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

Author:

Zhao Fenghui12,Hang Kaini34,Zhou Qingtong56ORCID,Shao Lijun34,Li Hao6,Li Wenzhuo12,Lin Shi6,Dai Antao12,Cai Xiaoqing12,Liu Yanyun127,Xu Yingna5,Feng Wenbo5ORCID,Yang Dehua1267ORCID,Wang Ming-Wei5689ORCID

Affiliation:

1. The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China

2. State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China

3. iHuman Institute, ShanghaiTech University, Shanghai 201210, China

4. School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China

5. Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China

6. Research Center for Deepsea Bioresources, Sanya, Hainan 572025, China

7. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China

8. Department of Chemistry, School of Science, The University of Tokyo, Tokyo 113-0033, Japan

9. School of Pharmacy, Hainan Medical University, Haikou 570228, China

Abstract

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, β-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 β-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).

Funder

MOST | National Natural Science Foundation of China

National Science and Technology Major Project

STI2030-Major Project

National Key Basic Research Program of China

Novo Nordisk-CAS Research Fund

SA-SIBS Scholarship Program

China Postdoctoral Science Foundation

Shanghai Sailing Program

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

Reference76 articles.

1. GPCR Signaling and Trafficking: The Long and Short of It

2. Signaling mechanisms of GPCR ligands;Strange P. G.;Curr. Opin. Drug. Discov. Dev.,2008

3. Combinatorial expression of GPCR isoforms affects signalling and drug responses

4. Consequences of splice variation on Secretin family G protein-coupled receptor function

5. A misspliced form of the cholecystokinin-B/gastrin receptor in pancreatic carcinoma: Role of reduced sellular U2AF35 and a suboptimal 3’-splicing site leading to retention of the fourth intron;Ding W. Q.;Cancer Res.,2002

Cited by 1 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. The unexpected role of GIP in transforming obesity treatment;Trends in Endocrinology & Metabolism;2024-08

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3