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Structure and mechanism of bactericidal mammalian perforin-2, an ancient agent of innate immunity.

<div class='caption-title'>Cryo-EM structure of the PFN2 pre-pore oligomer.</div>
<div class='caption-title'>The P2 domain β hairpin is responsible for membrane binding.</div>
<div class='caption-title'>HS-AFM of MPFN2 pre-pore structure and assembly.</div>
Ni T, Jiao F, Yu X, Aden S, Ginger L, Williams SI, Bai F, Pražák V, Karia D, Stansfeld P, Zhang P, Munson G, Anderluh G, Scheuring S, Gilbert RJC
OpenAccess logo Sci Adv 6 eaax8286 (2020)
Related entries: 6sb1, 6sb3, 6sb4

Cited: 29 times
EuropePMC logo PMID: 32064340

Abstract

Perforin-2 (MPEG1) is thought to enable the killing of invading microbes engulfed by macrophages and other phagocytes, forming pores in their membranes. Loss of perforin-2 renders individual phagocytes and whole organisms significantly more susceptible to bacterial pathogens. Here, we reveal the mechanism of perforin-2 activation and activity using atomic structures of pre-pore and pore assemblies, high-speed atomic force microscopy, and functional assays. Perforin-2 forms a pre-pore assembly in which its pore-forming domain points in the opposite direction to its membrane-targeting domain. Acidification then triggers pore formation, via a 180° conformational change. This novel and unexpected mechanism prevents premature bactericidal attack and may have played a key role in the evolution of all perforin family proteins.

Reviews - 6sb5 mentioned but not cited (2)

  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)
  2. Breaching the Bacterial Envelope: The Pivotal Role of Perforin-2 (MPEG1) Within Phagocytes. Merselis LC, Rivas ZP, Munson GP. Front Immunol 12 597951 (2021)

Articles - 6sb5 mentioned but not cited (3)



Reviews citing this publication (9)

  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. 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)
  3. 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)
  4. Perforins Expression by Cutaneous Gamma Delta T Cells. O'Neill K, Pastar I, Tomic-Canic M, Strbo N. Front Immunol 11 1839 (2020)
  5. Challenges and approaches to studying pore-forming proteins. Benton JT, Bayly-Jones C. Biochem Soc Trans 49 2749-2765 (2021)
  6. Towards Understanding the Function of Aegerolysins. Kraševec N, Skočaj M. Toxins (Basel) 14 629 (2022)
  7. Structure and dynamics of ESCRT-III membrane remodeling proteins by high-speed atomic force microscopy. Jukic N, Perrino AP, Redondo-Morata L, Scheuring S. J Biol Chem 299 104575 (2023)
  8. An Ancient Molecular Arms Race: Chlamydia vs. Membrane Attack Complex/Perforin (MACPF) Domain Proteins. Keb G, Fields KA. Front Immunol 11 1490 (2020)
  9. Acid-resistant enzymes: the acquisition strategies and applications. Zhang Z, Zhao Z, Huang K, Liang Z. Appl Microbiol Biotechnol 107 6163-6178 (2023)

Articles citing this publication (15)



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