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2020 - Structure and mechanism of bactericidal mammalian perforin-2, an ancient agent of innate immunity

Icon Orbit Mini   Orbit mini and   icon vpp   Vesicle Prep Pro publication in Science Advances (2020)

Authors:
Ni T., Jiao F., Yu X., Aden S., Ginger L., Williams S.I., Bai F., Pražák V., Karia D., Stansfeld P., Zhang P., Munson G., Anderluh G.,Scheuring S., Gilbert R.J.C.

Journal:
Science Advances (2020) 6(5): eaax8286


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.


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