2つのパッチされた分子は,シグナルコンペテンツ複合体を生成するヘッジホッグの異なるサイトを巻き込む
Xiaofeng Qi1, Philip Schmiege1, Elias Coutavas2
1Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Science (New York, N.Y.)
|August 25, 2018
まとめ
アベラント・ヘッジホッグ (HH) 信号は癌に関与しています. この研究では,ソニック・ヘッジホッグ (SHH-N) が2つのパッチド-1 (PTCH1) 受容体を同時に,異なるインターフェイスを通じて効果的に細胞信号伝達することを明らかにした.
科学分野:
- 分子生物学
- 構造生物学
- 生物化学
背景:
- アベラント・ヘッジホッグ (HH) 信号は様々な癌や発達異常と関連しています.
- N末端パルミトイロ化HHは,その受容体パッチド-1 (PTCH1) と結合してシグナル伝達を開始する.
- 以前の構造研究は,PTCH1-HH結合インターフェースの矛盾したモデルを示した.
研究 の 目的:
- PTCH1-HHの結合部位に関する異なった発見を調和させるため
- PTCH1とのソニック・ヘッジホッグ (SHH-N) 相互作用の構造的基礎を解明する.
- HHシグナル伝達における特定された結合インターフェースの機能的意義を決定する.
主な方法:
- クリオ電子顕微鏡 (cryo-EM) で,PTCH1と複合されたSHH-Nの3.5アンストーム解像度構造を決定する.
- 複合体の形成中の生理学的カルシウム濃度を利用した.
- PTCH1とSHH-Nのサイト指向型変異を用いた機能分析.
主要な成果:
- 新しい非対称的な複合構造は,2つのPTCH1受容体に結合する1つのSHH-N分子を明らかにします.
- SHH-Nは,PTCH1にパルミテート媒介と異なるカルシウム媒介のエピトープの両方を関与させる.
- 両方の結合界面の変異による破壊は,HHシグナル伝達効率を著しく低下させる.
結論:
- この研究は,二重インターフェースの結合メカニズムを実証することによって,矛盾するモデルを調和させています.
- PTCH1-SHHシグナル伝達には,パルミタートとカルシウム媒介のインターフェイスの両方の同時活性化が不可欠です.
- この構造的および機能的洞察は,健康と病気におけるHH経路の調節を理解するための基礎を提供します.
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