小柯机器人

美国加州大学圣迭戈分校Aashish Manglik、Yifan Cheng等研究人员合作揭示促甲状腺素受体激素作用的自身抗体模拟。相关论文于2022年8月8日在线发表于国际学术期刊《自然》。

研究人员表示，甲状腺激素对新陈代谢、生长和发育至关重要。甲状腺激素的合成由促甲状腺素（TSH）控制，它作用于促甲状腺素受体（TSHR）。激活TSHR的自身抗体会在葛瑞夫兹氏病中病理性地增加甲状腺激素。自身抗体如何模拟TSH功能仍不清楚。

研究人员确定了活性和非活性TSHR的冷冻电镜结构。在非活性的TSHR中，细胞外结构域靠近膜双分子层。由于保守的荷尔蒙糖和膜双层之间的立体冲突，TSH选择了细胞外结构域的直立方向。来自葛瑞夫兹氏病患者的一种激活的自身抗体选择了类似的细胞外结构域的直立方向。胞外结构域的重新定向通过一个保守的铰链结构域、一个拴住的多肽激动剂和一个在七个跨膜结构域内结合的磷脂，在七个跨膜结构域中传递构象变化。TSHR胞外结构域相对于膜双层的旋转足以激活受体，从而揭示了其他糖蛋白激素受体的一个共同机制，该机制也可能延伸到其他具有大胞外结构域的G蛋白偶联受体。

附：英文原文

Title: Autoantibody mimicry of hormone action at the thyrotropin receptor

Author: Faust, Bryan, Billesblle, Christian B., Suomivuori, Carl-Mikael, Singh, Isha, Zhang, Kaihua, Hoppe, Nicholas, Pinto, Antonio F. M., Diedrich, Jolene K., Muftuoglu, Yagmur, Szkudlinski, Mariusz W., Saghatelian, Alan, Dror, Ron O., Cheng, Yifan, Manglik, Aashish

Issue&Volume: 2022-08-08

Abstract: Thyroid hormones are vital to metabolism, growth and development1. Thyroid hormone synthesis is controlled by thyrotropin (TSH), which acts at the thyrotropin receptor (TSHR)2. Autoantibodies that activate the TSHR pathologically increase thyroid hormones in Graves’ disease3. How autoantibodies mimic TSH function remains unclear. We determined cryogenic-electron microscopy structures of active and inactive TSHR. In inactive TSHR, the extracellular domain lies close to the membrane bilayer. TSH selects an upright orientation of the extracellular domain due to steric clashes between a conserved hormone glycan and the membrane bilayer. An activating autoantibody from a Graves’ disease patient selects a similar upright orientation of the extracellular domain. Reorientation of the extracellular domain transduces a conformational change in the seven transmembrane domain via a conserved hinge domain, a tethered peptide agonist, and a phospholipid that binds within the seven transmembrane domain. Rotation of the TSHR extracellular domain relative to the membrane bilayer is sufficient for receptor activation, revealing a shared mechanism for other glycoprotein hormone receptors that may also extend to other G protein-coupled receptors with large extracellular domains.

DOI: 10.1038/s41586-022-05159-1

Source: https://www.nature.com/articles/s41586-022-05159-1

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