The pore conformation of lymphocyte perforin

Perforin is a pore-forming protein that facilitates rapid killing of pathogen- infected or cancerous cells by the immune system. Perforin is released from cytotoxic lymphocytes, together with proapoptotic granzymes, to bind to a target cell membrane where it oligomerizes and forms pores. The pores allow granzyme entry, which rapidly triggers the apoptotic death of the target cell. Here, we present a 4-angstrom resolution cryo-electron microscopy structure of the perforin pore, revealing previously unidentified inter- and intramolecular interactions stabilizing the assembly. During pore formation, the helix-turn-helix motif moves away from the bend in the central. sheet to form an intermolecular contact. Cryo-electron tomography shows that prepores form on the membrane surface with minimal conformational changes. Our findings suggest the sequence of conformational changes underlying oligomerization and membrane insertion, and explain how several pathogenic mutations affect function.

Automated summary

Perforin is a protein that forms pores to facilitate the killing of infected or cancerous cells by the immune system. It is released from cytotoxic lymphocytes and binds to target cell membranes, leading to the rapid death of the target cells. The structure and formation process of the perforin pores have been studied, providing insights into their stability and the effects of pathogenic mutations.