Objectif The fusion of biological membranes underlies basic cellular processes of vesicle transport as well as the infectivity of enveloped viruses. The haemagglutinin (HA) glycoprotein of influenza viruses mediates fusion between viral and cellular membranes at the pH of the endosome to deliver the viral genome into the cytosol. Despite its high surface variability, its fusion machinery is conserved among HA subtypes and is a prime target for broadly neutralizing antibodies. HA consists of the receptor-binding HA1 and the fusion-mediating HA2, which has two membrane-interacting elements: the N-terminal fusion peptide and a C-terminal transmembrane anchor. At low pH, HA2 undergoes a series of conformational changes that project the fusion peptide out of a protein pocket towards the target membrane, and subsequently bring fusion peptide and transmembrane anchor, and likely the two membranes, into close proximity. The conformational changes are defined by crystal structures at neutral and low pH, but the membrane-associated parts of the protein were absent from the crystallization constructs. To define their roles and interactions, I propose to solve the full-length structures of HA at neutral pH and of HA2 at low pH by x-ray crystallography using state-of-the art crystallisation methods. High amounts of detergent solubilized membrane protein can already be purified from virus. The crystallization process will be aided by biophysical protein characterization and electron microscopy. The structures will impact our understanding of the mechanism of membrane fusion and help develop broadly neutralizing antibodies as influenza therapeutics. The project will complement my previous training in the structural biology of soluble proteins to membrane protein specific methods, electron microscopy and virological assays. Champ scientifique natural sciencesbiological sciencesmicrobiologyvirologynatural sciencesearth and related environmental sciencesgeologymineralogycrystallographynatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsnatural sciencesphysical sciencesopticsmicroscopyelectron microscopymedical and health scienceshealth sciencesinfectious diseasesRNA virusesinfluenza Programme(s) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Thème(s) FP7-PEOPLE-2013-IEF - Marie-Curie Action: "Intra-European fellowships for career development" Appel à propositions FP7-PEOPLE-2013-IEF Voir d’autres projets de cet appel Régime de financement MC-IEF - Intra-European Fellowships (IEF) Coordinateur THE FRANCIS CRICK INSTITUTE LIMITED Contribution de l’UE € 221 606,40 Adresse 1 MIDLAND ROAD NW1 1AT London Royaume-Uni Voir sur la carte Région London Inner London — West Camden and City of London Type d’activité Research Organisations Contact administratif Heather Woods (Ms.) Liens Contacter l’organisation Opens in new window Site web Opens in new window Coût total Aucune donnée Participants (1) Trier par ordre alphabétique Trier par contribution de l’UE Tout développer Tout réduire MEDICAL RESEARCH COUNCIL Participation terminée Royaume-Uni Contribution de l’UE Aucune donnée Adresse 20 Park Crescent W1B 1AL LONDON Voir sur la carte Type d’activité Public bodies (excluding Research Organisations and Secondary or Higher Education Establishments) Contact administratif David Jones (Mr.) Liens Contacter l’organisation Opens in new window Site web Opens in new window Coût total Aucune donnée
