ヒトの構造 パッチドとその複合体は,ネイティブのパルミトイレイテッド・ソニック・ヘッジホッグ
Xiaofeng Qi1, Philip Schmiege1, Elias Coutavas2
1Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Nature
|July 12, 2018
まとめ
ヘッジホッグ (HH) のシグナル伝達は 発達と健康に不可欠です この研究は,HHタンパク質がパッチド1 (PTCH1) に結合する原子構造を明らかにし,HH経路の活性化における重要なステップと,がんなどの疾患におけるその役割を明らかにした.
科学分野:
- 分子生物学
- 構造生物学
- 生物化学
背景:
- ヘッジホッグ (HH) 信号は胚の発達と組織維持に不可欠です.
- HHシグナル伝達が調節不良であることは,先天性欠陥や癌と関連しています.
- HHタンパク質が受容体パッチ (PTCH) によって認識される正確なメカニズムは不明である.
研究 の 目的:
- パッチ 1 (PTCH1) によるヘッジホッグ (HH) タンパク質認識の構造的基礎を解明する.
- HH N-端末領域 (HH-N) と PTCH1 の間の相互作用のインターフェースに原子の洞察を与える.
- HHシグナル伝達経路の活性化と病気への影響の分子の枠組みを理解する.
主な方法:
- クリオ電子顕微鏡 (cryo-EM) を用いて,単独でPTCH1の構造と,音響ヘッジホッグのN末端領域 (SHH-N) との複合体を決定した.
- 代替結合界面と条件を調査するために生化学的測定を行った.
主要な成果:
- 凍結EM構造は,PTCH1の詳細な構造を明らかにし,そのトランスメブランコアと細胞外ドメインを含む.
- PTCH1の細胞外ドメインの間の空洞に挿入し,主相互作用インターフェースを定義することが観察されました.
- バイオケミカルデータによると,SHH-Nは,パルミタート改変なしに,別々のインターフェースを通じてPTCH1を勧誘することができ,共受容体結合の役割を示唆しています.
結論:
- この研究は,PTCH1-SHH-N複合体の最初の原子レベルの見方を提供し,HHタンパク質がどのように認識されているかを明らかにします.
- この発見は,PTCH1と潜在的共受容体へのHH-N結合を理解するための構造的基礎を提供する.
- この研究は,HHシグナル伝達,その調節,および人間の疾患における異常な役割を理解するために重要な分子枠組みを確立しています.
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