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A synergistic approach toward understanding receptor signaling in the cell at very high resolution

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.

Field of science

  • /natural sciences/biological sciences/molecular biology/structural biology

Call for proposal

ERC-2018-SyG
See other projects for this call

Funding Scheme

ERC-SyG - Synergy grant

Host institution

UNIVERSITAT ZURICH
Address
Ramistrasse 71
8006 Zurich
Switzerland
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 4 774 500

Beneficiaries (3)

UNIVERSITAT ZURICH
Switzerland
EU contribution
€ 4 774 500
Address
Ramistrasse 71
8006 Zurich
Activity type
Higher or Secondary Education Establishments
KOBENHAVNS UNIVERSITET
Denmark
EU contribution
€ 1 772 500
Address
Norregade 10
1165 Kobenhavn
Activity type
Higher or Secondary Education Establishments
AGENCIA ESTATAL CONSEJO SUPERIOR DEINVESTIGACIONES CIENTIFICAS
Spain
EU contribution
€ 1 726 457
Address
Calle Serrano 117
28006 Madrid
Activity type
Research Organisations