Structural basis of complement membrane attack complex formation

Marina Serna, Joanna L. Giles, B. Paul Morgan and Doryen Bubeck ()
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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

Nature Communications, 2016, vol. 7, issue 1, 1-7

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10587

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