Structure and mechanism of bactericidal mammalian perforin-2, an ancient agent of innate immunity.
Journal
Science advances
ISSN: 2375-2548
Titre abrégé: Sci Adv
Pays: United States
ID NLM: 101653440
Informations de publication
Date de publication:
01 2020
01 2020
Historique:
received:
26
04
2019
accepted:
21
11
2019
entrez:
18
2
2020
pubmed:
18
2
2020
medline:
20
11
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32064340
doi: 10.1126/sciadv.aax8286
pii: aax8286
pmc: PMC6989145
doi:
Substances chimiques
Pfn2 protein, mouse
0
Profilins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
eaax8286Subventions
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/M011224/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/N000331/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 206422/Z/17/Z
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/I019855/1
Pays : United Kingdom
Organisme : NIAID NIH HHS
ID : R01 AI110810
Pays : United States
Informations de copyright
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).
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