6u23
EM structure of MPEG-1(w.t.) soluble pre-pore
Structural highlights
FunctionMPEG1_HUMAN Plays a key role in the innate immune response following bacterial infection by inserting into the bacterial surface to form pores (By similarity). By breaching the surface of phagocytosed bacteria, allows antimicrobial effectors to enter the bacterial periplasmic space and degrade bacterial proteins such as superoxide dismutase sodC which contributes to bacterial virulence (By similarity). Shows antibacterial activity against a wide spectrum of Gram-positive, Gram-negative and acid-fast bacteria (PubMed:23753625, PubMed:26402460, PubMed:30609079). Reduces the viability of the intracytosolic pathogen L.monocytogenes by inhibiting acidification of the phagocytic vacuole of host cells which restricts bacterial translocation from the vacuole to the cytosol (By similarity). Required for the antibacterial activity of reactive oxygen species and nitric oxide (By similarity).[UniProtKB:A1L314][1] [2] [3] Publication Abstract from PubMedMacrophage-expressed gene 1 (MPEG1/Perforin-2) is a perforin-like protein that functions within the phagolysosome to damage engulfed microbes. MPEG1 is thought to form pores in target membranes, however, its mode of action remains unknown. We use cryo-Electron Microscopy (cryo-EM) to determine the 2.4 A structure of a hexadecameric assembly of MPEG1 that displays the expected features of a soluble prepore complex. We further discover that MPEG1 prepore-like assemblies can be induced to perforate membranes through acidification, such as would occur within maturing phagolysosomes. We next solve the 3.6 A cryo-EM structure of MPEG1 in complex with liposomes. These data reveal that a multi-vesicular body of 12 kDa (MVB12)-associated beta-prism (MABP) domain binds membranes such that the pore-forming machinery of MPEG1 is oriented away from the bound membrane. This unexpected mechanism of membrane interaction suggests that MPEG1 remains bound to the phagolysosome membrane while simultaneously forming pores in engulfed bacterial targets. The cryo-EM structure of the acid activatable pore-forming immune effector Macrophage-expressed gene 1.,Pang SS, Bayly-Jones C, Radjainia M, Spicer BA, Law RHP, Hodel AW, Parsons ES, Ekkel SM, Conroy PJ, Ramm G, Venugopal H, Bird PI, Hoogenboom BW, Voskoboinik I, Gambin Y, Sierecki E, Dunstone MA, Whisstock JC Nat Commun. 2019 Sep 19;10(1):4288. doi: 10.1038/s41467-019-12279-2. PMID:31537793[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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