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研究揭示激素和抗体介导的促甲状腺激素受体激活
2022-08-09 15:18
来源：小柯机器人

中国科学院上海药物研究所徐华强等研究人员合作揭示激素和抗体介导的促甲状腺激素受体激活。2022年8月8日，《自然》杂志在线发表了这项成果。

研究人员表示，促甲状腺激素（TSH）通过激活其G蛋白偶联的促甲状腺素受体（TSHR），控制甲状腺激素（TH）的合成，这是一种重要的代谢激素。自身抗体对TSHR的异常信号传导导致葛瑞夫兹氏病和甲状腺功能减退，影响了全世界数百万的患者。
 
研究人员报告了TSHR与TSH和激活的自身抗体M225的活性结构，两者都与异体激动剂ML-1096结合，以及与抑制性抗体K1-707的失活的TSHR结构。TSH和M22都推动TSHR的胞外结构域（ECD）进入直立的活性构象。相反，K1-70阻断了TSH的结合，不能将ECD推至直立构象。将TSHR的活性和失活结构与促黄体素-绒膜促性腺激素受体（LHCGR）的结构进行比较，发现糖蛋白激素受体的普遍激活机制，其中铰链C端环的一个保守的10个残基片段（P10）介导ECD与TSHR跨膜域的相互作用。
 
一个令人惊讶的特点是，TSHR周围有超过15个胆固醇，支持其在脂质筏中的优先位置。这些结构还强调了TSH和自身抗体M22激活TSHR的类似ECD推动机制，从而为葛瑞夫兹氏病提供了分子基础。
 
附：英文原文
 
Title: Hormone- and antibody-mediated activation of the thyrotropin receptor

Author: Duan, Jia, Xu, Peiyu, Luan, Xiaodong, Ji, Yujie, He, Xinheng, Song, Ning, Yuan, Qingning, Jin, Ye, Cheng, Xi, Jiang, Hualiang, Zheng, Jie, Zhang, Shuyang, Jiang, Yi, Xu, H. Eric

Issue&Volume: 2022-08-08

Abstract: Thyroid stimulating hormone (TSH), through activation of its G protein-coupled thyrotropin receptor (TSHR), controls the synthesis of thyroid hormone (TH), an essential metabolic hormone1-3. Aberrant signaling of TSHR by autoantibodies causes Graves’ disease and hypothyroidism that affect millions of patients worldwide4. Here we report the active structures of TSHR with TSH and an activating autoantibody M225, both bound to an allosteric agonist ML-1096, as well as an inactivated TSHR structure with inhibitory antibody K1-707. Both TSH and M22 push the extracellular domain (ECD) of TSHR into the upright active conformation. In contrast, K1-70 blocks TSH binding and is incapable of pushing the ECD to the upright conformation. Comparisons of the active and inactivated structures of TSHR with those of the luteinizing hormone–choriogonadotropin receptor (LHCGR) reveal a universal activation mechanism of glycoprotein hormone receptors, in which a conserved 10-residue fragment (P10) from the hinge C-terminal loop mediates ECD interactions with the TSHR transmembrane domain8. One surprisingly feature is that there are over 15 cholesterols surrounding TSHR, supporting its preferential location in lipid rafts9. These structures also highlight a similar ECD-push mechanism for TSH and autoantibody M22 to activate TSHR, thus providing the molecular basis for Graves’ disease.

DOI: 10.1038/s41586-022-05173-3

Source: https://www.nature.com/articles/s41586-022-05173-3

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html


本期文章：《自然》：Online/在线发表

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