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激素和抗体介导的甲状腺素受体的激活
Jia Duan1,2, Peiyu Xu1,3, Xiaodong Luan4,5,6,7
1The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Nature
|August 8, 2022
概括
对甲状腺刺激激素受体 (TSHR) 激活的结构洞察力揭示了TSH和自身抗体是如何导致格雷夫斯病的. 这项研究阐明了TSHR功能和功能障碍的分子机制.
科学领域:
- 结构生物学
- 内分泌学
- 免疫学
背景情况:
- 甲状腺刺激激素 (TSH) 通过甲状腺激素受体 (TSHR) 调节甲状腺激素的合成.
- 针对TSHR的自身抗体导致格雷夫斯病 (甲状腺功能过高) 和甲状腺功能下降,影响全球数百万人.
- 了解TSHR激活对于治疗这些自身免疫性甲状腺疾病至关重要.
研究的目的:
- 确定TSHR的活跃和非活跃结构状态.
- 阐明TSH和自身抗体激活TSHR的分子机制.
- 将TSHR激活与其他糖蛋白激素受体进行比较.
主要方法:
- 使用X射线结晶学获得TSH,M22自身抗体和K1- 70抑制抗体的高分辨率结构.
- 使用了ML-109和LHCGR的结构比较.
- 对TSHR与脂质的相互作用进行了分析.
主要成果:
- 报告TSHR与TSH结合并激活M22自身抗体的活性结构,以及具有抑制抗体K1- 70的非活性结构.
- 无论是TSH还是M22,都会诱导TSHR细胞外域 (ECD) 的直立活性构造.
- 一个保存的P10片段调解了ECD与跨膜域的相互作用,揭示了一个通用的糖蛋白激素受体激活机制.
结论:
- 这项研究揭示了TSH和自身抗体对TSHR激活的保存ECD推进机制.
- 强调了胆固醇在TSHR局部化中的作用.
- 这些发现为了解格雷夫斯病的发病提供了分子基础.
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