MEKは,KSRタンパク質のアロステリック制御を通じてBRAFの活性化を誘導する
Hugo Lavoie1, Malha Sahmi1, Pierre Maisonneuve2
1Institute for Research in Immunology and Cancer Laboratory of Intracellular Signaling Université de Montréal C.P. 6128, Succursale Centre-Ville Montréal, Québec H3C 3J7, Canada.
Nature
|February 13, 2018
まとめ
RAFキナーゼは癌に不可欠ですが その二分化が薬の開発を妨げます この研究は,BRAFとKSR1の間の新しい相互作用を明らかにし,RAFキナーゼの活性化とKSRへの挑戦のための新しいメカニズムを発見しました.
科学分野:
- 分子生物学
- 癌の研究
- 信号変換
背景:
- RAFファミリーキナーゼ (ARAF,BRAF,CRAF) とシドキナーゼ (KSR1,KSR2) は癌において重要な役割を果たしている.
- RAFキナーゼの活性化は二分化に依存し,薬物開発の課題です.
- KSRシドキナーゼはRAFとMEKを支えると考えられているが,その二分化調節は不明である.
研究 の 目的:
- RAFファミリーのメンバーとの KSR 偽キナーゼ ダイメリゼーションを規制する規制原則を明らかにする.
- BRAF-KSR1の異体化を媒介する特定の分子相互作用を特定する.
- KSR-MEK複合体がBRAFの触媒活動にどのように影響するかを理解する.
主な方法:
- 生物化学的測定を用いてタンパク質の相互作用を調査した.
- RAF- KSR1複合体の形成に関与する新しいタンパク質領域が特定されました.
- KSR1- MEK複合体によるBRAFキナーゼ活性のアロステリック調節を特徴づけた.
主要な成果:
- BRAFとKSR1の異体化が,BRAFのBRSドメインとKSR1のCC-SAMドメインを含むN端相互作用によって媒介されていることが発見されました.
- MEKがKSR1のキナーゼ領域に結合すると,BRAF-KSR1の異体化が起こることが示された.
- KSR-MEK複合体は,BRAFの触媒活動をアロステリックに刺激することが示された.
結論:
- BRAF-KSR1の異体化は,特定のN端接触とMEK結合によって制御される.
- KSR-MEK複合体は,BRAFをアロステリックに活性化し,KSRのエスカフォードのみの役割に異議を唱える.
- 発見はRAFキナーゼの調節と癌の潜在的な治療戦略に関する新しい洞察を提供します.
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