カルモジュリンによる心臓リアノジン受容体2の調節
Deshun Gong1, Ximin Chi2, Jinhong Wei3
1Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China. gds13@tsinghua.org.cn.
Nature
|July 7, 2019
まとめ
カルモジュリン (CaM) のRyR2カルシウムチャネルへの結合は,Ca2+レベルに依存する. このCa2+依存のCaM結合はRyR2構造を変化させ,心筋の刺激-収縮結合に影響する.
科学分野:
- 構造生物学
- 分子心臓科
- イオンチャネル規制
背景:
- ライオジン受容体2 (RyR2) は,重要な高伝導性細胞内カルシウムチャネルである.
- RyR2は心筋の刺激-収縮結合を媒介する.
- カルモジュリン (CaM) は,RyR2活動のCa2+依存型変調剤として知られています.
研究 の 目的:
- CaMによるRyR2調節の構造的メカニズムを解明する.
- Ca2+依存のCaM結合がRyR2チャネルゲーティングにどのように影響するかを理解する.
主な方法:
- 豚のRyR2とヒトのCaMの構造を8つの異なる条件で決定した.
- 構造を決定するために,冷凍電子顕微鏡 (冷凍EM) またはX線結晶学を使用した.
主要な成果:
- RyR2でアポ-CaMとCa2+-CaMの結合部位が異なるが重なり合っている.
- RyR2ではなくCaMへのCa2+結合がCaM結合部位のシフトを決定することを示した.
- 特定のRyR2活性化状態における孔の閉塞につながるCa2+-CaM誘発の構造変化 (PCB95,Ca2+-活性化) を観察した.
結論:
- Ca2+-CaM結合は,RyR2の中央ドメインの重要な形状変化を誘導し,孔の閉塞につながります.
- RyR2の孔は,ATP,カフェイン,およびCa2+の活性化下で,Ca2+-CaMが存在する場合でも開いている.
- Ca2+-CaMは,RyR2チャネルのゲートダイナミクスを影響する複数の競合するモデュレータの1つとして機能します.
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