Basis for antibody- and hormone-mediated activation of TSHR in Graves’ disease
Basis for antibody- and hormone-mediated activation of TSHR in Graves’ disease
Thyroid stimulating hormone (TSH), through activation of its G protein-coupled receptor TSHR, controls the synthesis of thyroid hormone (TH), an essential metabolic hormone. Aberrant signaling of TSHR by autoantibodies causes Graves’ disease and hypothyroidism that affect millions of patients worldwide. Here we report the active structures of TSHR with TSH and an activating autoantibody M22, both bound to an allosteric agonist ML-109, as well as an inactive TSHR structure with inhibitory antibody K1-70. Both TSH and M22 push the extracellular domain (ECD) of TSHR into the upright active conformation. In contrast, K1-70 blocks TSH binding and is incapable of pushing the ECD to the upright conformation. Comparisons of the active and inactive structures of TSHR with those of the luteinizing hormone–choriogonadotropin receptor (LHCGR) reveal a universal activation mechanism of glycoprotein hormone receptors, in which a conserved 10-residue fragment (P10) from the hinge C-terminal loop mediated interactions from the receptor ECD to its transmembrane domain. One surprisingly feature is that there are over 15 cholesterols surrounding TSHR, supporting its preferential location in lipid rafts. These structures also highlight a common mechanism for TSH and autoantibody M22 to activate TSHR, thus providing the molecular basis for Graves’ disease.
Jiang Hualiang、Zhang Shuyang、Luan Xiaodong、Jin Ye、Cheng Xi、Duan Jia、Yuan Qingning、He Xinheng、Xu H. Eric、Xu Peiyu、Jiang Yi、Ji Yujie
The CAS Key Laboratory of Receptor Research and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences||University of Chinese Academy of Sciences||School of Life Science and Technology, ShanghaiTech UniversityDepartment of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences||Medical Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences||School of Medicine, Tsinghua University||Tsinghua-Peking Center for life science, Tsinghua UniversityDepartment of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences||Medical Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences||School of Medicine, Tsinghua University||Tsinghua-Peking Center for life science, Tsinghua UniversityDepartment of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences||Medical Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical SciencesThe CAS Key Laboratory of Receptor Research and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesThe CAS Key Laboratory of Receptor Research and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences||University of Chinese Academy of SciencesThe CAS Key Laboratory of Receptor Research and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesThe CAS Key Laboratory of Receptor Research and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences||University of Chinese Academy of SciencesThe CAS Key Laboratory of Receptor Research and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences||University of Chinese Academy of Sciences||School of Life Science and Technology, ShanghaiTech UniversityThe CAS Key Laboratory of Receptor Research and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesThe CAS Key Laboratory of Receptor Research and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of SciencesThe CAS Key Laboratory of Receptor Research and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences||University of Chinese Academy of Sciences
基础医学生理学分子生物学
GPCRsautoimmune diseasethyroid hormone diseasesGraves’ diseaseantibody
Jiang Hualiang,Zhang Shuyang,Luan Xiaodong,Jin Ye,Cheng Xi,Duan Jia,Yuan Qingning,He Xinheng,Xu H. Eric,Xu Peiyu,Jiang Yi,Ji Yujie.Basis for antibody- and hormone-mediated activation of TSHR in Graves’ disease[EB/OL].(2025-03-28)[2025-04-28].https://www.biorxiv.org/content/10.1101/2022.06.13.496020.点此复制
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