Structural basis of complement membrane attack complex formation

Nat Commun. 2016 Feb 4;7:10587. doi: 10.1038/ncomms10587.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • Complement C6
  • Complement C7
  • Complement C8
  • Complement C9
  • Complement Membrane Attack Complex
  • Fluorescent Dyes
  • Multiprotein Complexes
  • Complement C5b