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Structural basis of complement membrane attack complex formation

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Title: Structural basis of complement membrane attack complex formation
Authors: Serna Gil, M
Bubeck, D
Giles, JL
Morgan, BP
Item Type: Journal Article
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.
Issue Date: 4-Feb-2016
Date of Acceptance: 31-Dec-2015
URI: http://hdl.handle.net/10044/1/29239
DOI: 10.1038/ncomms10587
ISSN: 2041-1723
Publisher: Nature Publishing Group
Start Page: 1
End Page: 7
Journal / Book Title: Nature Communications
Volume: 7
Copyright Statement: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Sponsor/Funder: Cancer Research UK
Royal Society
Funder's Grant Number: 16099
RG140240
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
PARTICLE ELECTRON CRYOMICROSCOPY
PORE FORMATION
CRYO-EM
MICROSCOPY
MECHANISM
BINDING
REVEALS
MODULES
DOMAIN
C5B-8
Chromatography, Liquid
Complement C5b
Complement C6
Complement C7
Complement C8
Complement C9
Complement Membrane Attack Complex
Cryoelectron Microscopy
Fluorescent Dyes
Humans
Image Processing, Computer-Assisted
Mass Spectrometry
Microscopy, Electron
Models, Molecular
Molecular Structure
Multiprotein Complexes
Protein Structure, Secondary
Humans
Multiprotein Complexes
Complement Membrane Attack Complex
Fluorescent Dyes
Microscopy, Electron
Cryoelectron Microscopy
Chromatography, Liquid
Molecular Structure
Protein Structure, Secondary
Models, Molecular
Image Processing, Computer-Assisted
Complement C6
Complement C7
Complement C8
Complement C9
Complement C5b
Mass Spectrometry
Publication Status: Published
Article Number: 10587
Online Publication Date: 2016-02-04
Appears in Collections:Faculty of Natural Sciences