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Molecular basis of signal transduction mediated by the human GIPR splice variants

文献类型：期刊论文

作者Zhao, Fenghui8,9; Hang, Kaini6,7; Zhou, Qingtong4,5; Shao, Lijun6,7; Li, Hao4; Li, Wenzhuo8,9; Lin, Shi4; Dai, Antao8,9; Cai, Xiaoqing8,9; Liu, Yanyun3,8,9
刊名PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
出版日期2023-10-10
卷号120期号:41页码:12
关键词glucose-dependent insulinotropic polypeptide receptor splice variants cryo-EM biased signaling ligand-independent modulation
ISSN号0027-8424
DOI10.1073/pnas.2306145120
通讯作者Yang, Dehua(dhyang@simm.ac.cn) ; Wang, Ming-Wei(mwwang@simm.ac.cn)
英文摘要Glucose-dependent insulinotropic polypeptide receptor (GIPR) is a potential drug target for metabolic disorders. It works with glucagon-like peptide-1 receptor and glucagon receptor in humans to maintain glucose homeostasis. Unlike the other two receptors, GIPR has at least 13 reported splice variants (SVs), more than half of which have sequence variations at either C or N terminus. To explore their roles in endogenous peptide-mediated GIPR signaling, we determined the cryoelectron microscopy (cryo-EM) structures of the two N terminus-altered SVs (referred as GIPR-202 and GIPR-209 in the Ensembl database, SV1 and SV2 here, respectively) and investigated the outcome of coexpressing each of them in question with GIPR in HEK293T cells with respect to ligand binding, receptor expression, cAMP (adenosine 3,5-cyclic monophosphate) accumulation, beta-arrestin recruitment, and cell surface localization. It was found that while both N terminus-altered SVs of GIPR neither bound to the hormone nor elicited signal transduction per se, they suppressed ligand binding and cAMP accumulation of GIPR. Meanwhile, SV1 reduced GIPR-mediated beta-arrestin 2 responses. The cryo-EM structures of SV1 and SV2 showed that they reorganized the extracellular halves of transmembrane helices 1, 6, and 7 and extracellular loops 2 and 3 to adopt a ligand-binding pocket-occupied conformation, thereby losing binding ability to the peptide. The results suggest a form of signal bias that is constitutive and ligand-independent, thus expanding our knowledge of biased signaling beyond pharmacological manipulation (i.e., ligand specific) as well as constitutive and ligand-independent (e.g., SV1 of the growth hormone-releasing hormone receptor).
WOS关键词CHOLECYSTOKININ-B/GASTRIN RECEPTOR ; PROTEIN-COUPLED RECEPTORS ; INCRETIN HORMONES ; EXTRACELLULAR DOMAIN ; GLUCAGON ; ACTIVATION ; FAMILY ; GLP-1 ; POLYPEPTIDE ; PEPTIDE
资助项目National Natural Science Foundation of China[82273961] ; National Natural Science Foundation of China[81872915] ; National Natural Science Foundation of China[82073904] ; National Natural Science Foundation of China[82273985] ; National Natural Science Foundation of China[82121005] ; National Natural Science Foundation of China[81973373] ; National Natural Science Foundation of China[21704064] ; National Natural Science Foundation of China[82204474] ; National Science & Technology Major Project of China-Key New Drug Creation and Manufacturing Program[2018ZX09735-001] ; National Science & Technology Major Project of China-Key New Drug Creation and Manufacturing Program[2018ZX09711002-002005] ; National Science & Technology Major Project of China-Key New Drug Creation and Manufacturing Program[2021ZD0203400] ; National Science & Technology Major Project of China-Key New Drug Creation and Manufacturing Program[2022ZD0213000] ; National Key Basic Research Program of China[2018YFA0507000] ; Novo Nordisk-CAS Research Fund[NNCAS-2017-1-CC] ; SA-SIBS Scholarship Program ; China Postdoctoral Science Foundation[2022M713266] ; Shanghai Sailing Program[22YF1457200]
WOS研究方向Science & Technology - Other Topics
语种英语
WOS记录号WOS:001289160900003
出版者NATL ACAD SCIENCES
源URL[http://119.78.100.183/handle/2S10ELR8/312806]  
专题中国科学院上海药物研究所
通讯作者Yang, Dehua; Wang, Ming-Wei
作者单位1.Hainan Med Univ, Sch Pharm, Haikou 570228, Hainan, Peoples R China
2.Univ Tokyo, Sch Sci, Dept Chem, Tokyo 1130033, Japan
3.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
4.Res Ctr Deepsea Bioresources, Sanya 572025, Hainan, Peoples R China
5.Fudan Univ, Sch Basic Med Sci, Dept Pharmacol, Shanghai 200032, Peoples R China
6.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
7.ShanghaiTech Univ, IHuman Inst, Shanghai 201210, Peoples R China
8.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Chem Biol, Shanghai 201203, Peoples R China
9.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Zhao, Fenghui,Hang, Kaini,Zhou, Qingtong,et al. Molecular basis of signal transduction mediated by the human GIPR splice variants[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2023,120(41):12.
APA Zhao, Fenghui.,Hang, Kaini.,Zhou, Qingtong.,Shao, Lijun.,Li, Hao.,...&Wang, Ming-Wei.(2023).Molecular basis of signal transduction mediated by the human GIPR splice variants.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,120(41),12.
MLA Zhao, Fenghui,et al."Molecular basis of signal transduction mediated by the human GIPR splice variants".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 120.41(2023):12.

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来源：上海药物研究所

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