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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)

  1. The evolution of SPHIRE-crYOLO particle picking and its application in automated cryo-EM processing workflows. Wagner T, Raunser S. Commun Biol 3 61 (2020)
  2. Staphylococcus epidermidis Boosts Innate Immune Response by Activation of Gamma Delta T Cells and Induction of Perforin-2 in Human Skin. Pastar I, O'Neill K, Padula L, Head CR, Burgess JL, Chen V, Garcia D, Stojadinovic O, Hower S, Plano GV, Thaller SR, Tomic-Canic M, Strbo N. Front Immunol 11 550946 (2020)
  3. Selective neuronal degeneration in MATR3 S85C knock-in mouse model of early-stage ALS. Kao CS, van Bruggen R, Kim JR, Chen XXL, Chan C, Lee J, Cho WI, Zhao M, Arndt C, Maksimovic K, Khan M, Tan Q, Wilson MD, Park J. Nat Commun 11 5304 (2020)
  4. Cryo-EM structures and functional properties of CALHM channels of the human placenta. Drożdżyk K, Sawicka M, Bahamonde-Santos MI, Jonas Z, Deneka D, Albrecht C, Dutzler R. Elife 9 e55853 (2020)
  5. Structural basis of soluble membrane attack complex packaging for clearance. Menny A, Lukassen MV, Couves EC, Franc V, Heck AJR, Bubeck D. Nat Commun 12 6086 (2021)
  6. Structural basis for tuning activity and membrane specificity of bacterial cytolysins. Shah NR, Voisin TB, Parsons ES, Boyd CM, Hoogenboom BW, Bubeck D. Nat Commun 11 5818 (2020)
  7. The pore conformation of lymphocyte perforin. Ivanova ME, Lukoyanova N, Malhotra S, Topf M, Trapani JA, Voskoboinik I, Saibil HR. Sci Adv 8 eabk3147 (2022)
  8. Perforin-2 is a pore-forming effector of endocytic escape in cross-presenting dendritic cells. Rodríguez-Silvestre P, Laub M, Krawczyk PA, Davies AK, Schessner JP, Parveen R, Tuck BJ, McEwan WA, Borner GHH, Kozik P. Science 380 1258-1265 (2023)
  9. Perforin-2 clockwise hand-over-hand pre-pore to pore transition mechanism. Jiao F, Dehez F, Ni T, Yu X, Dittman JS, Gilbert R, Chipot C, Scheuring S. Nat Commun 13 5039 (2022)
  10. Structure and assembly of a bacterial gasdermin pore. Johnson AG, Mayer ML, Schaefer SL, McNamara-Bordewick NK, Hummer G, Kranzusch PJ. Nature 628 657-663 (2024)
  11. Lipid specificity of the immune effector perforin. Hodel AW, Rudd-Schmidt JA, Trapani JA, Voskoboinik I, Hoogenboom BW. Faraday Discuss 232 236-255 (2021)
  12. Single-particle cryo-EM reveals conformational variability of the oligomeric VCC β-barrel pore in a lipid bilayer. Sengupta N, Mondal AK, Mishra S, Chattopadhyay K, Dutta S. J Cell Biol 220 e202102035 (2021)
  13. Lipid-Binding Aegerolysin from Biocontrol Fungus Beauveria bassiana. Kraševec N, Panevska A, Lemež Š, Razinger J, Sepčić K, Anderluh G, Podobnik M. Toxins (Basel) 13 820 (2021)
  14. Research Support, Non-U.S. Gov't MPEG1/Perforin-2 Haploinsufficiency Associated Polymicrobial Skin Infections and Considerations for Interferon-γ Therapy. Merselis LC, Jiang SY, Nelson SF, Lee H, Prabaker KK, Baker JL, Munson GP, Butte MJ. Front Immunol 11 601584 (2020)
  15. Mpeg1 is not essential for antibacterial or antiviral immunity, but is implicated in antigen presentation. Ebrahimnezhaddarzi S, Bird CH, Allison CC, Tuipulotu DE, Kostoulias X, Macri C, Stutz MD, Abraham G, Kaiserman D, Pang SS, Man SM, Mintern JD, Naderer T, Peleg AY, Pellegrini M, Whisstock JC, Bird PI. Immunol Cell Biol 100 529-546 (2022)
  16. Cryo-EM structures of perforin-2 in isolation and assembled on a membrane suggest a mechanism for pore formation. Yu X, Ni T, Munson G, Zhang P, Gilbert RJC. EMBO J 41 e111857 (2022)
  17. Dynamics and Molecular Interactions of GPI-Anchored CD59. Voisin TB, Couves EC, Tate EW, Bubeck D. Toxins (Basel) 15 430 (2023)
  18. The crystal structure of Cry78Aa from Bacillus thuringiensis provides insights into its insecticidal activity. Cao B, Nie Y, Guan Z, Chen C, Wang N, Wang Z, Shu C, Zhang J, Zhang D. Commun Biol 5 801 (2022)
  19. Macrophage-specific protein perforin-2 is associated with poor neurological recovery and reduced survival after sudden cardiac arrest. Kattel S, Bhatt H, Xu S, Gurung S, Pokharel S, Sharma UC. Resuscitation 155 180-188 (2020)
  20. Visible Light Control over the Cytolytic Activity of a Toxic Pore-Forming Protein. Volarić J, van der Heide NJ, Mutter NL, Samplonius DF, Helfrich W, Maglia G, Szymanski W, Feringa BL. ACS Chem Biol 19 451-461 (2024)
  21. Cryo-EM reconstruction of oleate hydratase bound to a phospholipid membrane bilayer. Oldham ML, Zuhaib Qayyum M, Kalathur RC, Rock CO, Radka CD. J Struct Biol 216 108116 (2024)
  22. Enhancing cryo-EM structure prediction with DeepTracer and AlphaFold2 integration. Chen J, Zia A, Luo A, Meng H, Wang F, Hou J, Cao R, Si D. Brief Bioinform 25 bbae118 (2024)
  23. Structural journey of an insecticidal protein against western corn rootworm. Marini G, Poland B, Leininger C, Lukoyanova N, Spielbauer D, Barry JK, Altier D, Lum A, Scolaro E, Ortega CP, Yalpani N, Sandahl G, Mabry T, Klever J, Nowatzki T, Zhao JZ, Sethi A, Kassa A, Crane V, Lu AL, Nelson ME, Eswar N, Topf M, Saibil HR. Nat Commun 14 4171 (2023)


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