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

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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
OpenAccess logo Nat Commun 10 4288 (2019)
Related entries: 6u23, 6u2j, 6u2k, 6u2w

Cited: 36 times
EuropePMC logo PMID: 31537793

Abstract

Macrophage-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 Å 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 Å cryo-EM structure of MPEG1 in complex with liposomes. These data reveal that a multi-vesicular body of 12 kDa (MVB12)-associated β-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.

Reviews - 6u2l mentioned but not cited (1)

  1. Ancient but Not Forgotten: New Insights Into MPEG1, a Macrophage Perforin-Like Immune Effector. Bayly-Jones C, Pang SS, Spicer BA, Whisstock JC, Dunstone MA. Front Immunol 11 581906 (2020)


Reviews citing this publication (12)

  1. Skin Microbiota and its Interplay with Wound Healing. Tomic-Canic M, Burgess JL, O'Neill KE, Strbo N, Pastar I. Am J Clin Dermatol 21 36-43 (2020)
  2. Knocking 'em Dead: Pore-Forming Proteins in Immune Defense. Liu X, Lieberman J. Annu Rev Immunol 38 455-485 (2020)
  3. Cryo-electron microscopy analysis of small membrane proteins. Nygaard R, Kim J, Mancia F. Curr Opin Struct Biol 64 26-33 (2020)
  4. Drug discovery in the era of cryo-electron microscopy. Robertson MJ, Meyerowitz JG, Skiniotis G. Trends Biochem Sci 47 124-135 (2022)
  5. Intracellular escape strategies of Staphylococcus aureus in persistent cutaneous infections. Huitema L, Phillips T, Alexeev V, Tomic-Canic M, Pastar I, Igoucheva O. Exp Dermatol 30 1428-1439 (2021)
  6. Membranes under the Magnetic Lens: A Dive into the Diverse World of Membrane Protein Structures Using Cryo-EM. Piper SJ, Johnson RM, Wootten D, Sexton PM. Chem Rev 122 13989-14017 (2022)
  7. To Kill But Not Be Killed: Controlling the Activity of Mammalian Pore-Forming Proteins. Krawczyk PA, Laub M, Kozik P. Front Immunol 11 601405 (2020)
  8. Perforins Expression by Cutaneous Gamma Delta T Cells. O'Neill K, Pastar I, Tomic-Canic M, Strbo N. Front Immunol 11 1839 (2020)
  9. Challenges and approaches to studying pore-forming proteins. Benton JT, Bayly-Jones C. Biochem Soc Trans 49 2749-2765 (2021)
  10. Breaching the Bacterial Envelope: The Pivotal Role of Perforin-2 (MPEG1) Within Phagocytes. Merselis LC, Rivas ZP, Munson GP. Front Immunol 12 597951 (2021)
  11. Towards Understanding the Function of Aegerolysins. Kraševec N, Skočaj M. Toxins (Basel) 14 629 (2022)
  12. An Ancient Molecular Arms Race: Chlamydia vs. Membrane Attack Complex/Perforin (MACPF) Domain Proteins. Keb G, Fields KA. Front Immunol 11 1490 (2020)

Articles citing this publication (23)



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