RT Journal Article
SR Electronic
T1 Autoantibody and hormone activation of the thyrotropin G protein-coupled receptor
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.01.06.475289
DO 10.1101/2022.01.06.475289
A1 Bryan Faust
A1 Isha Singh
A1 Kaihua Zhang
A1 Nicholas Hoppe
A1 Antonio F. M. Pinto
A1 Yagmur Muftuoglu
A1 Christian B. Billesbølle
A1 Alan Saghatelian
A1 Yifan Cheng
A1 Aashish Manglik
YR 2022
UL http://biorxiv.org/content/early/2022/01/07/2022.01.06.475289.abstract
AB Thyroid hormones are vital to growth and metabolism. Thyroid hormone synthesis is controlled by thyrotropin (TSH), which acts at the thyrotropin receptor (TSHR). Autoantibodies that activate the TSHR pathologically increase thyroid hormones in Graves’ disease. How autoantibodies mimic TSH function remains unclear. We determined cryogenic-electron microscopy structures of active and inactive TSHR. In inactive TSHR, the extracellular domain lies close to the membrane bilayer. TSH selects an upright conformation of the extracellular domain due to steric clashes between a conserved hormone glycan and the membrane bilayer. An activating autoantibody selects a similar upright conformation of the extracellular domain. Conformational changes in the extracellular domain are transduced to the seven transmembrane domain via a conserved hinge domain, a tethered peptide agonist, and a phospholipid that binds within the seven transmembrane domain. Rotation of the TSHR ECD relative to the membrane bilayer is sufficient for receptor activation, revealing a shared mechanism for other glycoprotein hormone receptors that may also extend to G protein-coupled receptors with large extracellular domains.Competing Interest StatementA.M. is a consultant for and stockholder in Septerna Inc.