Structural basis of controlling the membrane attack complex

ended

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.