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CryoEM reveals how the complement membrane attack complex ruptures lipid bilayers

DOI: 10.1038/s41467-018-07653-5 DOI Help

Authors: Anais Menny (Imperial College London) , Marina Serna (Imperial College London; Spanish National Cancer Research Centre) , Courtney N. Boyd (Imperial College London) , Scott Gardner (Imperial College London) , Agnel Praveen Joseph (Birkbeck, University of London) , B. Paul Morgan (Cardiff University) , Maya Topf (Birkbeck, University of London) , Nicholas J. Brooks (Imperial College London) , Doryen Bubeck (Imperial College London)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 9

State: Published (Approved)
Published: December 2018
Diamond Proposal Number(s): 19429 , 13304 , 16919 , 13893 , 12204 , 12388

Open Access Open Access

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.

Journal Keywords: Complement cascade; Cryoelectron microscopy

Subject Areas: Biology and Bio-materials

Diamond Offline Facilities: Electron Bio-Imaging Centre (eBIC)
Instruments: Krios I-Titan Krios I at Diamond , Krios II-Titan Krios II at Diamond

Documents:
s41467-018-07653-5.pdf