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Structure and mechanism of bactericidal mammalian perforin-2, an ancient agent of innate immunity
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Ni, Tao, Jiao, Fang, Yu, Xiulian, Aden, Saša, Ginger, Lucy, Williams, Sophie, Bai, Fangfang, Pražák, Vojtěch, Karia, Dimple, Stansfeld, Phillip J., Zhang, Peijun, Munson, George, Anderluh, Gregor, Scheuring, Simon and Gilbert, Robert J. C. (2020) Structure and mechanism of bactericidal mammalian perforin-2, an ancient agent of innate immunity. Science Advances, 6 (5). eaax8286. doi:10.1126/sciadv.aax8286 ISSN 2375-2548.
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Official URL: https://doi.org/10.1126/sciadv.aax8286
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.
Item Type: | Journal Article | ||||||
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | ||||||
Journal or Publication Title: | Science Advances | ||||||
Publisher: | American Association for the Advancement of Science | ||||||
ISSN: | 2375-2548 | ||||||
Official Date: | 29 January 2020 | ||||||
Dates: |
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Volume: | 6 | ||||||
Number: | 5 | ||||||
Article Number: | eaax8286 | ||||||
DOI: | 10.1126/sciadv.aax8286 | ||||||
Status: | Peer Reviewed | ||||||
Publication Status: | Published | ||||||
Access rights to Published version: | Open Access (Creative Commons) | ||||||
Date of first compliant deposit: | 13 November 2019 | ||||||
Date of first compliant Open Access: | 3 February 2020 | ||||||
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