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

Parsons, ES; Stanley, GJ; Pyne, ALB; Hodel, AW; Nievergelt, AP; Menny, A; Yon, AR; ... Hoogenboom, BW; + view all (2019) Single-molecule kinetics of pore assembly by the membrane attack complex. Nature Communications , 10 , Article 2066. 10.1038/s41467-019-10058-7. Green open access

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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.

Type: Article
Title: Single-molecule kinetics of pore assembly by the membrane attack complex
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41467-019-10058-7
Publisher version: https://doi.org/10.1038/s41467-019-10058-7
Language: English
Additional information: © The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/).
Keywords: Atomic force microscopy, Biological physics, Complement cascade, Reaction kinetics and dynamics, Nanoscale biophysics
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Physics and Astronomy
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > London Centre for Nanotechnology
URI: http://discovery.ucl.ac.uk/id/eprint/10073769
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