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

Autor: Parsons ES; London Centre for Nanotechnology, University College London, London, WC1H 0AH, UK. e.parsons@ucl.ac.uk., Stanley GJ; London Centre for Nanotechnology, University College London, London, WC1H 0AH, UK., Pyne ALB; London Centre for Nanotechnology, University College London, London, WC1H 0AH, UK., Hodel AW; London Centre for Nanotechnology, University College London, London, WC1H 0AH, UK.; Institute of Structural and Molecular Biology, University College London, London, WC1E 6BT, UK., Nievergelt AP; Laboratory for Bio- and Nano-Instrumentation, Swiss Federal Institute of Technology Lausanne (EPFL), 1015, Lausanne, Switzerland., Menny A; Department of Life Sciences, Imperial College London, South Kensington Campus, London, SW7 2AZ, UK., Yon AR; London Centre for Nanotechnology, University College London, London, WC1H 0AH, UK.; Institute of Structural and Molecular Biology, University College London, London, WC1E 6BT, UK., Rowley A; School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK., Richter RP; School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK.; School of Physics and Astronomy, Faculty of Mathematics and Physical Sciences, University of Leeds, Leeds, LS2 9JT, UK.; Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK., Fantner GE; Laboratory for Bio- and Nano-Instrumentation, Swiss Federal Institute of Technology Lausanne (EPFL), 1015, Lausanne, Switzerland., Bubeck D; Department of Life Sciences, Imperial College London, South Kensington Campus, London, SW7 2AZ, UK., Hoogenboom BW; London Centre for Nanotechnology, University College London, London, WC1H 0AH, UK. b.hoogenboom@ucl.ac.uk.; Institute of Structural and Molecular Biology, University College London, London, WC1E 6BT, UK. b.hoogenboom@ucl.ac.uk.; Department of Physics and Astronomy, University College London, London, WC1E 6BT, UK. b.hoogenboom@ucl.ac.uk.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2019 May 06; Vol. 10 (1), pp. 2066. Date of Electronic Publication: 2019 May 06.
DOI: 10.1038/s41467-019-10058-7
Abstrakt: 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.
Databáze: MEDLINE