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CryoEM reveals how the complement membrane attack complex ruptures lipid bilayers

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Title: CryoEM reveals how the complement membrane attack complex ruptures lipid bilayers
Authors: Menny, A
Serna, M
Boyd, C
Gardner, S
Joseph, AP
Morgan, BP
Topf, M
Brooks, NJ
Bubeck, D
Item Type: Journal Article
Abstract: The membrane attack complex (MAC) is one of the immune system’s first responders. Complement proteins assemble on target membranes to form pores that lyse pathogens and impact tissue homeostasis of self-cells. How MAC disrupts the membrane barrier remains unclear. Here we use electron cryo-microscopy and flicker spectroscopy to show that MAC interacts with lipid bilayers in two distinct ways. Whereas C6 and C7 associate with the outer leaflet and reduce the energy for membrane bending, C8 and C9 traverse the bilayer increasing membrane rigidity. CryoEM reconstructions reveal plasticity of the MAC pore and demonstrate how C5b6 acts as a platform, directing assembly of a giant β-barrel whose structure is supported by a glycan scaffold. Our work provides a structural basis for understanding how β-pore forming proteins breach the membrane and reveals a mechanism for how MAC kills pathogens and regulates cell functions.
Issue Date: 14-Dec-2018
Date of Acceptance: 12-Nov-2018
URI: http://hdl.handle.net/10044/1/66336
DOI: 10.1038/s41467-018-07653-5
ISSN: 2041-1723
Publisher: Nature Publishing Group
Journal / Book Title: Nature Communications
Volume: 9
Copyright Statement: © The Author(s) 2018. This article is licensed under a Creative CommonsAttribution 4.0 International License, which permits use, sharing,adaptation, distribution and reproduction in any medium or format, as long as you giveappropriate credit to the original author(s) and the source, provide a link to the CreativeCommons license, and indicate if changes were made. The images or other third partymaterial in this article are included in the article’s Creative Commons license, unlessindicated otherwise in a credit line to the material. If material is not included in thearticle’s Creative Commons license and your intended use is not permitted by statutoryregulation or exceeds the permitted use, you will need to obtain permission directly fromthe copyright holder. To view a copy of this license, visithttp://creativecommons.org/licenses/by/4.0/
Sponsor/Funder: Cancer Research UK
Wellcome Trust
Engineering & Physical Science Research Council (EPSRC)
Funder's Grant Number: 16099
212938/Z/18/Z
EP/J017566/1
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
CHOLESTEROL-DEPENDENT CYTOLYSIN
STRUCTURAL BASIS
EM STRUCTURE
INSERTION
C9
COMPONENT
CELL
REFINEMENT
MECHANISM
CD59
Complement C6
Complement C7
Complement C8
Complement C9
Complement Membrane Attack Complex
Cryoelectron Microscopy
Humans
Image Processing, Computer-Assisted
Lipid Bilayers
Liposomes
Models, Molecular
Polysaccharides
Protein Conformation
Protein Interaction Domains and Motifs
Spectrum Analysis
Humans
Polysaccharides
Lipid Bilayers
Complement Membrane Attack Complex
Liposomes
Cryoelectron Microscopy
Spectrum Analysis
Protein Conformation
Models, Molecular
Image Processing, Computer-Assisted
Complement C6
Complement C7
Complement C8
Complement C9
Protein Interaction Domains and Motifs
Publication Status: Published
Article Number: ARTN 5316
Online Publication Date: 2018-12-14
Appears in Collections:Chemistry
Biological and Biophysical Chemistry
Faculty of Natural Sciences