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Structural basis of soluble membrane attack complex packaging for clearance
DOI:
10.1038/s41467-021-26366-w
Authors:
Anais
Menny
(Imperial College London)
,
Marie V.
Lukassen
(Utrecht University; Netherlands Proteomics Center)
,
Emma C.
Couves
(Imperial College London)
,
Vojtech
Franc
(Utrecht University; Netherlands Proteomics Center)
,
Albert J. R.
Heck
(Utrecht University; Netherlands Proteomics Center)
,
Doryen
Bubeck
(Imperial College London)
Co-authored by industrial partner:
No
Type:
Journal Paper
Journal:
Nature Communications
, VOL 12
State:
Published (Approved)
Published:
October 2021
Diamond Proposal Number(s):
18659
Abstract: Unregulated complement activation causes inflammatory and immunological pathologies with consequences for human disease. To prevent bystander damage during an immune response, extracellular chaperones (clusterin and vitronectin) capture and clear soluble precursors to the membrane attack complex (sMAC). However, how these chaperones block further polymerization of MAC and prevent the complex from binding target membranes remains unclear. Here, we address that question by combining cryo electron microscopy (cryoEM) and cross-linking mass spectrometry (XL-MS) to solve the structure of sMAC. Together our data reveal how clusterin recognizes and inhibits polymerizing complement proteins by binding a negatively charged surface of sMAC. Furthermore, we show that the pore-forming C9 protein is trapped in an intermediate conformation whereby only one of its two transmembrane β-hairpins has unfurled. This structure provides molecular details for immune pore formation and helps explain a complement control mechanism that has potential implications for how cell clearance pathways mediate immune homeostasis.
Journal Keywords: Complement cascade; Cryoelectron microscopy; Mass spectrometry
Diamond Keywords: Alzheimer's Disease
Subject Areas:
Biology and Bio-materials
Diamond Offline Facilities:
Electron Bio-Imaging Centre (eBIC)
Instruments:
Krios I-Titan Krios I at Diamond
,
Krios II-Titan Krios II at Diamond
Added On:
25/10/2021 11:29
Documents:
s41467-021-26366-w.pdf
Discipline Tags:
Neurodegenerative Diseases
Non-Communicable Diseases
Health & Wellbeing
Neurology
Structural biology
Life Sciences & Biotech
Technical Tags:
Microscopy
Electron Microscopy (EM)
Cryo Electron Microscopy (Cryo EM)