FGF激素信号的结构基础
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.
Nature
|June 7, 2023
概括
肝素硫酸盐 (HS) 作为一个共受体,使纤维细胞生长因子 (FGF) 激素能够通过不对称的二分化激活FGF受体 (FGFR). 这一发现挑战了现有的模型,并为代谢疾病和癌症提供了新的治疗点.
科学领域:
- 生物化学
- 结构生物学
- 内分泌学
背景情况:
- 纤维细胞生长因子 (FGF) 激素需要αKlotho核受体和肝酸盐 (HS) 蛋白质糖体进行代谢信号传递.
- 作为FGF-FGFR复合体激活中的共受体,HS的精确分子机制尚不完全理解.
研究的目的:
- 阐明HS在FGF23介导的信号传递中的核心受体功能的结构基础.
- 确定FGFR受体二元化和激活的机制.
主要方法:
- 电子显微镜 (cryo-EM) 解决FGF23-FGFR-αKlotho-HS四元复合物的结构.
- 基于细胞的受体补充和异构化试验.
主要成果:
- 对三种不同的FGF23-FGFR-αKlotho-HS复合体的结构确定显示出1:1:1的三元复合体,通过HS招募二次FGFR.
- 一个单一的HS链促进了不对称的FGFR二分化和激活,这种机制也适用于膜FGF信号传递.
- 发现αKlotho在二次受体招募或二元化中没有直接参与.
结论:
- 这项研究推翻了对称的FGFR二元化模型,建立了由HS驱动的不对称机制.
- 这些发现为开发针对代谢疾病和癌症的新疗法提供了结构基础.
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