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Autoantibody mimicry of hormone action at the thyrotropin receptor

Author

Listed:
  • Bryan Faust

    (University of California
    University of California
    University of California)

  • Christian B. Billesbølle

    (University of California)

  • Carl-Mikael Suomivuori

    (Stanford University
    Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University)

  • Isha Singh

    (University of California)

  • Kaihua Zhang

    (University of California)

  • Nicholas Hoppe

    (University of California
    University of California)

  • Antonio F. M. Pinto

    (Salk Institute for Biological Studies)

  • Jolene K. Diedrich

    (Salk Institute for Biological Studies)

  • Yagmur Muftuoglu

    (Stanford University School of Medicine)

  • Mariusz W. Szkudlinski

    (Trophogen)

  • Alan Saghatelian

    (Salk Institute for Biological Studies)

  • Ron O. Dror

    (Stanford University
    Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University)

  • Yifan Cheng

    (University of California
    University of California
    University of California)

  • Aashish Manglik

    (University of California
    University of California
    University of California
    Chan Zuckerberg Biohub)

Abstract

Thyroid hormones are vital in metabolism, growth and development1. Thyroid hormone synthesis is controlled by thyrotropin (TSH), which acts at the thyrotropin receptor (TSHR)2. In patients with Graves’ disease, autoantibodies that activate the TSHR pathologically increase thyroid hormone activity3. How autoantibodies mimic thyrotropin function remains unclear. Here we determined cryo-electron microscopy structures of active and inactive TSHR. In inactive TSHR, the extracellular domain lies close to the membrane bilayer. Thyrotropin selects an upright orientation of the extracellular domain owing to steric clashes between a conserved hormone glycan and the membrane bilayer. An activating autoantibody from a patient with Graves’ disease selects a similar upright orientation of the extracellular domain. Reorientation of the extracellular domain transduces a conformational change in the seven-transmembrane-segment domain via a conserved hinge domain, a tethered peptide agonist and a phospholipid that binds within the seven-transmembrane-segment 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.

Suggested Citation

  • Bryan Faust & Christian B. Billesbølle & Carl-Mikael Suomivuori & Isha Singh & Kaihua Zhang & Nicholas Hoppe & Antonio F. M. Pinto & Jolene K. Diedrich & Yagmur Muftuoglu & Mariusz W. Szkudlinski & Al, 2022. "Autoantibody mimicry of hormone action at the thyrotropin receptor," Nature, Nature, vol. 609(7928), pages 846-853, September.
  • Handle: RePEc:nat:nature:v:609:y:2022:i:7928:d:10.1038_s41586-022-05159-1
    DOI: 10.1038/s41586-022-05159-1
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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. Jianying Zhu & Qi Zhang & Hui Zhang & Zuoqiang Shi & Mingxu Hu & Chenglong Bao, 2023. "A minority of final stacks yields superior amplitude in single-particle cryo-EM," Nature Communications, Nature, vol. 14(1), pages 1-11, December.

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