Project description
Profiling a killer to minimise bystander damage
Complement is a system of more than 20 proteins circulating in the blood and tissue fluids. Normally inactive, these proteins become sequentially activated in a proteolytic enzyme cascade in response to recognition of pathogens. The end effect is activation of the membrane attack complex (MAC) that forms cytotoxic pores on the membrane surfaces of microbes, lysing the pathogenic cells. Uncontrolled MAC activity can result in collateral damage to healthy cells, but therapeutic targets to control MAC activity require detailed understanding of MAC structure and function – knowledge missing until recently. Now, cryoelectron microscopy studies have elucidated the interaction between MAC and the membrane targets as well as the entire transmembrane pore structure with atomic resolution. The scientists who carried out this pioneering work are looking for the control mechanisms in the context of the EU-funded Controlling MAC project.
Objective
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.
Fields of science
- medical and health sciencesclinical medicineangiologyvascular diseases
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- natural sciencesphysical sciencesopticsmicroscopyelectron microscopy
- medical and health sciencesbasic medicineimmunology
- natural sciencesbiological sciencesbiochemistrybiomoleculeslipids
Keywords
Programme(s)
Funding Scheme
ERC-COG - Consolidator GrantHost institution
SW7 2AZ LONDON
United Kingdom