Engineering and Physical Sciences Research Council
EP/L015498/1
United Kingdom
Citation
Journal: Nat Commun / Year: 2021 Title: Structural basis of soluble membrane attack complex packaging for clearance. Authors: Anaïs Menny / Marie V Lukassen / Emma C Couves / Vojtech Franc / Albert J R Heck / Doryen Bubeck / Abstract: Unregulated complement activation causes inflammatory and immunological pathologies with consequences for human disease. To prevent bystander damage during an immune response, extracellular ...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.
History
Deposition
Mar 22, 2021
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Header (metadata) release
Oct 6, 2021
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Map release
Oct 6, 2021
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Update
Nov 17, 2021
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Current status
Nov 17, 2021
Processing site: PDBe / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
Name: 2C9-sMAC / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#7 Details: This sMAC oligomer contains one copy of C5b8 and 2 copies of C9, as well as multiple copies of the chaperones vitronectin and clusterin
Source (natural)
Organism: Homo sapiens (human)
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Experimental details
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Structure determination
Method
cryo EM
Processing
single particle reconstruction
Aggregation state
particle
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Sample preparation
Concentration
0.065 mg/mL
Buffer
pH: 7.4
Vitrification
Cryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 295 K / Instrument: FEI VITROBOT MARK III
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Electron microscopy
Microscope
FEI TITAN KRIOS
Image recording
Film or detector model: GATAN K2 QUANTUM (4k x 4k) / Detector mode: COUNTING / Average electron dose: 40.0 e/Å2
Electron beam
Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
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