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

DOI: 10.1126/sciadv.aax8286 DOI Help

Authors: Tao Ni (Wellcome Centre for Human Genetics, University of Oxford) , Fang Jiao (Weill Cornell Medical College) , Xiulian Yu (Wellcome Centre for Human Genetics, University of Oxford) , Saša Aden (National Institute of Chemistry, Slovenia) , Lucy Ginger (Wellcome Centre for Human Genetics, University of Oxford) , Sophie I. Williams (Wellcome Centre for Human Genetics, University of Oxford) , Fangfang Bai (University of Miami Miller School of Medicine) , Vojtech Prazak (Wellcome Centre for Human Genetics, University of Oxford) , Dimple Karia (Wellcome Centre for Human Genetics, University of Oxford) , Phillip Stansfeld (University of Oxford) , Peijun Zhang (Wellcome Centre for Human Genetics, University of Oxford) , George Munson (University of Miami Miller School of Medicine) , Gregor Anderluh (National Institute of Chemistry, Slovenia) , Simon Scheuring (Weill Cornell Medical College) , Robert J. C. Gilbert (Wellcome Centre for Human Genetics, University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Science Advances , VOL 6

State: Published (Approved)
Published: January 2020

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.

Subject Areas: Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

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