細胞外領域による滑らかな調節の構造的基礎
Eamon F X Byrne1, Ria Sircar2, Paul S Miller1
1Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Nature
|July 21, 2016
まとめ
ヘッジホッグ (Hh) 経路
科学分野:
- 生物化学
- 分子生物学
- 構造生物学
背景:
- 発達信号はFrizzledクラスのGタンパク質結合受容体 (GPCR) によって変換される.
- 大きな細胞外ドメインによるGPCR信号の調節は不明である.
- Smoothened (SMO) はHh経路トランスデューサーであり,オンコタンパク質GPCRである.
研究 の 目的:
- SMOの活性化と調節の構造的メカニズムを解明する.
- 細胞外ドメインがGPCRにおけるトランスメブランシグナル伝達にどのように影響するかを理解する.
主な方法:
- SMO構造を決定するX線結晶学.
- 機能的なインターフェースを検出するための構造誘導型変異.
- Hh信号とコレステロール結合を評価する生化学的測定法
主要な成果:
- 結晶構造は,トランスメブラン領域 (TMD) とシステイン豊富な領域 (CRD) での異なるリガンド結合部位を持つSMOを明らかにした.
- コレステロール分子がCRD部位に結合し,Hh信号伝達に不可欠であることが判明した.
- アンタゴニストがTMDに結合すると,CRD- リンカー- TMDインターフェースとコレステロール結合に影響を与える形状の変化が生じる.
結論:
- GPCRの活動は,細胞外と膜外ドメイン間のリガンド誘発相互作用によって調節される.
- コレステロールがCRDに結合することは,SMOを通じてHh経路のシグナル伝達に不可欠です.
- CRD,リンク,およびTMDインターフェースは,SMOの非アクティブ状態を安定させます.
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