Objectif Our body constantly encounters pathogens or malignant transformation. Consequently, the adaptive immune system is in place to eliminate infected or cancerous cells. Specific immune reactions are triggered by selected peptide epitopes presented on major histocompatibility complex class I (MHC-I) molecules, which are scanned by cytotoxic T lymphocytes.Intracellular transport, loading, and editing of antigenic peptides onto MHC-I are coordinated by a highly dynamic multisubunit peptide-loading complex (PLC) in the ER membrane. This multitasking machinery orchestrates the translocation of proteasomal degradation products into the ER as well as the loading and proofreading of MHC-I molecules.Sampling of myriads of different peptide/MHC-I allomorphs requires a precisely coordinated quality control network in a single macromolecular assembly, including the transporter associated with antigen processing TAP1/2, the MHC-I heterodimer, the oxidoreductase ERp57, and the ER chaperones tapasin and calreticulin. Proofreading by MHC-I editing complexes guarantees that only very stable peptide/MHC-I complexes are released to the cell surface.This proposal aims to gain a holistic understanding of the PLC and MHC-I proofreading complexes, which are essential for cellular immunity. We strive to elucidate the mechanistic basis of the antigen translocation complex TAP as well as the MHC-I chaperone complexes within the PLC. This high-risk/high-gain project will define the inner working of the PLC, which constitutes the central machinery of immune surveillance in health and diseases. The results will provide detailed insights into the architecture and dynamics of the PLC and will ultimately pave the way for unraveling general principles of intracellular membrane-embedded multiprotein assemblies in the human body. Furthermore, we will deliver a detailed understanding of mechanisms at work in viral immune evasion. Champ scientifique natural sciencesbiological sciencesbiochemistrybiomoleculesmedical and health sciencesbasic medicineimmunology Mots‑clés Membrane Proteins Macromolecular Complexes ER Quality Control Membrane Transporters Fluorescence Labeling Chemical Biology Super-resolution Microscopy Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Thème(s) ERC-2017-ADG - ERC Advanced Grant Appel à propositions ERC-2017-ADG Voir d’autres projets de cet appel Régime de financement ERC-ADG - Advanced Grant Institution d’accueil JOHANN WOLFGANG GOETHE-UNIVERSITAET FRANKFURT AM MAIN Contribution nette de l'UE € 2 181 250,00 Adresse THEODOR W ADORNO PLATZ 1 60323 Frankfurt Am Main Allemagne Voir sur la carte Région Hessen Darmstadt Frankfurt am Main, Kreisfreie Stadt Type d’activité Higher or Secondary Education Establishments Liens Contacter l’organisation Opens in new window Site web Opens in new window Participation aux programmes de R&I de l'UE Opens in new window Réseau de collaboration HORIZON Opens in new window Coût total € 2 181 250,00 Bénéficiaires (1) Trier par ordre alphabétique Trier par contribution nette de l'UE Tout développer Tout réduire JOHANN WOLFGANG GOETHE-UNIVERSITAET FRANKFURT AM MAIN Allemagne Contribution nette de l'UE € 2 181 250,00 Adresse THEODOR W ADORNO PLATZ 1 60323 Frankfurt Am Main Voir sur la carte Région Hessen Darmstadt Frankfurt am Main, Kreisfreie Stadt Type d’activité Higher or Secondary Education Establishments Liens Contacter l’organisation Opens in new window Site web Opens in new window Participation aux programmes de R&I de l'UE Opens in new window Réseau de collaboration HORIZON Opens in new window Coût total € 2 181 250,00