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Hormone- and antibody-mediated activation of the thyrotropin receptor

Author

Listed:
  • Jia Duan

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Peiyu Xu

    (Chinese Academy of Sciences
    Massachusetts Institute of Technology)

  • Xiaodong Luan

    (Peking Union Medical College and Chinese Academy of Medical Sciences
    Peking Union Medical College and Chinese Academy of Medical Sciences
    Tsinghua University
    Tsinghua University)

  • Yujie Ji

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Xinheng He

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    Chinese Academy of Sciences)

  • Ning Song

    (University of Chinese Academy of Sciences
    Chinese Academy of Sciences)

  • Qingning Yuan

    (Chinese Academy of Sciences)

  • Ye Jin

    (Peking Union Medical College and Chinese Academy of Medical Sciences
    Peking Union Medical College and Chinese Academy of Medical Sciences)

  • Xi Cheng

    (Chinese Academy of Sciences)

  • Hualiang Jiang

    (University of Chinese Academy of Sciences
    Chinese Academy of Sciences
    ShanghaiTech University)

  • Jie Zheng

    (Chinese Academy of Sciences)

  • Shuyang Zhang

    (Peking Union Medical College and Chinese Academy of Medical Sciences
    Peking Union Medical College and Chinese Academy of Medical Sciences
    Tsinghua University
    Tsinghua University)

  • Yi Jiang

    (ShanghaiTech University
    Lingang Laboratory)

  • H. Eric Xu

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    ShanghaiTech University)

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.

Suggested Citation

  • 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 & H. Eric Xu, 2022. "Hormone- and antibody-mediated activation of the thyrotropin receptor," Nature, Nature, vol. 609(7928), pages 854-859, September.
  • Handle: RePEc:nat:nature:v:609:y:2022:i:7928:d:10.1038_s41586-022-05173-3
    DOI: 10.1038/s41586-022-05173-3
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    Citations

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    Cited by:

    1. Dawei Sun & Yonglian Sun & Eric Janezic & Tricia Zhou & Matthew Johnson & Caleigh Azumaya & Sigrid Noreng & Cecilia Chiu & Akiko Seki & Teresita L. Arenzana & John M. Nicoludis & Yongchang Shi & Baome, 2023. "Structural basis of antibody inhibition and chemokine activation of the human CC chemokine receptor 8," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Jia Duan & Peiyu Xu & Huibing Zhang & Xiaodong Luan & Jiaqi Yang & Xinheng He & Chunyou Mao & Dan-Dan Shen & Yujie Ji & Xi Cheng & Hualiang Jiang & Yi Jiang & Shuyang Zhang & Yan Zhang & H. Eric Xu, 2023. "Mechanism of hormone and allosteric agonist mediated activation of follicle stimulating hormone receptor," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    3. Aika Iwama & Ryoji Kise & Hiroaki Akasaka & Fumiya K. Sano & Hidetaka S. Oshima & Asuka Inoue & Wataru Shihoya & Osamu Nureki, 2024. "Structure and dynamics of the pyroglutamylated RF-amide peptide QRFP receptor GPR103," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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