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

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
Science advances | 2020

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.

Pubmed ID: 32064340

Research resources used in this publication

None found

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Associated grants

  • Agency: Biotechnology and Biological Sciences Research Council, United Kingdom
    Id: BB/M011224/1
  • Agency: Medical Research Council, United Kingdom
    Id: MR/N000331/1
  • Agency: Wellcome Trust, United Kingdom
    Id: 206422/Z/17/Z
  • Agency: Biotechnology and Biological Sciences Research Council, United Kingdom
    Id: BB/I019855/1
  • Agency: NIAID NIH HHS, United States
    Id: R01 AI110810

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