中国科学院上海药物研究所徐华强等研究人员合作揭示激素和抗体介导的促甲状腺激素受体激活。2022年8月8日,《自然》杂志在线发表了这项成果。
Author: Duan, Jia, Xu, Peiyu, Luan, Xiaodong, Ji, Yujie, He, Xinheng, Song, Ning, Yuan, Qingning, Jin, Ye, Cheng, Xi, Jiang, Hualiang, Zheng, Jie, Zhang, Shuyang, Jiang, Yi, Xu, H. Eric
Issue&Volume: 2022-08-08
Abstract: Thyroid stimulating hormone (TSH), through activation of its G protein-coupled thyrotropin receptor (TSHR), controls the synthesis of thyroid hormone (TH), an essential metabolic hormone1-3. Aberrant signaling of TSHR by autoantibodies causes Graves’ disease and hypothyroidism that affect millions of patients worldwide4. Here we report the active structures of TSHR with TSH and an activating autoantibody M225, both bound to an allosteric agonist ML-1096, as well as an inactivated TSHR structure with inhibitory antibody K1-707. 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 inactivated 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 mediates ECD interactions with the TSHR transmembrane domain8. One surprisingly feature is that there are over 15 cholesterols surrounding TSHR, supporting its preferential location in lipid rafts9. These structures also highlight a similar ECD-push mechanism for TSH and autoantibody M22 to activate TSHR, thus providing the molecular basis for Graves’ disease.
DOI: 10.1038/s41586-022-05173-3
Source: https://www.nature.com/articles/s41586-022-05173-3
Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html