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

Projektbeschreibung

Untersuchung von Rezeptoren in deren zellulärer Umgebung mit Auflösung auf atomarer Ebene

Mitglieder der Familie der epidermalen Wachstumsfaktor-Rezeptoren (Epidermal Growth Factor Receptor, EGF-Rezeptor) regulieren das Zellwachstum und die Zellproliferation und sind an allen Phasen der Tumorprogression beteiligt. Das EU-finanzierte Projekt HighResCells verfolgt einen interdisziplinären Ansatz und nutzt EGF-Rezeptoren als Modellsystem, um ihre Konformations- und Oligomerzustände, gebundene Liganden und Signaltransduktionsmoleküle in verschiedenen Aktivierungszuständen mit atomarer Auflösung in situ zu untersuchen. Die Studie wird die Eigenschaften der EGF-Rezeptoren über einen breiten Bereich an Komplexität in der zellulären Umgebung durch ihre hochauflösenden Strukturen und Veränderungen während des Rezeptor-Recyclings beleuchten. Die entwickelte Technologie wird dazu beitragen, die strukturbiologische Forschung auf die nächsthöhere Ebene zu bringen und die Beschreibung der Rezeptoren in ihrer zellulären Umgebung in atomarer Auflösung ermöglichen.

Ziel

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.

Finanzierungsplan

ERC-SyG - Synergy grant

Gastgebende Einrichtung

UNIVERSITAT ZURICH
Netto-EU-Beitrag
€ 4 774 500,00
Adresse
RAMISTRASSE 71
8006 Zurich
Schweiz

Auf der Karte ansehen

Region
Schweiz/Suisse/Svizzera Zürich Zürich
Aktivitätstyp
Higher or Secondary Education Establishments
Links
Gesamtkosten
€ 4 774 500,00

Begünstigte (3)