ライソソーマル・フォリキュリン複合体によるRag GTPase活性化チェックポイントの構造機構
Rosalie E Lawrence1,2, Simon A Fromm1, Yangxue Fu1
1Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720, USA.
まとめ
mTORC1のシグナル伝達を調節する. 溶解体機能は,冷凍-EMによって明らかにされ,溶解体生殖を制御するチェックポイントとして機能する.
科学分野:
- 細胞生物学
- 分子生物学
- 生物化学
背景:
- mTORC1のシグナル伝達には,腫瘍抑制ホルモン (FLCN) が不可欠である.
- FLCNは,mTORC1の重要な調節体であるRagCに対して,グアノシントリフォスファターゼ (GTPase) 活性化タンパク質 (GAP) の活性を示している.
- 飢餓の間,FLCNは細胞溶液からリゾソームに移動し,リゾソーム機能の役割を示唆する.
研究 の 目的:
- FLCNのリゾソーム的機能を解明するために,ヒトリゾソームのFLCN複合体 (LFC) の構造を決定する.
- FLCNのGAP活性が溶解体環境内でどのように調節されているかを理解する.
- mTORC1シグナル伝達とリソソーム生物生成の制御におけるLFCの役割を調査する.
主な方法:
- FLCN,FNIP2,RagAGDP:RagCGTP,およびラグレーター複合体を含むヒトのリゾソーム性FLCN複合体 (LFC) の再構成
- LFCの冷凍電子顕微鏡 (cryo-EM) 構造を3.6アングストームの解像度で決定する.
- 再構成されたLFC内のFLCNのRagC-GAP活性に関する分析
主要な成果:
- FLCNのRagC-GAP活動は,触媒アルギニンの残留物のステリック阻害により,LFC内で抑制されていることが,冷凍-EM構造によって明らかになった.
- LFCを分解すると,FLCNのGAP活動が解放されます.
- この調節されたGAP活動は,リゾソーム生物生成の主調節因子であるmTORC1依存の調節に影響を与えます.
結論:
- 溶解体FLCN複合体 (LFC) は,mTORC1のシグナル伝達における重要なチェックポイントとして機能する.
- LFC内のFLCNの阻害状態は,栄養不足中にmTORC1の早期活性化を防ぐ.
- LFCの制御された分解は,細胞のシグナルに反応して,リゾソームの生体生成を適切に制御することを可能にします.
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