サイトクロームcとdATPに依存するApaf-1/caspase-9複合体の形成は,アポプトティックプロテアースカスケードを開始する

P Li¹, D Nijhawan, I Budihardjo

¹Howard Hughes Medical Institute, and Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, 75235, USA.

Cell

|December 9, 1997

まとめ

この研究では,カスパース-9がアポトーシスのカスケードにおける重要なタンパク質であることを確認した. カスパース3を活性化し,シトクロームcとdATPによって誘発されたプログラム細胞死を開始します.

科学分野:

バイオケミストリーバイオケミストリー
分子生物学は分子生物学である.
細胞生物学細胞生物学

背景:

カスパース3の活性化は,プログラム細胞死 (アポプトシス) の重要なステップです.
いくつかのタンパク質因子が,このプロセスに参加することが知られている.
カスパース-3の正確な上流アクティベーターは,完全に解明されていません.

研究の目的:

カスパース3の活性化に関与するタンパク質因子を特定し,特徴づけること.
カスパーゼ3の活性化経路におけるApaf-3の役割を明らかにする.
アポプトティックプロテアゼカスケードの上流成分を決定する.

主な方法:

Apaf-3を分離するためにタンパク質を浄化する.
タンパク質とタンパク質の相互作用と酵素の活性化を研究するためのインビトロアッセイ.
S-100抽出物と体内での枯渇と変異の研究.
カスパース活性化と細胞のアポプトシス反応の分析.

主要な成果:

Apaf-3はcaspase-9.9として特定されました.
Caspase-9とApaf-1は,CED-3の同類ドメインを介して結合し,シトクロームcとdATPの存在下でcaspase-9の活性化につながります.
活性化されたカスパース-9はカスパース-3を割って活性化します.
カスパース-9の枯渇または変異は,カスパース-3の活性化と vivo のアポプトシス反応を著しく低下させる.

結論:

カスパース-9は,サイトクロームc/dATP誘発のアポプトシスプロテアースカスケードで確認された最も上流のタンパク質因子です.
カスパゼ9は,カスパゼ3を直接活性化させ,アポトーシスの開始に重要な役割を果たします.
この発見は,アポトーシスの本質的な経路における重要な規制ステップを明確にします.

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