Structural mechanism of cooperative activation of the human calcium-sensing receptor by Ca2+ ions and L-tryptophan | |
Ling, Shenglong1,2; Shi, Pan1,2; Liu, Sanling1,2; Meng, Xianyu1,2; Zhou, Yingxin1,2; Sun, Wenjing1,2; Chang, Shenghai3; Zhang, Xing3; Zhang, Longhua1,2; Shi, Chaowei1,2 | |
刊名 | CELL RESEARCH |
2021-02-18 | |
ISSN号 | 1001-0602 |
DOI | 10.1038/s41422-021-00474-0 |
通讯作者 | Sun, Demeng(dmsun@ustc.edu.cn) ; Liu, Lei(lliu@mail.tsinghua.edu.cn) ; Tian, Changlin(cltian@ustc.edu.cn) |
英文摘要 | The human calcium-sensing receptor (CaSR) is a class C G protein-coupled receptor (GPCR) responsible for maintaining Ca2+ homeostasis in the blood. The general consensus is that extracellular Ca2+ is the principal agonist of CaSR. Aliphatic and aromatic L-amino acids, such as L-Phe and L-Trp, increase the sensitivity of CaSR towards Ca2+ and are considered allosteric activators. Crystal structures of the extracellular domain (ECD) of CaSR dimer have demonstrated Ca2+ and L-Trp binding sites and conformational changes of the ECD upon Ca2+/L-Trp binding. However, it remains to be understood at the structural level how Ca2+/L-Trp binding to the ECD leads to conformational changes in transmembrane domains (TMDs) and consequent CaSR activation. Here, we determined the structures of full-length human CaSR in the inactive state, Ca2+- or L-Trp-bound states, and Ca2+/L-Trp-bound active state using single-particle cryo-electron microscopy. Structural studies demonstrate that L-Trp binding induces the closure of the Venus flytrap (VFT) domain of CaSR, bringing the receptor into an intermediate active state. Ca2+ binding relays the conformational changes from the VFT domains to the TMDs, consequently inducing close contact between the two TMDs of dimeric CaSR, activating the receptor. Importantly, our structural and functional studies reveal that Ca2+ ions and L-Trp activate CaSR cooperatively. Amino acids are not able to activate CaSR alone, but can promote the receptor activation in the presence of Ca2+. Our data provide complementary insights into the activation of class C GPCRs and may aid in the development of novel drugs targeting CaSR. |
资助项目 | National Natural Science Foundation of China[21825703] ; National Natural Science Foundation of China[21778051] ; National Natural Science Foundation of China[91753205] ; National Natural Science Foundation of China[31971152] ; National Key R&D Program of China[2017YFA0505400] ; National Key R&D Program of China[2017YFA0505200] ; National Key R&D Program of China[2016YFA0400900] ; National Key R&D Program of China[2017YFA0505300] ; China Postdoctoral Science Foundation[2017M612084] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDB37000000] ; Amgen Postdoc Fellowship (China) |
WOS研究方向 | Cell Biology |
语种 | 英语 |
出版者 | SPRINGERNATURE |
WOS记录号 | WOS:000619400000003 |
资助机构 | National Natural Science Foundation of China ; National Key R&D Program of China ; China Postdoctoral Science Foundation ; Strategic Priority Research Program of the Chinese Academy of Sciences ; Amgen Postdoc Fellowship (China) |
内容类型 | 期刊论文 |
源URL | [http://ir.hfcas.ac.cn:8080/handle/334002/120221] |
专题 | 中国科学院合肥物质科学研究院 |
通讯作者 | Sun, Demeng; Liu, Lei; Tian, Changlin |
作者单位 | 1.Univ Sci & Technol China, Hefei Natl Lab Phys Sci Microscale, Anhui Lab Adv Photon Sci & Technol, Hefei 230026, Anhui, Peoples R China 2.Univ Sci & Technol China, Sch Life Sci, Hefei 230026, Anhui, Peoples R China 3.Zhejiang Univ, Sch Med, Hangzhou 310011, Zhejiang, Peoples R China 4.Tsinghua Univ, Dept Chem, Tsinghua Peking Joint Ctr Life Sci, Minist Educ,Key Lab Bioorgan Phosphorus Chem & Ch, Beijing 100084, Peoples R China 5.Chinese Acad Sci, High Field Magnet Lab, Hefei 230030, Anhui, Peoples R China 6.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China |
推荐引用方式 GB/T 7714 | Ling, Shenglong,Shi, Pan,Liu, Sanling,et al. Structural mechanism of cooperative activation of the human calcium-sensing receptor by Ca2+ ions and L-tryptophan[J]. CELL RESEARCH,2021. |
APA | Ling, Shenglong.,Shi, Pan.,Liu, Sanling.,Meng, Xianyu.,Zhou, Yingxin.,...&Tian, Changlin.(2021).Structural mechanism of cooperative activation of the human calcium-sensing receptor by Ca2+ ions and L-tryptophan.CELL RESEARCH. |
MLA | Ling, Shenglong,et al."Structural mechanism of cooperative activation of the human calcium-sensing receptor by Ca2+ ions and L-tryptophan".CELL RESEARCH (2021). |
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