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TitleStructure and mechanism of bactericidal mammalian perforin-2, an ancient agent of innate immunity.
Journal, issue, pagesSci Adv, Vol. 6, Issue 5, Page eaax8286, Year 2020
Publish dateJan 29, 2020
AuthorsTao 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 /
PubMed AbstractPerforin-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 ...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.
External linksSci Adv / PubMed:32064340 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.05 - 5.0 Å
Structure data

10134

6sb3

EMDB-10134, PDB-6sb3:
CryoEM structure of murine perforin-2 ectodomain in a pre-pore form
Method: EM (single particle) / Resolution: 3.5 Å

10135

6sb5

EMDB-10135, PDB-6sb5:
CryoEM structure of murine perforin-2 ectodomain in a pore form
Method: EM (single particle) / Resolution: 5.0 Å

PDB-6sb1:
Crystal structure of murine perforin-2 P2 domain crystal form 1
Method: X-RAY DIFFRACTION / Resolution: 2.05 Å

PDB-6sb4:
Crystal structure of murine perforin-2 P2 domain crystal form 2
Method: X-RAY DIFFRACTION / Resolution: 3.17 Å

Chemicals

ChemComp-GOL:
GLYCEROL / Glycerol

ChemComp-CL:
Unknown entry / Chloride

ChemComp-HOH:
WATER / Water

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

Source
  • mus musculus (house mouse)
KeywordsTOXIN / Pore-forming protein / perforin / MACPF / pre-pore / P2 domain / membrane binding / beta-hairpin

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