Controlling MAC pore formation

The membrane attack complex (MAC) is a large macromolecular immune pore that punches holes in target cells. While a potent weapon of the innate immune defense, MAC pores can also damage human cells if not properly controlled. Here we use cryoEM to understand the molecular basis for how MAC pore formation is controlled in human cells during an immune response. By solving the structure of a soluble regulated form of MAC called sMAC, we explain how blood-based chaperones scavenge and clear potentially harmful complement activation by-products. Most recently we have created a membrane model system with a synthetic GPI-anchored cellular receptor (CD59) that inhibits MAC. Using cryoEM, we
show how CD59 captures and deflects pore-forming beta-hairpins of complement proteins, rerouting their membrane trajectory. Moreover, we have discovered how the membrane environment influences the role of CD59 in complement regulation and in host-pathogen interactions. Our results open new lines of investigation into the importance of lipids in immune homeostasis that may be relevant for therapies that
regulate complement.