Project description
Investigating receptors in their cellular environment at atomic-level resolution
Members of the epidermal growth factor receptor family (EGFRs) regulate cell growth and proliferation and are implicated in all phases of tumour progression. The EU-funded HighResCells project is taking an interdisciplinary approach and using EGFRs as a model system to study their conformational and oligomeric states, bound ligands and signal transduction molecules in different activation states at atomic resolution in situ. The research will elucidate the properties of the EGFRs across a wide range of complexity in the cellular environment through their high-resolution structures and changes during receptor recycling. The developed technology will help take structural biology research to the next level, enabling atomic-resolution description of receptors in their cellular environment.
Objective
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.
Fields of science
- engineering and technologyenvironmental engineeringwaste managementwaste treatment processesrecycling
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- natural sciencesphysical sciencesopticsmicroscopyelectron microscopy
- natural sciencesbiological sciencesmolecular biologystructural biology
- natural sciencesphysical sciencesopticsspectroscopy
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Funding Scheme
ERC-SyG - Synergy grantHost institution
8006 Zurich
Switzerland