title: Structural basis of complement membrane attack complex formation.
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.
authors: Department of Life Sciences, Imperial College London, Sir Ernst Chain Building, South Kensington Campus, London SW7 2AZ, UK.
authors: Marina
authors: M
authors: Serna
authors: Institute of Infection and Immunity, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
authors: Joanna L
authors: JL
authors: Giles
authors: Institute of Infection and Immunity, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
authors: B Paul
authors: BP
authors: Morgan
authors: Department of Life Sciences, Imperial College London, Sir Ernst Chain Building, South Kensington Campus, London SW7 2AZ, UK.
authors: Doryen
authors: D
authors: Bubeck
mesh_terms: D002853:Chromatography, Liquid; D050776:Complement C5b / Q000648:ultrastructure*; D003183:Complement C6 / Q000648:ultrastructure*; D003184:Complement C7 / Q000648:ultrastructure*; D003185:Complement C8 / Q000648:ultrastructure*; D003186:Complement C9 / Q000648:ultrastructure*; D015938:Complement Membrane Attack Complex / Q000648:ultrastructure*; D020285:Cryoelectron Microscopy; D005456:Fluorescent Dyes; D006801:Humans; D007091:Image Processing, Computer-Assisted; D013058:Mass Spectrometry; D008854:Microscopy, Electron; D008958:Models, Molecular; D015394:Molecular Structure; D046912:Multiprotein Complexes / Q000648:ultrastructure*; D017433:Protein Structure, Secondary
chemical_list: D003183:Complement C6; D003184:Complement C7; D003185:Complement C8; D003186:Complement C9; D015938:Complement Membrane Attack Complex; D005456:Fluorescent Dyes; D046912:Multiprotein Complexes; D050776:Complement C5b