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Structural basis of complement membrane attack complex formation

Author

Listed:
  • Marina Serna

    (Imperial College London, Sir Ernst Chain Building, South Kensington Campus, London SW7 2AZ, UK)

  • Joanna L. Giles

    (Institute of Infection and Immunity, School of Medicine, Cardiff University)

  • B. Paul Morgan

    (Institute of Infection and Immunity, School of Medicine, Cardiff University)

  • Doryen Bubeck

    (Imperial College London, Sir Ernst Chain Building, South Kensington Campus, London SW7 2AZ, UK)

Abstract

In response to complement activation, the membrane attack complex (MAC) assembles from fluid-phase proteins to form pores in lipid bilayers. MAC directly lyses pathogens by a ‘multi-hit’ mechanism; however, sublytic MAC pores on host cells activate signalling pathways. Previous studies have described the structures of individual MAC components and subcomplexes; however, the molecular details of its assembly and mechanism of action remain unresolved. Here we report the electron cryo-microscopy structure of human MAC at subnanometre resolution. Structural analyses define the stoichiometry of the complete pore and identify a network of interaction interfaces that determine its assembly mechanism. MAC adopts a ‘split-washer’ configuration, in contrast to the predicted closed ring observed for perforin and cholesterol-dependent cytolysins. Assembly precursors partially penetrate the lipid bilayer, resulting in an irregular β-barrel pore. Our results demonstrate how differences in symmetric and asymmetric components of the MAC underpin a molecular basis for pore formation and suggest a mechanism of action that extends beyond membrane penetration.

Suggested Citation

  • Marina Serna & Joanna L. Giles & B. Paul Morgan & Doryen Bubeck, 2016. "Structural basis of complement membrane attack complex formation," Nature Communications, Nature, vol. 7(1), pages 1-7, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10587
    DOI: 10.1038/ncomms10587
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    Cited by:

    1. Emma C. Couves & Scott Gardner & Tomas B. Voisin & Jasmine K. Bickel & Phillip J. Stansfeld & Edward W. Tate & Doryen Bubeck, 2023. "Structural basis for membrane attack complex inhibition by CD59," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Anaïs Menny & Marie V. Lukassen & Emma C. Couves & Vojtech Franc & Albert J. R. Heck & Doryen Bubeck, 2021. "Structural basis of soluble membrane attack complex packaging for clearance," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    3. Fang Jiao & François Dehez & Tao Ni & Xiulian Yu & Jeremy S. Dittman & Robert Gilbert & Christophe Chipot & Simon Scheuring, 2022. "Perforin-2 clockwise hand-over-hand pre-pore to pore transition mechanism," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    4. Sunita Gulati & Frank J Beurskens & Bart-Jan de Kreuk & Marcel Roza & Bo Zheng & Rosane B DeOliveira & Jutamas Shaughnessy & Nancy A Nowak & Ronald P Taylor & Marina Botto & Xianbao He & Robin R Ingal, 2019. "Complement alone drives efficacy of a chimeric antigonococcal monoclonal antibody," PLOS Biology, Public Library of Science, vol. 17(6), pages 1-29, June.

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