Hormone- and antibody-mediated activation of the thyrotropin receptor

doi:10.1038/s41586-022-05173-3

	Hormone- and antibody-mediated activation of the thyrotropin receptor
	Duan, Jia 1,2; Xu, Peiyu 1,11; Luan, Xiaodong 3,4,5,6; Ji, Yujie 1,2; He, Xinheng 1,2,7; Song, Ning 2,8; Yuan, Qingning 1; Jin, Ye 3,4; Cheng, Xi 7; Jiang, Hualiang2,7,9 ; Zheng, Jie 8; Zhang, Shuyang 3,4,5,6; Jiang, Yi9,10 ; Xu, H. Eric1,2,9
	2022-08-01
发表期刊	NATURE (IF:50.5[JCR-2023],54.4[5-Year])
ISSN	0028-0836
EISSN	1476-4687
发表状态	已发表
DOI	10.1038/s41586-022-05173-3
摘要	Thyroid-stimulating hormone (TSH), through activation of its G-protein-coupled thyrotropin receptor (TSHR), controls the synthesis of thyroid hormone-an essential metabolic hormone(1-3). Aberrant signalling of TSHR by autoantibodies causes Graves' disease (hyperthyroidism) and hypothyroidism, both of which affect millions of patients worldwide(4). Here we report the active structures of TSHR with TSH and the activating autoantibody M22(5), both bound to the allosteric agonist ML-109(6), as well as an inactivated TSHR structure with the inhibitory antibody K1-70(7). Both TSH and M22 push the extracellular domain (ECD) of TSHR into an upright active conformation. By contrast, K1-70 blocks TSH binding and cannot push the ECD into 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 ten-residue fragment (P10) from the hinge C-terminal loop mediates ECD interactions with the TSHR transmembrane domain(8). One notable feature is that there are more than 15 cholesterols surrounding TSHR, supporting its preferential location in lipid rafts(9). These structures also highlight a similar ECD-push mechanism for TSH and autoantibody M22 to activate TSHR, therefore providing the molecular basis for Graves' disease.
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收录类别	SCI ; SCIE
语种	英语
资助项目	Ministry of Science and Technology (China)[2018YFA0507002] ; CAS Strategic Priority Research Program[XDB37030103] ; National Natural Science Foundation of China["32130022","32171187","82121005"] ; CAMS Innovation Fund for Medical Sciences["2021-CAMS-JZ004","2021-I2M-1-003"] ; Tsinghua University-Peking University Center for Life Sciences[045-61020100121] ; National Science & Technology Major Project 'Key New Drug Creation and Manufacturing Program' of China[2018ZX09711002] ; Science and Technology Commission of Shanghai Municipal[20431900100] ; Jack Ma Foundation[2020-CMKYGG-05]
WOS研究方向	Science & Technology - Other Topics
WOS类目	Multidisciplinary Sciences
WOS记录号	WOS:000852585100002
出版者	NATURE PORTFOLIO
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/229828
专题	免疫化学研究所_特聘教授组_蒋华良组生命科学与技术学院生命科学与技术学院_特聘教授组_徐华强组
通讯作者	Zhang, Shuyang; Jiang, Yi; Xu, H. Eric
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai, Peoples R China 2.Univ Chinese Acad Sci, Beijing, Peoples R China 3.Peking Union Med Coll & Chinese Acad Med Sci, Peking Union Med Coll Hosp, Dept Cardiol, Beijing, Peoples R China 4.Peking Union Med Coll & Chinese Acad Med Sci, Peking Union Med Coll Hosp, Med Res Ctr, Beijing, Peoples R China 5.Tsinghua Univ, Sch Med, Beijing, Peoples R China 6.Tsinghua Univ, Tsinghua Peking Ctr Life Sci, Beijing, Peoples R China 7.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China 8.Chinese Acad Sci, Ctr Immunol Dis, Shanghai Inst Mat Med, Shanghai, Peoples R China 9.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China 10.Lingang Lab, Shanghai, Peoples R China 11.MIT, McGovern Inst Brain Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA
通讯作者单位	生命科学与技术学院
推荐引用方式 GB/T 7714	Duan, Jia,Xu, Peiyu,Luan, Xiaodong,et al. Hormone- and antibody-mediated activation of the thyrotropin receptor[J]. NATURE,2022.
APA	Duan, Jia.,Xu, Peiyu.,Luan, Xiaodong.,Ji, Yujie.,He, Xinheng.,...&Xu, H. Eric.(2022).Hormone- and antibody-mediated activation of the thyrotropin receptor.NATURE.
MLA	Duan, Jia,et al."Hormone- and antibody-mediated activation of the thyrotropin receptor".NATURE (2022).