Engineering and Physical Sciences Research Council
EP/L015498/1
英国
引用
ジャーナル: Nat Commun / 年: 2021 タイトル: Structural basis of soluble membrane attack complex packaging for clearance. 著者: Anaïs Menny / Marie V Lukassen / Emma C Couves / Vojtech Franc / Albert J R Heck / Doryen Bubeck / 要旨: 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.
名称: 3C9-sMAC / タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: #1-#9 詳細: This sMAC oligomer contains one copy of C5b8 and 3 copies of C9, as well as multiple copies of the chaperones vitronectin and clusterin
由来(天然)
生物種: Homo sapiens (ヒト)
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実験情報
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構造解析
手法
クライオ電子顕微鏡法
解析
単粒子再構成法
試料の集合状態
particle
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試料調製
濃度
0.065 mg/mL
緩衝液
pH: 7.4
凍結
凍結剤: ETHANE / チャンバー内湿度: 95 % / チャンバー内温度: 295 K / 装置: FEI VITROBOT MARK III