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Nat Commun ; 7: 10587, 2016 Feb 04.
Article in English | MEDLINE | ID: mdl-26841837

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 ß-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.


Subject(s)
Complement C5b/ultrastructure , Complement C6/ultrastructure , Complement C7/ultrastructure , Complement C8/ultrastructure , Complement C9/ultrastructure , Complement Membrane Attack Complex/ultrastructure , Multiprotein Complexes/ultrastructure , Chromatography, Liquid , Cryoelectron Microscopy , Fluorescent Dyes , Humans , Image Processing, Computer-Assisted , Mass Spectrometry , Microscopy, Electron , Models, Molecular , Molecular Structure , Protein Structure, Secondary
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