Description du projet
Étude des récepteurs dans leur environnement cellulaire à une résolution au niveau atomique
Les membres de la famille des récepteurs du facteur de croissance endothélial («epidermal growth factor receptor» ou EGFR) régulent la croissance et la prolifération des cellules et sont impliqués dans toutes les phases de la progression tumorale. Le projet HighResCells, financé par l’UE, adopte une approche interdisciplinaire et utilise les EGFR comme système modèle pour étudier leurs états conformationnels et oligomériques, les ligands liés et les molécules de transmission des signaux cellulaires dans différents états d’activation à une résolution atomique in situ. La recherche permettra d’éclaircir les propriétés des EGFR à travers un large éventail de complexité dans l’environnement cellulaire, grâce à leurs structures à haute résolution et aux changements survenant pendant le recyclage des récepteurs. La technologie développée contribuera à faire passer la recherche en biologie structurelle au niveau supérieur, en permettant une description à résolution atomique des récepteurs dans leur environnement cellulaire.
Objectif
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.
Champ scientifique
- engineering and technologyenvironmental engineeringwaste managementwaste treatment processesrecycling
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- natural sciencesphysical sciencesopticsmicroscopyelectron microscopy
- natural sciencesbiological sciencesmolecular biologystructural biology
- natural sciencesphysical sciencesopticsspectroscopy
Mots‑clés
Programme(s)
Thème(s)
Régime de financement
ERC-SyG - Synergy grantInstitution d’accueil
8006 Zurich
Suisse