Description du projet
Profiler un tueur pour minimiser les dégâts aux spectateurs
Le complément est un système de plus de 20 protéines circulant dans le sang et les fluides tissulaires. Normalement inactives, ces protéines deviennent séquentiellement activées dans une cascade d’enzymes protéolytiques en réponse à la reconnaissance d’agents pathogènes. L’effet final est l’activation du complexe d’attaque membranaire (CAM) qui forme des pores cytotoxiques sur les surfaces membranaires des microbes, lysant les cellules pathogènes. L’activité CAM non contrôlée peut entraîner des dommages collatéraux aux cellules saines, mais les cibles thérapeutiques destinées à contrôler l’activité CAM nécessitent une compréhension détaillée de la structure et de la fonction CAM — des connaissances qui manquaient jusqu’à récemment. Maintenant, les études de microscopie cryoélectronique ont élucidé l’interaction entre le CAM et les cibles membranaires ainsi que l’ensemble de la structure des pores transmembranaires avec une résolution atomique. Les scientifiques qui ont réalisé ce travail de pionnier recherchent les mécanismes de contrôle dans le cadre du projet Controlling MAC, financé par l’UE.
Objectif
Structural basis of controlling the membrane attack complex
Complement is a fundamental component of the human immune system; central to the battle between hosts and pathogens. The membrane attack complex (MAC) is the direct killing arm of complement that acts by forming large pores in target cell membranes. Uncontrolled activation results in by-stander damage, which can have devastating consequences for host cells and impact inflammatory pathologies, thrombosis and cancer. Understanding how MAC activity is controlled on human cells during an immune response is a major unresolved question.
My lab has pioneered the use of cryo electron microscopy (cryoEM) to investigate the molecular mechanism underpinning MAC assembly. We have defined the stoichiometry of the complex and identified interaction interfaces that determine its sequential assembly mechanism. Recent data from my lab has now revealed atomic resolution information for the complete transmembrane pore. Results from my lab have provided a molecular and biophysical basis for MAC pore formation, which has led to a general mechanism for how proteins cross lipid bilayers.
Here, the goal is to understand the structural basis for how MAC activity is controlled by (i) cell surface receptor CD59, (ii) removal of pores from the plasma membrane, and (iii) clearance of assembly by-products from the plasma. MAC interacts with a defined set of cellular proteins through these three pathways. In this proposal, we will integrate structural information that spans cellular to molecular length scales. Recent technical advances in cryoEM, cryo soft X-ray tomography (cryoSXT) and correlated fluorescence imaging make it now possible to address how MAC activity is controlled in and around the plasma membrane. In doing so, we will answer a longstanding question in immunology and open new research directions exploring fundamental cellular processes. These results will provide a foundation for the development of novel therapeutics.
Champ scientifique
- medical and health sciencesclinical medicineangiologyvascular diseases
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- natural sciencesphysical sciencesopticsmicroscopyelectron microscopy
- medical and health sciencesbasic medicineimmunology
- natural sciencesbiological sciencesbiochemistrybiomoleculeslipids
Mots‑clés
Programme(s)
Régime de financement
ERC-COG - Consolidator GrantInstitution d’accueil
SW7 2AZ LONDON
Royaume-Uni