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-Structure paper
Title | Structure and mechanism of bactericidal mammalian perforin-2, an ancient agent of innate immunity. |
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Journal, issue, pages | Sci Adv, Vol. 6, Issue 5, Page eaax8286, Year 2020 |
Publish date | Jan 29, 2020 |
![]() | 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 / ![]() ![]() ![]() |
PubMed 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 ...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. |
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Methods | EM (single particle) / X-ray diffraction |
Resolution | 2.05 - 5.0 Å |
Structure data | EMDB-10134, PDB-6sb3: EMDB-10135, PDB-6sb5: ![]() PDB-6sb1: ![]() PDB-6sb4: |
Chemicals | ![]() ChemComp-GOL: ![]() ChemComp-CL: ![]() ChemComp-HOH: ![]() ChemComp-NAG: |
Source |
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![]() | TOXIN / Pore-forming protein / perforin / MACPF / pre-pore / P2 domain / membrane binding / beta-hairpin |