EGF受容体触媒ドメインの活性化メカニズムは,柔膜セグメントによるものです
Natalia Jura1, Nicholas F Endres, Kate Engel
1Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
Cell
|July 1, 2009
まとめ
Epidermal成長因子受容体 (EGFR) のシグナル伝達は,キナーゼドメインの二分化に依存しています. 柔膜セグメントは,この二分化を促進し,リガンド結合時に受容体の活性化を可能にします.
科学分野:
- セルラー・シグナリング
- 分子生物学は分子生物学である.
- バイオケミストリー バイオケミストリー
背景:
- 皮膚表皮成長因子受容体 (EGFR) のシグナル伝達は,細胞プロセスにとって極めて重要です.
- EGFRの活性化には,2つの受容体のキナーゼドメイン間のアロステリック相互作用が必要です.
- EGFRの柔膜セグメントは,キナーゼ活性を増強することが知られている.
研究 の 目的:
- EGFRキナーゼドメインの二分化と活性化におけるジュクスタムブランセグメントの役割を明らかにする.
- EGFRシグナリングの基礎となる構造的メカニズムを理解する.
- リンガンド結合がEGFRの二分化と活性化をどのように調節するかを調査する.
主な方法:
- EGFRキナーゼドメインと柔膜セグメントの構造分析.
- バイオケミカルアッセイで受容体二酸化とキナーゼ活性について研究する.
- ミュタゲネーシス研究で,ダイメリゼーションとアクティベーションに関与する主要な残基を特定する.
主要な成果:
- EGFRの細胞内柔膜セグメントはキナーゼドメインを二酸化する.
- 柔性膜セグメントのC端の半分は,アクティベータと活性化キナーゼドメインを接続するラッチとして作用します.
- 柔膜セグメントのN端の半分は,潜在的に反並列の螺旋型ジマー経膜ヘリクを巻き込む経膜ジマー経由で二分化を促進します.
- 細胞外ドメインは通常,二分化をブロックし,リガンド結合によりこのブロックが放出されます.
- C末端の尾は,不活性ジマーにおける活性化ジクスタメンブレーンラッチの形成を防止し,リガンド独立活性化を阻害する.
結論:
- 柔膜セグメントはEGFRキナーゼドメインの二分化と活性化を媒介する上で重要な役割を果たします.
- 細胞外ドメインへのリガンド結合は阻害を解放し,柔膜媒介の二分化とシグナリングを可能にします.
- 柔膜セグメントとC端尾を含む構造的メカニズムは,EGFRの活動を調節し,異常信号伝達を防止します.
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