人間によるSonic Hedgehogの認識のための構造的基礎
Xin Gong1, Hongwu Qian1, Pingping Cao1
1State Key Laboratory of Membrane Biology, Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.
Science (New York, N.Y.)
|June 30, 2018
まとめ
研究者は,Patched (Ptch1) 受容体の構造を単独で決定し,Sonic hedgehog (ShhN) に結合した. これは,発達と再生におけるヘッジホッグ経路の活性化に不可欠なステロイド依存の相互作用を明らかにします.
科学分野:
- 生物化学
- 構造生物学
- 発達生物学
背景:
- ヘッジホッグ (Hh) 経路は重要な発達と再生プロセスを制御する.
- Hh経路の活性化には,Hhリガンドに結合する膜受容体Patched (Ptch) が関与する.
研究 の 目的:
- ヒトPtch1の構造とソニック・ヘッジホッグのN端域 (ShhN) との複合体を決定することによって,Hh経路の活性化の構造的基礎を解明する.
主な方法:
- クリオ電子顕微鏡 (cryo-EM) を使用して,Ptch1の構造を単独で,ShhNとの複合体で高解像度で決定した.
- 特定された構造的特徴の機能的役割を調査するために,構造誘導型変異分析が採用されました.
主要な成果:
- 構造は,ステロール感知ドメイン (SSD) を形成する細胞外ドメイン (ECD1,ECD2) とトランスメブランセグメント (TM) を含むPtch1の構造を明らかにした.
- ステロイド状の2つの密度が観察された: ECD1/2内の1つ,SSD腔内の1つ,Ptch1機能におけるステロイドの役割を示唆する.
- 変異分析により,ShNとPtch1の相互作用はステロイド結合に依存しており,ステロイド結合が欠乏した変異体は有意な構造変化を示した.
結論:
- 決定された構造は,Ptch1によるHh経路調節の分子メカニズムに関する前例のない洞察を提供します.
- Ptch1へのステロイド結合は,ShNとの相互作用にとって重要であり,Hh経路の活性を調節する上で重要な役割を果たす可能性が高い.
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