人間のCFTRイオンチャネルの分子構造
Fangyu Liu1, Zhe Zhang2, László Csanády3
1Laboratory of Membrane Biophysics and Biology, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA; Tri-Institutional Training Program in Chemical Biology, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
Cell
|March 25, 2017
まとめ
新しい冷凍-EM構造は,非酸化性システィック線維症トランスメブラン伝導性調節器 (CFTR) の開閉を阻害しています. この発見は,CFTRの説明に役立ちます.
科学分野:
- 構造生物学
- イオンチャンネル生理学
- 生物化学
背景:
- 胞性線維症トランスメブラン伝導性調節器 (CFTR) は,ユニークなイオンチャネル機能を持つATP結合カセット (ABC) トランスポーターである.
- CFTRの構造を理解することは,そのゲートメカニズムを明らかにし,治療法を開発するために不可欠です.
研究 の 目的:
- 人体CFTRの高解像度構造を決定する.
- CFTRチャネル活動を調節する構造的特徴を特定する.
- 構造と運動に基づいたCFTR活性化メカニズムを提案する.
主な方法:
- 電子冷凍顕微鏡 (cryo-EM) を用いて,非酸化ヒトCFTRの3. 9 Å構造を決定した.
- 斑馬魚のCFTRと他のABCトランスポーター (例えばMRP1) との比較が行われました.
- CFTR電流活性化運動のシグモイド時間経過の分析
主要な成果:
- ヒトCFTRの3. 9 Åの冷凍-EM構造が得られた.
- 以前解明されていないRドメインのヘリックスが 細胞内前庭にドッキングされ,チャネルが開くのを防ぎました.
- 超膜ヘリックス8におけるユニークなヘリックス・ループの移行は,CFTRを他のABCトランスポーターと区別する.
結論:
- ドッキングされたRドメインのヘリクスは,非酸化CFTRの閉じた状態を説明します.
- PKAのリン酸化は,Rドメインの解約を容易にし,チャネル開通を可能にします.
- TM8におけるヘリックスループの移行は,CFTRのイオンチャネル機能の構造的基礎として提案されている.
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