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Single-molecule kinetics of pore assembly by the membrane attack complex

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Title: Single-molecule kinetics of pore assembly by the membrane attack complex
Authors: Parsons, E
Stanley, G
Pyne, A
Hodel, A
Nievergelt, A
Menny, A
Yon, A
Rowley, A
Richter, R
Fantner, G
Bubeck, D
Hoogenboom, B
Item Type: Journal Article
Abstract: The membrane attack complex (MAC) is a hetero-oligomeric protein assembly that kills pathogens by perforating their cell envelopes. The MAC is formed by sequential assembly of soluble complement proteins C5b, C6, C7, C8 and C9, but little is known about the rate-limiting steps in this process. Here, we use rapid atomic force microscopy (AFM) imaging to show that MAC proteins oligomerize within the membrane, unlike structurally homologous bacterial pore-forming toxins. C5b-7 interacts with the lipid bilayer prior to recruiting C8. We discover that incorporation of the first C9 is the kinetic bottleneck of MAC formation, after which rapid C9 oligomerization completes the pore. This defines the kinetic basis for MAC assembly and provides insight into how human cells are protected from bystander damage by the cell surface receptor CD59, which is offered a maximum temporal window to halt the assembly at the point of C9 insertion.
Issue Date: 6-May-2019
Date of Acceptance: 12-Apr-2019
URI: http://hdl.handle.net/10044/1/70218
DOI: 10.1038/s41467-019-10058-7
ISSN: 2041-1723
Publisher: Nature Research (part of Springer Nature)
Start Page: 1
End Page: 10
Journal / Book Title: Nature Communications
Volume: 10
Copyright Statement: © The Author(s) 2019. 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
Funder's Grant Number: 16099
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
QUARTZ-CRYSTAL MICROBALANCE
STRUCTURAL BASIS
LIPID-BILAYER
CHOLESTEROL
PERFORIN
CD59
C8
C9
VISUALIZATION
ACTIVATION
CD59 Antigens
Cell Membrane
Complement C5
Complement C8
Complement C9
Complement Membrane Attack Complex
Humans
Kinetics
Microscopy, Atomic Force
Protein Multimerization
Single Molecule Imaging
Cell Membrane
Humans
Complement Membrane Attack Complex
Microscopy, Atomic Force
Kinetics
Complement C5
Complement C8
Complement C9
Protein Multimerization
Single Molecule Imaging
CD59 Antigens
Publication Status: Published
Article Number: ARTN 2066
Online Publication Date: 2019-05-06
Appears in Collections:Faculty of Natural Sciences