Autoantibody mimicry of hormone action at the thyrotropin receptor

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 activity(3). 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.

Automated summary

Thyroid hormones play a crucial role in metabolism, growth, and development. In patients with Graves' disease, autoantibodies can pathologically increase thyroid hormone activity, but how they mimic the function of thyroid-stimulating hormone remains unclear. This study used cryo-electron microscopy to determine the structures of active and inactive thyroid-stimulating hormone receptor (TSHR). The findings reveal that the extracellular domain of TSHR undergoes a conformational change upon activation induced by thyroid-stimulating hormone or activating autoantibodies, providing insights into the mechanism of receptor activation.