1. Autoantibody mimicry of hormone action at the thyrotropin receptor.
- Author
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Faust B, Billesbølle CB, Suomivuori CM, Singh I, Zhang K, Hoppe N, Pinto AFM, Diedrich JK, Muftuoglu Y, Szkudlinski MW, Saghatelian A, Dror RO, Cheng Y, and Manglik A
- Subjects
- Cell Membrane metabolism, Graves Disease immunology, Graves Disease metabolism, Humans, Phospholipids metabolism, Protein Domains, Receptors, G-Protein-Coupled agonists, Receptors, G-Protein-Coupled chemistry, Receptors, G-Protein-Coupled ultrastructure, Rotation, Cryoelectron Microscopy, Immunoglobulins, Thyroid-Stimulating chemistry, Immunoglobulins, Thyroid-Stimulating immunology, Immunoglobulins, Thyroid-Stimulating pharmacology, Immunoglobulins, Thyroid-Stimulating ultrastructure, Receptors, Thyrotropin agonists, Receptors, Thyrotropin chemistry, Receptors, Thyrotropin immunology, Receptors, Thyrotropin ultrastructure, Thyrotropin chemistry, Thyrotropin metabolism, Thyrotropin pharmacology
- Abstract
Thyroid hormones are vital in metabolism, growth and development
1 . 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., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2022
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