Fas_Life-Death · A Biophysical Investigation of the Duality in Fas Receptor
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2021-04-01 → 2023-03-31
- EU contribution
- €184,708
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
A Biophysical Investigation of the Duality in Fas Receptor
Signaling receptors in the plasma membrane control information exchange within and across cells. Among the different transmembrane signaling receptors, the Fas protein is receiving growing attention, mainly because of its ‘dual character’ in promoting as well as preventing cell growth in both cancer and normal cells. Here, we engineer a bottom-up approach to investigate the physical mechanism behind the duality in Fas receptor-ligand complexes that control the cell functions. Multi-domain signaling receptors, including Fas are known to undergo molecular conformational changes to facilitate the downstream recruitment of signaling molecules. Such a conformational switch is usually driven by the change in chemical state (ligand, phosphorylation, glycosylation, etc). Fas_Life-Death combines biochemical (for in-vitro protein reconstitution), synthetic biology (for site-specific fluorescence labeling), and optical methods (single-molecule FRET, single particle tracking) to explore new conformations, and molecular mechanisms of Fas-mediated clustering in membranes. Investigating the influence of structural and molecular dynamics of transmembrane proteins on the physiological activity of cells have both scientific and pharmaceutical significance. These could provide comprehensive insights to transmembrane communication and identify points of intervention for drug design.
Data: CORDIS, © European Union
Project objective
Membrane receptors control fundamental physiological processes in cells, and are major targets of medical drugs. The goal of this project is to investigate the nanoscale motion of the membrane receptor Fas and its functional role in maintaining immune surveillance. Fas is ubiquitously expressed in human body and has significant roles in disease progressions. A type I single pass transmembrane protein, Fas is known for its ‘dual character’ in triggering signaling pathways leading to both cell survival and cell death. In the presence of its ligand, the receptor undergoes higher-order clustering to form a death-inducing signaling complex (DISC) in the intracellular region. Immune cells use Fas-mediated DISC formation as a mechanism to ‘kill’ virus infected or malignant cells. The Fas ligand, which is a type II transmembrane protein, can be cleaved which results in its soluble variant. Unlike the membrane anchored Fas ligand, the cleaved variant is known to induce an alternative motility inducing signaling complex (MISC) in Fas receptor that results in cell migration. Although the functions of the Fas receptor (and the notion of duality) are well established, how it selects for non-apoptotic or apoptotic pathways is an open question. It has been postulated that the membrane bound and cleaved variants of the Fas ligand induce different structural orientation and conformations in the intracellular domains of the receptors to control DISC/MISC formation. However, due to the immediate higher order aggregations upon ligand-binding and the presence of other modulating proteins during in-vivo experiments, it has been a great challenge to test this hypothesis. This project will investigate the biophysical mechanism behind the duality in full-length Fas receptors by exploiting single-molecule Förster resonance energy transfer (smFRET) and membrane nanodisc platform. Mechanistic understanding of Fas transmembrane signaling has both scientific and pharmaceutical significance.
Original text from CORDIS.
Participants
- INSTITUT CURIE · ParisCoordinatorFrance
Links
Data: CORDIS, © European Union