促甲状腺激素受体
细胞外
化学
跨膜结构域
受体
表皮生长因子样结构域
细胞生物学
G蛋白偶联受体
激素受体
生物物理学
生物化学
生物
内分泌学
内科学
甲状腺
格雷夫斯病
绑定域
结合位点
医学
癌症
乳腺癌
作者
Bryan Faust,Isha Singh,Kaihua Zhang,Nick Hoppe,António Pinto‐Duarte,Yagmur Muftuoglu,Christian B. Billesbølle,Alan Saghatelian,Yifan Cheng,Aashish Manglik
标识
DOI:10.1101/2022.01.06.475289
摘要
Abstract 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.
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