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Structural basis for membrane attack complex inhibition by CD59.

<div class='caption-title'>Schematic of MAC assembly.</div>
<div class='caption-title'>Structure of the C5b8-CD59 complex.</div>
<div class='caption-title'>CD59 interaction interfaces.</div>
Couves EC, Gardner S, Voisin TB, Bickel JK, Stansfeld PJ, Tate EW, Bubeck D
OpenAccess logo Nat Commun 14 890 (2023)
Related entries: 8b0f, 8b0g

Cited: 10 times
EuropePMC logo PMID: 36797260

Abstract

CD59 is an abundant immuno-regulatory receptor that protects human cells from damage during complement activation. Here we show how the receptor binds complement proteins C8 and C9 at the membrane to prevent insertion and polymerization of membrane attack complex (MAC) pores. We present cryo-electron microscopy structures of two inhibited MAC precursors known as C5b8 and C5b9. We discover that in both complexes, CD59 binds the pore-forming β-hairpins of C8 to form an intermolecular β-sheet that prevents membrane perforation. While bound to C8, CD59 deflects the cascading C9 β-hairpins, rerouting their trajectory into the membrane. Preventing insertion of C9 restricts structural transitions of subsequent monomers and indirectly halts MAC polymerization. We combine our structural data with cellular assays and molecular dynamics simulations to explain how the membrane environment impacts the dual roles of CD59 in controlling pore formation of MAC, and as a target of bacterial virulence factors which hijack CD59 to lyse human cells.

Reviews citing this publication (2)

  1. A guide to complement biology, pathology and therapeutic opportunity. Mastellos DC, Hajishengallis G, Lambris JD. Nat Rev Immunol 24 118-141 (2024)
  2. The complement cascade in lung injury and disease. Detsika MG, Palamaris K, Dimopoulou I, Kotanidou A, Orfanos SE. Respir Res 25 20 (2024)

Articles citing this publication (8)

  1. Dynamics and Molecular Interactions of GPI-Anchored CD59. Voisin TB, Couves EC, Tate EW, Bubeck D. Toxins (Basel) 15 430 (2023)
  2. Different Complement Activation Patterns Following C5 Cleavage in MOGAD and AQP4-IgG+NMOSD. Kaneko K, Kuroda H, Matsumoto Y, Sakamoto N, Yamazaki N, Yamamoto N, Umezawa S, Namatame C, Ono H, Takai Y, Takahashi T, Fujimori J, Nakashima I, Harigaya Y, Lassmann H, Fujihara K, Misu T, Aoki M. Neurol Neuroimmunol Neuroinflamm 11 e200293 (2024)
  3. Molecular mechanism of complement inhibition by the trypanosome receptor ISG65. Cook AD, Carrington M, Higgins MK. Elife 12 RP88960 (2024)
  4. CD59 Protects Primary Human Cerebrovascular Smooth Muscle Cells from Cytolytic Membrane Attack Complex. Whinnery CD, Nie Y, Boskovic DS, Soriano S, Kirsch WM. Brain Sci 14 601 (2024)
  5. Distant relatives of a eukaryotic cell-specific toxin family evolved a complement-like mechanism to kill bacteria. Abrahamsen HL, Sanford TC, Collamore CE, Johnstone BA, Coyne MJ, García-Bayona L, Christie MP, Evans JC, Farrand AJ, Flores K, Morton CJ, Parker MW, Comstock LE, Tweten RK. Nat Commun 15 5028 (2024)
  6. Downregulation of miRNA-26a by HIV-1 Enhances CD59 Expression and Packaging, Impacting Virus Susceptibility to Antibody-Dependent Complement-Mediated Lysis. Bellini N, Ye C, Ajibola O, Murooka TT, Lodge R, Cohen ÉA. Viruses 16 1076 (2024)
  7. Editorial Special Issue "COVID-19 Coagulopathy: Advances on Pathophysiology and Therapies". Russu E, Arbănaşi EM, Șchiopu A. Int J Mol Sci 25 3548 (2024)
  8. Unveiling CD59-Antibody Interactions to Design Paratope-Mimicking Peptides for Complement Modulation. Sandomenico A, Ruggiero A, Iaccarino E, Oliver A, Squeglia F, Moreira M, Esposito L, Ruvo M, Berisio R. Int J Mol Sci 24 8561 (2023)


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