Structure and mechanism of bactericidal mammalian perforin-2, an ancient agent of innate immunity
| Autor: | Gregor Anderluh, Fangfang Bai, Xiulian Yu, Fang Jiao, Lucy Ginger, Robert J.C. Gilbert, Peijun Zhang, Saša Aden, George P. Munson, D. Karia, Simon Scheuring, Vojtěch Pražák, Tao Ni, Sophie I. Williams, Phillip J. Stansfeld |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Conformational change
Protein Conformation 030303 biophysics Biophysics chemical and pharmacologic phenomena Evolution Molecular Mice Profilins 03 medical and health sciences Animals Humans Research Articles 030304 developmental biology Mammals Phagocytes 0303 health sciences Multidisciplinary Innate immune system Bacteria biology Atomic force microscopy Chemistry Mechanism (biology) Macrophages SciAdv r-articles hemic and immune systems Immunity Innate Cell biology Membrane Perforin biology.protein Research Article |
| Zdroj: | Science Advances |
| ISSN: | 2375-2548 |
| Popis: | Bactericidal perforin-2 assembles an inactivated pre-pore complex and undergoes a 180° reconfiguration for membrane attack. 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. |
| Databáze: | OpenAIRE |
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