Hormone- and antibody-mediated activation of the thyrotropin receptor

Jia Duan, Peiyu Xu, Xiaodong Luan, Yujie Ji, Xinheng He, Ning Song, Qingning Yuan, Ye Jin, Xi Cheng, Hualiang Jiang, Jie Zheng, Shuyang Zhang (), Yi Jiang () and H. Eric Xu ()
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Jia Duan: Chinese Academy of Sciences
Peiyu Xu: Chinese Academy of Sciences
Xiaodong Luan: Peking Union Medical College and Chinese Academy of Medical Sciences
Yujie Ji: Chinese Academy of Sciences
Xinheng He: Chinese Academy of Sciences
Ning Song: University of Chinese Academy of Sciences
Qingning Yuan: Chinese Academy of Sciences
Ye Jin: Peking Union Medical College and Chinese Academy of Medical Sciences
Xi Cheng: Chinese Academy of Sciences
Hualiang Jiang: University of Chinese Academy of Sciences
Jie Zheng: Chinese Academy of Sciences
Shuyang Zhang: Peking Union Medical College and Chinese Academy of Medical Sciences
Yi Jiang: ShanghaiTech University
H. Eric Xu: Chinese Academy of Sciences

Nature, 2022, vol. 609, issue 7928, 854-859

Abstract: Abstract Thyroid-stimulating hormone (TSH), through activation of its G-protein-coupled thyrotropin receptor (TSHR), controls the synthesis of thyroid hormone—an essential metabolic hormone1–3. Aberrant signalling of TSHR by autoantibodies causes Graves’ disease (hyperthyroidism) and hypothyroidism, both of which affect millions of patients worldwide4. Here we report the active structures of TSHR with TSH and the activating autoantibody M225, both bound to the allosteric agonist ML-1096, as well as an inactivated TSHR structure with the inhibitory antibody K1-707. Both TSH and M22 push the extracellular domain (ECD) of TSHR into an upright active conformation. By contrast, K1-70 blocks TSH binding and cannot push the ECD into 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 ten-residue fragment (P10) from the hinge C-terminal loop mediates ECD interactions with the TSHR transmembrane domain8. One notable feature is that there are more than 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, therefore providing the molecular basis for Graves’ disease.

Date: 2022
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DOI: 10.1038/s41586-022-05173-3

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