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在甲状腺蛋白受体上对激素作用的自身抗体模拟
Bryan Faust1,2,3, Christian B Billesbølle1, Carl-Mikael Suomivuori4,5,6,7
1Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA.
Nature
|August 8, 2022
概括
通过Graves病自身抗体激活甲状腺激素受体,通过定向受体的细胞外域来模仿甲状腺激素. 这种方向变化是甲状腺激素调节和疾病的关键.
科学领域:
- 生物化学
- 分子生物学
- 内分泌学
背景情况:
- 甲状腺激素调节新陈代谢,生长和发育.
- 甲状腺激素通过甲状腺激素受体 (TSHR) 控制甲状腺激素的合成.
- 格雷夫斯病涉及激活TSHR的自身抗体,导致甲状腺功能过高.
研究的目的:
- 阐明自身抗体激活TSHR的结构机制.
- 了解自身抗体如何模仿甲状腺蛋白的功能.
主要方法:
- 确定了活性和非活性TSHR的冷电子显微镜结构.
- 分析了TSHR,甲状腺蛋白和激活自身抗体之间的结构相互作用.
主要成果:
- 在非活跃状态和活跃状态中确定了TSHR细胞外域的不同方向.
- 证明甲状腺蛋白和格雷夫斯病自身抗体都会诱导细胞外域的直立方向.
- 发现细胞外域的重定向会触发膜外域的结构变化,导致受体的激活.
结论:
- 对TSHR细胞外域的重新定位足以激活受体.
- 这种激活机制在糖蛋白激素受体和潜在的其他具有大型细胞外域的GPCR中共享.
- 了解这种机制可以了解格雷夫斯病的发病机制和潜在的治疗点.
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