抑制ドメイン (TOROID) に組織されたTORC1は,TORC1の活動を調節する
Manoël Prouteau1,2, Ambroise Desfosses3, Christian Sieben4,5
1Department of Molecular Biology, University of Geneva, 30 quai Ernest-Ansermet, CH1211 Geneva, Switzerland.
Nature
|October 5, 2017
まとめ
酵母におけるラパミシン複合体1 (TORC1) の標的を迅速に無効化する. この無活性化には,Rag GTPasesによって調節される,TOROIDと呼ばれる高次元の螺旋構造を形成するTORC1が含まれます.
科学分野:
- 細胞生物学
- 分子生物学
- 生物化学
背景:
- ラパミシン (TOR) キナーゼの標的は,TORC1およびTORC2複合体を通して細胞の成長と代謝を調節する.
- GTPasesは,様々な信号への反応としてTORC1の活性に影響することが知られているが,その正確な役割は完全に理解されていない.
研究 の 目的:
- 発芽酵母におけるグルコース抽出中のGTPasesによるTORC1調節のメカニズムを調査する.
- TORC1不活性化の構造的基礎を明らかにする.
主な方法:
- 超解像度光学顕微鏡でTORC1の位置を確認する.
- TORC1アセンブリの構造を決定するための冷凍電子顕微鏡と3D復元.
- TORC1の組み立てと活動に影響を与えるTOR1アレルを作るための遺伝子操作.
主要な成果:
- グルコース離脱は,TORC1のRag GTPase依存の急速な再分配を,真空球に関連した円筒状の構造に誘導する.
- Cryo-EMはTORC1を空洞の螺旋状の集合体としてオリゴメライズし,TOROIDと呼ばれています.
- TORC1のオリゴメリゼーションは,活性部位をステリックに遮断し,不活性化につながります.
- TOROIDの形成を防ぐ特定のTOR1変異は,TORC1の不活性化も防止しました.
結論:
- TORC1の不活性化は,高級のTOROID構造に組み立てられることで媒介されます.
- Rag GTPasesは,このTORC1アセンブリと,その後の無活性化の重要なレギュレータです.
- タンパク質キナーゼを高次元の構造に逆転させることは,新しい調節メカニズムを表しています.
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