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Structural basis of omega-3 fatty acid receptor FFAR4 activation and G protein coupling selectivity

Cell Research volume 33, pages 644–647 (2023)Cite this article

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Dear Editor,

Omega (ω)-3 fatty acids are known to have multiple beneficial effects on health, including anti-inflammation, enhancement of glucose uptake and promotion of brain development.1 The effects of ω-3 fatty acids are mainly mediated by free fatty acid receptor 4 (FFAR4, also known as GPR120), a member of G protein-coupled receptor (GPCR) superfamily. FFAR4 plays crucial roles in maintaining metabolic homeostasis via regulating adipogenesis, insulin sensitivity and inflammation, and is a highly valuable target for treating metabolic diseases such as diabetes. Other FFARs include FFAR1 (GPR40) which responds to long-chain FFAs (> 12 carbons), and FFAR2 (GPR43) and FFAR3 (GPR41) that respond to short-chain FFAs (< 6 carbons). FFAR4 responds to long-chain FFAs, and a common feature of FFAR4 ligands is the existence of multiple cis double-bonds on the acyl chain of the fatty acids, such as α-linolenic acid (18:3, aLa), stearidonic acid (18:4), eicosapentaenoic acid (20:5, EPA) and docosahexaenoic acid (22:6, DHA).1 FFAR4 primarily couples to Gq pathway, but also has been reported to signal through Gs and Gi.1

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Fig. 1: Structure basis of FFAR4 activation and G protein selectivity.

Data availability

All data produced or analyzed in this study are included in the main text or the supplementary materials. The cryo-EM density maps and atomic coordinates have been deposited in the Electron Microscopy Data Bank (EMDB) and Protein Data Bank (PDB) under accession numbers EMD-34479 and 8H4K for FFAR4/GW9508/miniGsq complex, EMD-34480 and 8H4L for FFAR4/DHA/miniGsq complex, EMD-34478 and 8H4I for FFAR4/DHA/miniGs complex, and EMD-35830 and 8IYS for FFAR4/TUG-891/Gq complex, respectively.

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Acknowledgements

We thank Kayo Sato, Shigeko Nakano and Ayumi Inoue (Tohoku University) for their assistance in plasmid preparation, maintenance of cell culture and the cell-based GPCR assays. We also thank Kouki Kawakami and Tatsuya Ikuta for the setup of the HiBiT assay. This work was supported by the Startup Funds of HIT Center for Life Sciences; the National Natural Science Foundation of China (32070048 to Y.H.). A.I. was funded by Japan Society for the Promotion of Science (JSPS) KAKENHI grants (21H04791, 21H05113, JPJSBP120213501 and JPJSBP120218801); the FOREST Program grant (JPMJFR215T) and the Moonshot Research and Development Program grant (JPMJMS2023) from the Japan Science and Technology Agency (JST).

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Authors and Affiliations

  1. Laboratory of Receptor Structure and Signaling, HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang, China

    Han Yin, Zhengxiong Ma, Xinyan Zhu, Ruixue Xia, Zhenmei Xu, Na Wang, Yaning Duan, Anqi Zhang, Changyou Guo & Yuanzheng He

  2. Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, Sendai, Miyagi, Japan

    Asuka Inoue

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Contributions

H.Y. initialed the project, made the expression constructs, purified the proteins, prepared and screened grids for cryo-EM, performed functional assays and edited the manuscript. A.I. performed TGF-α shedding assay, analyzed data and edited the manuscript. Z.M, X.Z., R.X., Z.X., N.W. and Y.D. set up the experiments, prepared plasmids and cultured cells. A.Z. and C.G. collected the cryo-EM data. Y.H. conceived the project, designed experiments, analyzed data, solved the structures, performed docking, wrote the manuscript and supervised the whole project.

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Correspondence to Yuanzheng He.

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Yin, H., Inoue, A., Ma, Z. et al. Structural basis of omega-3 fatty acid receptor FFAR4 activation and G protein coupling selectivity. Cell Res 33, 644–647 (2023). https://doi.org/10.1038/s41422-023-00835-x

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