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.
Original language | English |
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Article number | 10587 |
Pages (from-to) | 10587 |
Journal | Nature Communications |
Volume | 7 |
DOIs | |
Publication status | Published - 04 Feb 2016 |
Keywords
- Chromatography, Liquid
- Complement C5b/ultrastructure
- Complement C6/ultrastructure
- Complement C7/ultrastructure
- Complement C8/ultrastructure
- Complement C9/ultrastructure
- Complement Membrane Attack Complex/ultrastructure
- Cryoelectron Microscopy
- Fluorescent Dyes
- Humans
- Image Processing, Computer-Assisted
- Mass Spectrometry
- Microscopy, Electron
- Models, Molecular
- Molecular Structure
- Multiprotein Complexes/ultrastructure
- Protein Structure, Secondary