mTORC1をリソソーム表面にドッキングするための構造的基礎
Kacper B Rogala1,2,3,4,5, Xin Gu1,2,3,4,5, Jibril F Kedir1,2,3,4,5
1Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
まとめ
ラパミシン複合体1 (mTORC1) タンパク質キナーゼの機械的標的
科学分野:
- 細胞生物学
- 分子生物学
- 生物化学
背景:
- ラパミシン複合体1 (mTORC1) のメカニズム的標的は,細胞成長の重要な調節剤である.
- mTORC1の活動は,栄養素と成長因子によって制御され,リゾソームへの局所化に影響されます.
- Rag GTPase-Regulator複合体は,栄養に依存するmTORC1をリソソームに誘導する.
研究 の 目的:
- Rag GTPase-Regulator複合体とのmTORC1相互作用の構造的基礎を解明する.
- 栄養素の利用がmTORC1の局所化と活性化にどのように影響するかを理解する.
- 溶解体表面での活性mTORC1の構造モデルを提供する.
主な方法:
- クリオ電子顕微鏡 (cryo-EM) を用いて,ラプター・ラグ・ラグレーター超複合体の構造を決定した.
- Rag- Raptorの相互作用の機能的影響を評価するために,生化学的測定と変異分析が使用されました.
- mTORC1-Rheb複合体による比較構造分析が行われました.
主要な成果:
- 凍結-EM構造は,ラプターサブユニットとラグGTPasesの間の詳細な相互作用を明らかにし,ヌクレオチド感知機構を定義しました.
- ラプターはRagAとRagCのヌクレオチド結合状態を直接感知し,mTORC1の採用に不可欠です.
- ラグ・ラプター結合の障害は,mTORC1の溶解体局所化とシグナル伝達を阻害し,これらの相互作用の機能的重要性を確認した.
結論:
- この研究は,mTORC1-Rag-Regulator複合体の高解像度構造を提供し,mTORC1に栄養信号がどのように伝達されるかを明らかにしています.
- この発見は,mTORC1がリソソームに局所され活性化される分子機構を明らかにした.
- 構造的および機能的データを統合したリソソームにドッキングされた活性mTORC1のモデルが提案されました.
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