Structure and mechanism of bactericidal mammalian perforin-2, an ancient agent of innate immunity

Tao Ni, Fang Jiao, Xiulian Yu, Saša Aden, Lucy Ginger, Sophie I. Williams, Fangfang Bai, Vojtěch Pražák, Dimple Karia, Phillip Stansfeld, Peijun Zhang, George Munson, Gregor Anderluh, Simon Scheuring, Robert J.C. Gilbert

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Perforin-2 (MPEG1) is thought to enable the killing of invading microbes engulfed by macrophages and other phagocytes, forming pores in their membranes. Loss of perforin-2 renders individual phagocytes and whole organisms significantly more susceptible to bacterial pathogens. Here, we reveal the mechanism of perforin-2 activation and activity using atomic structures of pre-pore and pore assemblies, high-speed atomic force microscopy, and functional assays. Perforin-2 forms a pre-pore assembly in which its pore-forming domain points in the opposite direction to its membrane-targeting domain. Acidification then triggers pore formation, via a 180° conformational change. This novel and unexpected mechanism prevents premature bactericidal attack and may have played a key role in the evolution of all perforin family proteins.

Original languageEnglish (US)
Article numbereaax8286
JournalScience Advances
Volume6
Issue number5
DOIs
StatePublished - Jan 29 2020

ASJC Scopus subject areas

  • General

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