Autoantibody and hormone activation of the thyrotropin G protein-coupled receptor Article Swipe

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Bryan Faust , Isha Singh , Kaihua Zhang , Nick Hoppe , Antônio F. M. Pinto , Yagmur Muftuoglu , Christian B. Billesbølle , Alan Saghatelian , Yifan Cheng , Aashish Manglik ·

YOU? · · 2022 · Open Access · · DOI: https://doi.org/10.1101/2022.01.06.475289

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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Chemistry

Cell Biology

G Protein-Coupled Receptor

Concepts

Thyrotropin receptor Extracellular Chemistry Transmembrane domain Receptor EGF-like domain Cell biology G protein-coupled receptor Hormone receptor Biophysics Biochemistry Biology Endocrinology Internal medicine Thyroid Graves' disease Binding domain Binding site Medicine Breast cancer Cancer

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Type: preprint
Language: en
Landing Page: https://doi.org/10.1101/2022.01.06.475289
OA Status: green
Cited By: 5
References: 63
Related Works: 10
OpenAlex ID: https://openalex.org/W4205670903

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DOI: https://doi.org/10.1101/2022.01.06.475289

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Title: Autoantibody and hormone activation of the thyrotropin G protein-coupled receptor

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Type: preprint

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Language: en

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Publication year: 2022

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Publication date: 2022-01-07

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Authors: Bryan Faust, Isha Singh, Kaihua Zhang, Nick Hoppe, Antônio F. M. Pinto, Yagmur Muftuoglu, Christian B. Billesbølle, Alan Saghatelian, Yifan Cheng, Aashish Manglik

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Landing page: https://doi.org/10.1101/2022.01.06.475289

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Concepts: Thyrotropin receptor, Extracellular, Chemistry, Transmembrane domain, Receptor, EGF-like domain, Cell biology, G protein-coupled receptor, Hormone receptor, Biophysics, Biochemistry, Biology, Endocrinology, Internal medicine, Thyroid, Graves' disease, Binding domain, Binding site, Medicine, Breast cancer, Cancer

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Cited by: 5

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Citations by year (recent): 2025: 1, 2023: 1, 2022: 3

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