Parole chiave
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-COG - Consolidator GrantIstituzione ospitante
1211 Geneve
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