Hole punching proteins of the immune system

The MACPF/CDC family proteins use a common fold to oligomerise into a ring-shaped transmembrane pore capable of either direct cell lysis or passive transport other factors proteins. Members of this family are found in all kingdoms of life with a range of functions including as immune effectors, pathogenicity factors, parasite egress, fungal defense and development. Decades of structural research on the MACPF/CDC family suggested that oligomer assembly on the target membrane is mediated via a dedicated ancillary domain. This is followed by planar diffusion upon the target membrane into a ring shaped prepore. The prepore undergoes a concerted conformational change to form the final pore. This model of mechanism, however, is only consistent with Cholesterol Dependent Cytolysins (CDCs), pleurotolysin and perforin that all have dedicated membrane binding ancillary domains. It is now emerging that this canonical mechanism does not explain how two important pathogen-targeting systems function: Membrane Attack Complex (MAC) and MPEG-1. Recent structures of the MAC and MPEG-1 challenge the existing dogma in MACPF/CDC pore assembly. We aim to research how the MACPF/CDC pores used by the immune system have evolved to be able to target highly variable surfaces by evolving different assembly pathways. Understanding the mechanism of these systems will be used develop protein based systems that target cancerous cells and antimicrobial resistant bacteria.