Structural basis for membrane attack complex inhibition by CD59.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
16 02 2023
16 02 2023
Historique:
received:
19
10
2022
accepted:
01
02
2023
entrez:
16
2
2023
pubmed:
17
2
2023
medline:
22
2
2023
Statut:
epublish
Résumé
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 cryo-electron microscopy structures of two inhibited MAC precursors known as C5b8 and C5b9. We discover that in both complexes, CD59 binds the pore-forming β-hairpins of C8 to form an intermolecular β-sheet that prevents membrane perforation. While bound to C8, CD59 deflects the cascading C9 β-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.
Identifiants
pubmed: 36797260
doi: 10.1038/s41467-023-36441-z
pii: 10.1038/s41467-023-36441-z
pmc: PMC9935631
doi:
Substances chimiques
Complement Membrane Attack Complex
0
Complement C9
0
CD59 Antigens
0
Complement C8
0
CD59 protein, human
101754-01-2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
890Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
Pays : United Kingdom
Informations de copyright
© 2023. The Author(s).
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