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RHEBによるmTORC1活性化とPRASによる抑制のメカニズム40

Haijuan Yang¹, Xiaolu Jiang^1,2, Buren Li¹

¹Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.

|December 14, 2017

まとめ

ラパミシン複合体1 (mTORC1) 構造のメカニズム的標的は,RHEB結合がキナーゼを活性化する方法と,がん変異がこの活性化を模倣する方法を示しています. これらの洞察は,mTORC1の基板選択と調節を説明する.

科学分野:

生物化学
構造生物学
細胞生物学

背景:

ラパミシン複合体1 (mTORC1) のメカニズム的標的は,細胞の成長と代謝の重要な調節剤である.
mTORC1の活動は,栄養素,エネルギー状態,成長因子によって調節されます.
主な成分にはmTORキナーゼ,RAPTOR,RHEB (活性化剤),PRAS40 (抑制剤) が含まれています.

研究の目的:

mTORC1の活性化と調節の基礎となる構造的メカニズムを解明する.
RHEBがmTORC1キナーゼをアロステリックに活性化させる役割を調査する.
PRAS40による基板認識と阻害のための構造的基礎を定義する.

主な方法:

クリオ電子顕微鏡 (cryo-EM) でmTORC1と活性化されたRHEB-mTORC1の構造を決定する.
RAPTOR-TOSモチーフ複合体,mTOR FRB基板複合体,mTOR-PRAS40複合体の構造を解明するためのX線結晶学.
バイオケミカルアッセイでキナーゼの活性と変異の影響を評価する

主要な成果:

RHEB-mTORC1の冷凍-EM構造は,RHEB結合がmTORキナーゼ活性部位をアロステリックに活性化する全体的な形状変化を誘導することを示しています.
がんに関連した変異は,不活性状態を維持する領域にマッピングされ,RHEB媒介の活性化を模倣することを示唆しました.
結晶構造はRAPTORによるTOSモチーフ認識を定義し,mTOR FRBドメインを通じて第2の基板採用メカニズムを特定しました.
PRAS40は,両方の基質集約部位を抑制することが示された.

結論:

構造的および生化学的なデータは,mTORC1が基質をどのように選択し,そのキナーゼ活性がどのように調節されるかを説明する.
この発見は,RHEBによるmTORC1の活性化とがん関連変異に関するメカニズム的な洞察を提供します.
これらの発見は,がんのような疾患におけるmTORC1の調節障害を理解するための基盤を提供します.

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