Autoantibody mimicry of hormone action at the thyrotropin receptor

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, Alan Saghatelian, Ron O. Dror, Yifan Cheng () and Aashish Manglik ()
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Bryan Faust: University of California
Christian B. Billesbølle: University of California
Carl-Mikael Suomivuori: Stanford University
Isha Singh: University of California
Kaihua Zhang: University of California
Nicholas Hoppe: 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
Yifan Cheng: University of California
Aashish Manglik: University of California

Nature, 2022, vol. 609, issue 7928, 846-853

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41586-022-05159-1

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