Structural basis for membrane attack complex inhibition by CD59

DOI: 10.1038/s41467-023-36441-z

Authors: Emma C. Couves (Imperial College London) , Scott Gardner (Imperial College London) , Tomas B. Voisin (Imperial College London) , Jasmine K. Bickel (Imperial College London) , Phillip J. Stansfeld (University of Warwick) , Edward W. Tate (Imperial College London) , Doryen Bubeck (Imperial College London)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 14

State: Published (Approved)
Published: February 2023
Diamond Proposal Number(s): 25127

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 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.

Journal Keywords: Complement; Complement cascade; Cryoelectron microscopy; Immunology

Subject Areas: Biology and Bio-materials

Diamond Offline Facilities: Electron Bio-Imaging Centre (eBIC)
Instruments: Krios II-Titan Krios II at Diamond , Krios III-Titan Krios III at Diamond , Krios IV-Titan Krios IV at Diamond

Added On: 22/02/2023 09:54

Documents:
s41467-023-36441-z.pdf

Discipline Tags:

Health & Wellbeing Structural biology Life Sciences & Biotech

Technical Tags:

Microscopy Electron Microscopy (EM) Cryo Electron Microscopy (Cryo EM)