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FGFホルモンシグナリングの構造的基礎

Lingfeng Chen1,2, Lili Fu1,3,4, Jingchuan Sun1,5

  • 1Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China.

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|June 7, 2023
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まとめ
この要約は機械生成です。

ヘパラン硫酸 (HS) は共受容体として働き,繊維細胞成長因子 (FGF) ホルモンが非対称的二分化によってFGF受容体 (FGFRs) を活性化させる. この発見は既存のモデルに 異議を唱え 代謝疾患や癌に対する 新しい治療目標を提供します

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科学分野:

  • 生物化学
  • 構造生物学
  • 内分泌学

背景:

  • フィブロブラスト成長因子 (FGF) ホルモンは,αKlothoコレセプターとヘパラン硫酸 (HS) プロテオグリカンを代謝シグナルに必要とします.
  • FGF-FGFR複合体の活性化における共受容体としてのHSの正確な分子機構は,まだ完全に理解されていません.

研究 の 目的:

  • FGF23媒介のシグナル伝達におけるHSのコレセプター機能の構造的基礎を解明する.
  • FGF受容体 (FGFR) の二分化と活性化のメカニズムを決定する.

主な方法:

  • FGF23-FGFR-αKlotho-HS四次複合体の構造を解明するための冷凍電子顕微鏡 (冷凍-EM).
  • 細胞ベースの受容体補足と異体化試験

主要な成果:

  • 3つの異なるFGF23-FGFR-αKlotho-HS複合体の構造的決定は,HS経由で二次FGFRを勧誘する1:1:1の三角複合体を明らかにした.
  • 単一のHS鎖は非対称なFGFRの二分化と活性化を促進し,これはパラクリンFGFシグナル伝達にも適用できるメカニズムである.
  • αKlothoは二次受容体募集または二分化に直接参加しないことが判明しました.

結論:

  • この研究は,対称的なFGFR二分化モデルを覆し,HSによって誘発される非対称的なメカニズムを確立した.
  • これらの発見は,代謝疾患と癌におけるFGFシグナリングを標的とした新しい治療法の開発のための構造的基盤を提供します.