Descrizione del progetto
Studiare i recettori nel loro ambiente cellulare mediante risoluzione a livello atomico
I membri della famiglia di ricettori del fattore di crescita dell’epidermide (EGFR, Epidermal Growth Factor Receptor) regolano la crescita e la proliferazione delle cellule, e sono implicati in tutte le fasi di progressione del tumore. Il progetto HighResCells, finanziato dall’UE, ha optato per un approccio interdisciplinare, utilizzando gli EGFR come sistema modello per studiare i loro stati conformazionali e oligomerici, i ligandi ad essi legati e le molecole di trasduzione del segnale in diversi stati di attivazione mediante risoluzione atomica in situ. La ricerca chiarirà le proprietà degli EGFR in una vasta gamma di complessità nell’ambiente cellulare mediante le loro strutture e modifiche ad alta risoluzione durante il riciclaggio del recettore. La tecnologia sviluppata contribuirà a portare la ricerca in ambito di biologia strutturale al livello successivo, rendendo possibile la descrizione a risoluzione atomica dei recettori nel loro ambiente cellulare.
Obiettivo
Members of the Epidermal Growth Factors Receptor family (EGFRs) influence cell growth and proliferation, and are pivotal in all phases of tumor progression. We will use this receptor family as an example with which to develop a ground-breaking new technology to study cellular signaling towards atomic resolution, in situ. Therefore, we propose to employ an interdisciplinary approach for studying EGFR family of receptors, where we follow their conformational and oligomeric states as well as bound ligands and signal transduction molecules during different activation states at atomic resolution in situ. We will progress from engineered to native receptor forms, and from defined membrane vesicles to whole cells, and employ 3D structure analysis by cryo-electron tomography, greatly enhanced by novel image processing approaches, mass spectroscopy definitions of receptor modifications and interaction partners, as well as advanced protein engineering to identify, orient and freeze receptors for this method development. This collaborative project addresses the properties of the EGFR family across a wide range of complexity and dimensions, in the cellular environment, through their high-resolution structures and changes during receptor recycling. This collaborative network, addressing EGFR from complementary angles, is most likely to generate substantial new information on these assemblies and to yield a deep understanding of the mechanisms underlying their structure and function. The EGFR family has been the focus of many tumor therapies, with the aim of intercepting their signaling, and this project will contribute to a more detailed understanding of their mode of action and thus the more rational development of such therapies in the future. However, the technology that will be developed will be generally applicable and may thus help to contribute to a paradigm change for structural biology, enabling atomic resolution description of receptors in their cellular environment.
Campo scientifico
- engineering and technologyenvironmental engineeringwaste managementwaste treatment processesrecycling
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- natural sciencesphysical sciencesopticsmicroscopyelectron microscopy
- natural sciencesbiological sciencesmolecular biologystructural biology
- natural sciencesphysical sciencesopticsspectroscopy
Parole chiave
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-SyG - Synergy grantIstituzione ospitante
8006 Zurich
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