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Structural basis of soluble membrane attack complex packaging for clearance

DOI: 10.1038/s41467-021-26366-w DOI Help

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

Open Access Open Access

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:

Life Sciences & Biotech Health & Wellbeing Neurodegenerative Diseases Neurology Structural biology

Technical Tags:

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