@article{07c7043371e44ad6b854ec076eb3f692,
title = "Structure and mechanism of bactericidal mammalian perforin-2, an ancient agent of innate immunity",
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.",
author = "Tao Ni and Fang Jiao and Xiulian Yu and Sa{\v s}a Aden and Lucy Ginger and Williams, {Sophie I.} and Fangfang Bai and Vojt{\v e}ch Pra{\v z}{\'a}k and Dimple Karia and Phillip Stansfeld and Peijun Zhang and George Munson and Gregor Anderluh and Simon Scheuring and Gilbert, {Robert J.C.}",
note = "Funding Information: This work was funded by the Medical Research Council (MR/N000331/1) and via a Biotechnology and Biological Sciences Research Council Interdisciplinary Bioscience DPhil studentship to S.I.W. (grant number BB/M011224/1). The Division of Structural Biology is a part of the Wellcome Centre for Human Genetics (Wellcome Trust Core grant number 090532/Z/09/Z). Research in P.S.'s laboratory is supported by grants from the BBSRC (BB/I019855/1) and the Wellcome Trust. S.A. and G.A. acknowledge support of the Slovenian Research Agency (program grant {"}Molecular Interactions{"} P1-0391). Publisher Copyright: Copyright {\textcopyright} 2020 The Authors, some rights reserved.",
year = "2020",
month = jan,
day = "29",
doi = "10.1126/sciadv.aax8286",
language = "English (US)",
volume = "6",
journal = "Science advances",
issn = "2375-2548",
publisher = "American Association for the Advancement of Science",
number = "5",
}