Journal
SCIENCE ADVANCES
Volume 6, Issue 5, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.aax8286
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Funding
- Medical Research Council [MR/N000331/1]
- Biotechnology and Biological Sciences Research Council Interdisciplinary Bioscience DPhil studentship [BB/M011224/1]
- Wellcome Trust [090532/Z/09/Z]
- BBSRC [BB/I019855/1]
- Slovenian Research Agency (program grant Molecular Interactions) [P1-0391]
- BBSRC [BB/P01948X/1, BB/S003339/1, BB/P01948X/2] Funding Source: UKRI
- EPSRC [EP/R029407/1] Funding Source: UKRI
- MRC [MR/N000331/1] Funding Source: UKRI
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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 degrees 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.
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