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

Edward S. Parsons (), George J. Stanley, Alice L. B. Pyne, Adrian W. Hodel, Adrian P. Nievergelt, Anaïs Menny, Alexander R. Yon, Ashlea Rowley, Ralf P. Richter, Georg E. Fantner, Doryen Bubeck and Bart W. Hoogenboom ()
Additional contact information
Edward S. Parsons: University College London
George J. Stanley: University College London
Alice L. B. Pyne: University College London
Adrian W. Hodel: University College London
Adrian P. Nievergelt: Swiss Federal Institute of Technology Lausanne (EPFL)
Anaïs Menny: Imperial College London, South Kensington Campus
Alexander R. Yon: University College London
Ashlea Rowley: University of Leeds
Ralf P. Richter: University of Leeds
Georg E. Fantner: Swiss Federal Institute of Technology Lausanne (EPFL)
Doryen Bubeck: Imperial College London, South Kensington Campus
Bart W. Hoogenboom: University College London

Nature Communications, 2019, vol. 10, issue 1, 1-10

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10058-7

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