STRUCTURAL AND MECHANISTIC INSIGHTS INTO PORE FORMATION BY PROTEINS OF THE MEMBRANE ATTACK COMPLEX/PERFORIN SUPERFAMILY

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Pore forming proteins play an important role in mediating host pathogen interactions. They are found in bacteria and eukaryotes, and span immune effectors, toxins, and pathogenic virulence factors. Members of the membrane attack complex/perforin (MACPF) superfamily of pore-forming proteins are characterised by a common three-dimensional fold able to puncture lipid membranes. This project aims to derive a molecular mechanism for how MACPF-containing proteins form pores and how this process is influenced by regulator proteins and the local lipid environment. It will explore molecular dynamics simulations of the immune effector, membrane attack complex (MAC), bound to its inhibitor CD59 to identify protein-lipid interactions and explore changes in membrane thickness, which may serve as CD59 recruitment signals. Building on these data, this project will also investigate how bacterial virulence factors co-opt CD59 to nucleate pore formation. Cholesterol-dependent cytolysins (CDCs) are a broad family of bacterial pore-forming proteins, a subset of which use CD59 on human cells as part of their pore formation pathway. Here we will use a combination of biochemical, structural, and computational approaches to understand their pore-forming mechanism.