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
Jul 24, 2024
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Current status
Jul 24, 2024
Processing site: PDBe / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
Protein or peptide: Complement component C8 beta chain
Protein or peptide: Complement component C8 alpha chain
Protein or peptide: Complement component C9
Protein or peptide: Complement component C7
Protein or peptide: Complement component C6
Protein or peptide: Complement component C8 gamma chain
Protein or peptide: Complement C5
Ligand: alpha-D-mannopyranose
Ligand: CALCIUM ION
Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Ligand: alpha-L-fucopyranose
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Supramolecule #1: 2C9-sMAC
Supramolecule
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
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