Descripción del proyecto
Investigación de los receptores en su entorno celular con resolución atómica
Los miembros de la familia de receptores de los factores de crecimiento epidérmico (RFCE) regulan el crecimiento y la proliferación celular, e intervienen en todas las fases de la progresión tumoral. El proyecto financiado con fondos europeos HighResCells adopta un método interdisciplinario y emplea los RFCE como sistema modelo para estudiar sus estados conformacionales y oligoméricos, los ligandos unidos y las moléculas de transducción de señales en distintos estados de activación con resolución atómica «in situ». La investigación dilucidará las propiedades de los RFCE en un amplio rango de complejidad en el entorno celular a través de sus estructuras de alta resolución y los cambios durante el reciclaje de receptores. La tecnología desarrollada ayudará a llevar la investigación de la biología estructural hasta el siguiente nivel y facilitará así la descripción con resolución atómica de los receptores en su entorno celular.
Objetivo
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.
Ámbito científico
- engineering and technologyenvironmental engineeringwaste managementwaste treatment processesrecycling
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- natural sciencesphysical sciencesopticsmicroscopyelectron microscopy
- natural sciencesbiological sciencesmolecular biologystructural biology
- natural sciencesphysical sciencesopticsspectroscopy
Palabras clave
Programa(s)
Tema(s)
Régimen de financiación
ERC-SyG - Synergy grantInstitución de acogida
8006 Zurich
Suiza