The structure of Macrophage Expressed Gene-1, a phagolysosome immune effector that is activated upon acidification
The structure of Macrophage Expressed Gene-1, a phagolysosome immune effector that is activated upon acidification
Macrophage Expressed Gene-1 (MPEG-1; also termed Perforin-2) is an endosomal / phagolysosomal perforin-like protein that is conserved across the metazoan kingdom and that functions within the phagolysosome to damage engulfed microbes. Like the Membrane Attack Complex and perforin, MPEG-1 has been postulated to form pores in target membranes, however, its mode of action remains to be established. We used single particle cryo-Electron Microscopy to determine the 2.4 ? structure of a hexadecameric assembly of MPEG-1 that displays the expected features of a soluble pre-pore complex. We further discovered that the MPEG-1 pre-pore-like assemblies can be induced to perforate membranes through mild acidification, such as would occur within maturing phagolysosomes. We next solved the 3.6 ? cryo-EM structure of MPEG-1 in complex with liposomes. Remarkably these data revealed that a C-terminal Multi-vesicular body of 12 kDa (MVB12)-associated β-prism (MABP) domain interacts with target membranes in a mode that positions the pore forming machinery of MPEG-1 to point away from the bound membrane. This unexpected mechanism of membrane interaction raises the intriguing possibility that MPEG-1 may be able to remain bound to the phagolysosome membrane while simultaneously forming pores in engulfed bacterial targets.
Whisstock James C.、Ekkel Sue M.、Ramm Georg、Venugopal Hariprasad、Bird Phillip I.、Gambin Yann、Sierecki Emma、Radjainia Mazdak、Voskoboinik Ilia、Hodel Adrian W.、Law Ruby H.P.、Bayly-Jones Charles、Dunstone Michelle A.、Hoogenboom Bart W.、Conroy Paul J.、Pang Siew Siew、Spicer Bradley A.
ARC Centre of Excellence in Advanced Molecular Imaging||Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University||EMBL Australia, Monash UniversityARC Centre of Excellence in Advanced Molecular Imaging||Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash UniversityBiomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash UniversityBiomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash UniversityBiomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash UniversitySchool of Medical Science, Faculty of Medicine, University of New South Wales||EMBL AustraliaSchool of Medical Science, Faculty of Medicine, University of New South Wales||EMBL AustraliaBiomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University||FEI Company, Achtseweg Noord 5, Building 5651 GG EindhovenCancer Immunology Program, Peter MacCallum Cancer Centre||Department of Genetics, The University of MelbourneLondon Centre for Nanotechnology, University College London||Institute of Structural and Molecular Biology, University College LondonARC Centre of Excellence in Advanced Molecular Imaging||Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash UniversityARC Centre of Excellence in Advanced Molecular Imaging||Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash UniversityARC Centre of Excellence in Advanced Molecular Imaging||Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash UniversityLondon Centre for Nanotechnology, University College London||Institute of Structural and Molecular Biology, University College London||Department of Physics and Astronomy, University College LondonARC Centre of Excellence in Advanced Molecular Imaging||Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash UniversityARC Centre of Excellence in Advanced Molecular Imaging||Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash UniversityARC Centre of Excellence in Advanced Molecular Imaging||Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University
基础医学分子生物学细胞生物学
Whisstock James C.,Ekkel Sue M.,Ramm Georg,Venugopal Hariprasad,Bird Phillip I.,Gambin Yann,Sierecki Emma,Radjainia Mazdak,Voskoboinik Ilia,Hodel Adrian W.,Law Ruby H.P.,Bayly-Jones Charles,Dunstone Michelle A.,Hoogenboom Bart W.,Conroy Paul J.,Pang Siew Siew,Spicer Bradley A..The structure of Macrophage Expressed Gene-1, a phagolysosome immune effector that is activated upon acidification[EB/OL].(2025-03-28)[2025-05-01].https://www.biorxiv.org/content/10.1101/580712.点此复制
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