Published in

American Association for the Advancement of Science, Science Advances, 5(6), p. eaax8286, 2020

DOI: 10.1126/sciadv.aax8286

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

This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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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.