Serna, Marina, Giles, Joanna L., Morgan, Bryan Paul  ORCID: https://orcid.org/0000-0003-4075-7676 and Bubeck, Doryen
2016.
Structural basis of complement membrane attack complex formation.
Nature Communications
7
, 10587.
10.1038/ncomms10587
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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.
| Item Type: | Article |
|---|---|
| Date Type: | Published Online |
| Status: | Published |
| Schools: | Schools > Medicine |
| Publisher: | Nature Publishing Group |
| ISSN: | 2041-1723 |
| Date of First Compliant Deposit: | 5 July 2017 |
| Date of Acceptance: | 31 December 2015 |
| Last Modified: | 05 May 2023 07:32 |
| URI: | https://orca.cardiff.ac.uk/id/eprint/102068 |
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