Autoantibody mimicry of hormone action at the thyrotropin receptor,Nature

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Autoantibody mimicry of hormone action at the thyrotropin receptor
Nature ( IF 50.5 ) Pub Date : 2022-08-08 , DOI: 10.1038/s41586-022-05159-1
Bryan Faust _{1,

2,

3} , Christian B Billesbølle ₁ , Carl-Mikael Suomivuori _{4,

5,

6,

7} , Isha Singh ₁ , Kaihua Zhang ₂ , Nicholas Hoppe _{1,

3} , Antonio F M Pinto ₈ , Jolene K Diedrich ₈ , Yagmur Muftuoglu ₉ , Mariusz W Szkudlinski ₁₀ , Alan Saghatelian ₁₁ , Ron O Dror _{4,

5,

6,

7} , Yifan Cheng _{2,

3,

12} , Aashish Manglik _{1,

3,

13,

14}

Affiliation

Department of Pharmaceutical Chemistry, University of California, San Francisco, CA, USA.
Department of Biochemistry and Biophysics, University of California, San Francisco, CA, USA.
Biophysics Graduate Program, University of California, San Francisco, CA, USA.
Department of Computer Science, Stanford University, Stanford, CA, USA.
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.
Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.
Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA, USA.
Mass Spectrometry Core for Proteomics and Metabolomics, Salk Institute for Biological Studies, La Jolla, CA, USA.
Stanford University School of Medicine, Stanford, CA, USA.
Trophogen, Rockville, MD, USA.
Clayton Foundation Laboratory for Peptide Biology Lab, Salk Institute for Biological Studies, La Jolla, CA, USA.
Howard Hughes Medical Institute, University of California, San Francisco, CA, USA.
Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA.
Chan Zuckerberg Biohub, San Francisco, CA, USA.

Thyroid hormones are vital to metabolism, growth and development¹. Thyroid hormone synthesis is controlled by thyrotropin (TSH), which acts at the thyrotropin receptor (TSHR)². Autoantibodies that activate the TSHR pathologically increase thyroid hormones in Graves’ disease³. 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 orientation of the extracellular domain due to steric clashes between a conserved hormone glycan and the membrane bilayer. An activating autoantibody from a Graves’ disease patient selects a similar upright orientation of the extracellular domain. Reorientation of the extracellular domain transduces a conformational change in 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 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.

中文翻译：

自身抗体模拟促甲状腺素受体的激素作用

甲状腺激素对于新陈代谢、生长和发育至关重要¹ 。甲状腺激素合成由促甲状腺素 (TSH) 控制，促甲状腺素作用于促甲状腺素受体 (TSHR) ² 。病理性激活 TSHR 的自身抗体会增加格雷夫斯病中的甲状腺激素³ 。自身抗体如何模拟 TSH 功能仍不清楚。我们确定了活性和非活性 TSHR 的低温电子显微镜结构。在非活性 TSHR 中，细胞外结构域靠近膜双层。由于保守的激素聚糖和膜双层之间的空间冲突，TSH 选择细胞外结构域的直立方向。来自格雷夫斯病患者的激活自身抗体选择类似的细胞外结构域的直立方向。胞外结构域的重新定向通过保守的铰链结构域、束缚肽激动剂和在七跨膜结构域内结合的磷脂来转导七跨膜结构域的构象变化。 TSHR胞外结构域相对于膜双层的旋转足以激活受体，揭示了其他糖蛋白激素受体的共享机制，该机制也可能延伸到其他具有大胞外结构域的G蛋白偶联受体。

更新日期：2022-08-09

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