TBK1によるSTING結合とリン酸化の構造的基礎
Conggang Zhang1, Guijun Shang2, Xiang Gui1
1Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Nature
|March 8, 2019
まとめ
細胞質DNAが cGAS-STING経路を誘発する この研究は,cGAMPに結合したSTINGがTBK1キナーゼを活性化する方法を示し,STINGのリン酸化と免疫反応のためにタンパク質のオリゴメリゼーションを必要とします.
科学分野:
- 免疫学
- 分子生物学
- 構造生物学
背景:
- 細胞質DNAの侵入は 危険を警告し 宿主の免疫を cGAS-STING経路で活性化する
- サイクルGMP- AMP合成酶 (cGAS) はDNAを感知し,インターフェロン遺伝子の刺激剤 (STING) を活性化するためにサイクルGMP- AMP (cGAMP) を生成します.
- 活性化されたSTINGはTBK1キナーゼを誘導し,IRF3のリン酸化とI型インターフェロン誘導につながりますが,活性化メカニズムは不明です.
研究 の 目的:
- cGAMPに結合したSTINGがTBK1キナーゼを活性化する構造的メカニズムを解明する.
- STINGがTBK1によってリン酸化され,下流の免疫シグナル伝達を開始する方法を理解する.
主な方法:
- クリオ電子顕微鏡 (cryo-EM) で,cGAMP結合STINGと複合したヒトTBK1の構造を決定する.
- 提案された相互作用モデルを検証するための変異分析.
主要な成果:
- 凍結EM構造はSTINGのC端尾が TBK1ダイマー内の溝に入っていることを示しています
- この結合モードは,TBK1の活性部位によるSTINGの直接のリン酸化を防止し,オリゴメリゼーションの必要性を示唆する.
- 変異データは,cGAMPがSTINGとTBK1のオリゴメリゼーションを誘導し,STINGのリン酸化を促進するモデルを支持する.
結論:
- TBK1によるSTINGのリン酸化は,cGAMP結合によって誘発される両方のタンパク質のオリゴメリゼーションに依存する.
- この構造的な洞察は,cGAS-STINGの先天的な免疫信号伝達経路の重要なステップを明確にします.
- この発見はDNAによる免疫活性化を 理解するためのメカニズム的基礎を提供する.
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