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CryoEM reveals how the complement membrane attack complex ruptures lipid bilayers

Author

Listed:
  • Anaïs Menny

    (Sir Ernst Chain Building, Imperial College London)

  • Marina Serna

    (Sir Ernst Chain Building, Imperial College London
    Spanish National Cancer Research Centre, CNIO, Melchor Fernández Almagro)

  • Courtney M. Boyd

    (Sir Ernst Chain Building, Imperial College London)

  • Scott Gardner

    (Sir Ernst Chain Building, Imperial College London)

  • Agnel Praveen Joseph

    (Birkbeck, University of London
    Science and Technology Facilities Council, Research Complex at Harwell)

  • B. Paul Morgan

    (Cardiff University, Heath Park)

  • Maya Topf

    (Birkbeck, University of London)

  • Nicholas J. Brooks

    (Imperial College London)

  • Doryen Bubeck

    (Sir Ernst Chain Building, Imperial College London)

Abstract

The membrane attack complex (MAC) is one of the immune system’s first responders. Complement proteins assemble on target membranes to form pores that lyse pathogens and impact tissue homeostasis of self-cells. How MAC disrupts the membrane barrier remains unclear. Here we use electron cryo-microscopy and flicker spectroscopy to show that MAC interacts with lipid bilayers in two distinct ways. Whereas C6 and C7 associate with the outer leaflet and reduce the energy for membrane bending, C8 and C9 traverse the bilayer increasing membrane rigidity. CryoEM reconstructions reveal plasticity of the MAC pore and demonstrate how C5b6 acts as a platform, directing assembly of a giant β-barrel whose structure is supported by a glycan scaffold. Our work provides a structural basis for understanding how β-pore forming proteins breach the membrane and reveals a mechanism for how MAC kills pathogens and regulates cell functions.

Suggested Citation

  • Anaïs Menny & Marina Serna & Courtney M. Boyd & Scott Gardner & Agnel Praveen Joseph & B. Paul Morgan & Maya Topf & Nicholas J. Brooks & Doryen Bubeck, 2018. "CryoEM reveals how the complement membrane attack complex ruptures lipid bilayers," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07653-5
    DOI: 10.1038/s41467-018-07653-5
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    Cited by:

    1. Olivia J. S. Macleod & Alexander D. Cook & Helena Webb & Mandy Crow & Roisin Burns & Maria Redpath & Stefanie Seisenberger & Camilla E. Trevor & Lori Peacock & Angela Schwede & Nicola Kimblin & Amanda, 2022. "Invariant surface glycoprotein 65 of Trypanosoma brucei is a complement C3 receptor," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    2. 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.
    3. 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.
    4. Hagen Sülzen & Jakub Began & Arun Dhillon & Sami Kereïche & Petr Pompach & Jitka Votrubova & Farnaz Zahedifard & Adriana Šubrtova & Marie Šafner & Martin Hubalek & Maaike Thompson & Martin Zoltner & S, 2023. "Cryo-EM structures of Trypanosoma brucei gambiense ISG65 with human complement C3 and C3b and their roles in alternative pathway restriction," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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