The cryo-EM structure of the acid activatable pore-forming immune effector Macrophage-expressed gene 1

• DOI: 10.1038/s41467-019-12279-2
• Publication Date: 2019-09-19T10:04:13Z
• Authors: Siew Siew Pang; Charles Bayly-Jones; Mazdak Radjainia; Bradley A. Spicer; Ruby H. P. Law; Adrian W. Hodel; Edward S. Parsons; Susan M. Ekkel; Paul J. Conroy; Georg Ramm; Hariprasad Venugopal; Phillip I. Bird; Bart W. Hoogenboom; Ilia Voskoboinik; Yann Gambin; Emma Sierecki; Michelle A. Dunstone; James C. Whisstock
• Keywords: Phagolysosome; Cryo-Electron Microscopy

Abstract Macrophage-expressed gene 1 (MPEG1/Perforin-2) is a perforin-like protein that functions within the phagolysosome to damage engulfed microbes. MPEG1 thought form pores in target membranes, however, its mode of action remains unknown. We use cryo-Electron Microscopy (cryo-EM) determine 2.4 Å structure hexadecameric assembly displays expected features soluble prepore complex. further discover prepore-like assemblies can be induced perforate membranes through acidification, such as would occur maturing phagolysosomes. next solve 3.6 cryo-EM complex with liposomes. These data reveal multi-vesicular body 12 kDa (MVB12)-associated β-prism (MABP) domain binds pore-forming machinery oriented away from bound membrane. This unexpected mechanism membrane interaction suggests while simultaneously forming bacterial targets.