PorcupineによるWntアサイレーションのメカニズムと抑制
Yang Liu1, Xiaofeng Qi1, Linda Donnelly1
1Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Nature
|July 13, 2022
まとめ
この研究は,Wntシグナル伝達に不可欠なPorcupine (PORCN) によるWntタンパク質変異のメカニズムを明らかにしています. 構造は,抗癌薬であるLGK974が,基板へのアクセスを遮断し,がん治療の発展を助けることによって,PORCNを抑制することを示しています.
科学分野:
- 生物化学
- 構造生物学
- 分子生物学
背景:
- Wnt信号は胚の発達と 組織ホメオスタシスに不可欠です
- 異常なWnt信号は様々な癌と関連しています
- Wntのシグナルには,ポルクピーン (PORCN) によるパルミトオイレーションが必要です.
研究 の 目的:
- PORCNによるWntタンパク質のパルミトエオイレーションの構造的メカニズムを解明する.
- 抗癌薬LGK974によるPORCNの抑制メカニズムを理解する.
- 癌治療のための新しいPORCN阻害剤の開発のための洞察を提供するために.
主な方法:
- クリオ電子顕微鏡 (cryo-EM) を用いて,人間のPORCNの4つの高解像度構造を決定した.
- パルミトレオイル-コア,LGK974,WNT3Aヘアピン2 (WNT3Ap),およびWNT3Apアナログと複合したPORCNの構造が得られた.
主要な成果:
- 構造は,WNT3Aのヘアピン2がPORCNに,光線側から挿入され,パルミトレオイル-コアが細胞側からアクセスしていることを示している.
- 触媒ヒスティジンは,パルミトレオイル基のWntヘアピン2への転移を促進する.
- LGK974は,パルミトレオイル- CoA部位に結合し,基板へのアクセスを阻害します.
結論:
- この研究は,PORCNによるWntアサイレーションの詳細なメカニズムを理解します.
- この発見は,異常なWnt信号によって引き起こされる癌の治療戦略として,PORCN阻害剤の開発を進めています.
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