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PreprintCited by 86Complement system in diseasesLipid Membrane Structure and BehaviorBiomarkers in Disease Mechanisms

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Structural basis for membrane attack complex inhibition by CD59

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Couves, Emma C., Gardner, Scott, Voisin, Tomas B., Bickel, Jasmine K., Stansfeld, Phillip J., Tate, Edward W., Bubeck, Doryen·2022·Nature Communications
DOI 10.1101/2022.09.05.506672PMC PMC9935631

Preprint — published as 10.1038/s41467-023-36441-z · Paper page

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Abstract

CD59 is an abundant immuno-regulatory receptor that protects human cells from damage during complement activation. Here we show how the receptor binds complement proteins C8 and C9 at the membrane to prevent insertion and polymerization of membrane attack complex (MAC) pores. We present cryoelectron microscopy structures of two inhibited MAC precursors known as C5b8 and C5b9. We discover that in both complexes, CD59 binds the pore-forming ◻-hairpins of C8 to form an intermolecular ◻-sheet that prevents membrane perforation. While bound to C8, CD59 deflects the cascading C9 ◻-hairpins, rerouting their trajectory into the membrane. Preventing insertion of C9 restricts structural transitions of subsequent monomers and indirectly halts MAC polymerization. We combine our structural data with cellular assays and molecular dynamics simulations to explain how the membrane environment impacts the dual roles of CD59 in controlling pore formation of MAC, and as a target of bacterial virulence factors which hijack CD59 to lyse human cells.

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Metadata

Authors
Couves, E. C., Gardner, S., Voisin, T. B., Bickel, J. K., Stansfeld, P. J., Tate, E. W., & Bubeck, D.
Affiliations
  • Imperial College London (GB)
  • University of Warwick (GB)
Corresponding author
Bubeck, Doryen
ORCID
Venue
Nature Communications
Publisher
openRxiv
Published
2022-09-05
Volume
14
Issue
1
Pages
890-890
ISSN
2041-1723 (ISSN-L)
DOI
10.1101/2022.09.05.506672
PMC
PMC9935631
OpenAlex
W4321078922
Cited by
86
References
1
Citations by year
2026: 30 · 2025: 35 · 2024: 15 · 2023: 6
FWCI
9.34
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Warwick Research Archive Portal (University of Warwick) (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Spiral (Imperial College London) (submittedVersion, other-oa)
  • Spiral (Imperial College London) (submittedVersion, cc-by-nc-nd)
Funders
  • Wellcome Trust (BB/S003339/1, Z/17/Z, 208361, 208361/Z/17/Z)
  • Francis Crick Institute
  • Diamond Light Source
  • Cancer Research UK (864751, EP/L015498/1, C24523/A26234, EP/R029407/1, A26234, C24523, BB/M011178/1)
  • Imperial College London (BB/M011178/1, A26234)
  • European Commission (HORIZON2020)
  • Medical Research Council (MR/S009213/1)
  • Engineering and Physical Sciences Research Council (EP/R029407/2, 864751, EP/R029407/1, R029407, EP/R029407, 1364172, BB/M011178/1, C24523/A26234, EP/L015498/1)
  • Biotechnology and Biological Sciences Research Council (BB/M011178/1, EP/R029407/1, C24523/A26234, BB/S003339/1, BB/P01948X/1, BB/P01948X/2, P01948X, R002517, S003339, EP/L015498/1, 864751, BB/R002517/1)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
  • Life Sciences › Immunology and Microbiology › Immunology › Biomarkers in Disease Mechanisms
Keywords
CD59, membrane attack complex, complement regulation, perfluorooctanoic acid, C9, beta-hairpin, intermolecular beta-sheet, membrane perforation, bacterial virulence factors, complement receptors, cryo-EM structure
MeSH terms
Complement Activation, Complement C8, Complement C9, Humans, Complement Membrane Attack Complex, CD59 Antigens, Cryoelectron Microscopy

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