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Molecular recognition and activation mechanism of short-chain fatty acid receptors FFAR2/3

Cell Research volume 34, pages 323–326 (2024)Cite this article

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Dear Editor,

Saturated short-chain fatty acids (SCFAs) (with carbon chains containing 1–6 carbon atoms) a aliphatic organic acids derived from gut bacterial fermentation products. Different bacterial taxa are associated with the production of distinct SCFAs, which mediate diverse biological effects (Supplementary information, Table S1). SCFAs act as agonists for free fatty acid receptors 2 and 3 (FFAR2/3), which belong to G protein-coupled receptor (GPCR) superfamily.1 FFAR2/3 serve as messengers connecting gut microbiota and host, playing vital roles in regulating metabolism, inflammation and hormone homeostasis (Supplementary information, Fig. S1). They are also valuable targets for treating diabetes, obesity, asthma, allergies and inflammatory bowel disease (Supplementary information, Table S2).1,2 FFAR2 is activated by acetate (AA), propionate (PA) and butyrate (BA), while FFAR3 is primarily activated by C3–C6 saturated fatty acids, including PA, BA, valerate (VA) and caproate (CA).1 FFAR2 couples to Gαi and Gαq pathways, while FFAR3 primarily couples to Gαi pathway. Considering the vital physiological functions of SCFAs, a paucity of knowledge about the recognition patterns of C2–C4 and C3–C6 SCFAs by FFAR2 and FFAR3 results in the urgent need to elucidate the molecular mechanisms behind FFAR2/3 signaling.

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Fig. 1: Structure basis of FFAR2/3 activation and ligand selectivity.

Data availability

The cryo-EM density maps have been deposited in the Electron Microscopy Data Bank (EMDB) and Protein Data Bank (PDB) under accession numbers EMD-35944 and 8J24 for AA–FFAR2C complex; EMD-35942 and 8J22 for TUG-1375–FFAR2C complex; EMD-35941 and 8J21 for BA–FFAR3C complex; EMD-35940 and 8J20 for VA-AR420626–FFAR3C complex.

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Acknowledgements

We acknowledge support from the National Natural Science Foundation of China (22121003, 21837005, 91953202, 22193023, 32027901 and 31971200), the National Key R&D Program of China (2019YFA0904200, 2019YFA0904101, 2021YFA0910202 and 2022YFA1304701), the Strategic Priority Research Program of Chinese Academy of Sciences (XDB37040203) and the CAS Project for Young Scientists in Basic Research (YSBR-015 and YSBR-072-6).

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Author notes

  1. These authors contributed equally: Fahui Li, Linhua Tai, Xiaoyu Sun, Zhenyu Lv, Wenqin Tang.

Authors and Affiliations

  1. Institute of Biophysics, Chinese Academy of Sciences, Beijing, China

    Fahui Li, Linhua Tai, Xiaoyu Sun, Zhenyu Lv, Wenqin Tang, Ziyi Zhao, Daohong Gong, Shaohua Ma, Shichen Tang, Quanchang Gu, Xiaolei Zhu, Minling Yu, Xiaohong Liu & Jiangyun Wang

  2. School of Life Sciences, University of Chinese Academy of Sciences, Beijing, China

    Fahui Li, Xiaoyu Sun, Wenqin Tang, Ziyi Zhao, Shaohua Ma, Shichen Tang, Quanchang Gu, Xiaolei Zhu, Xiaohong Liu & Jiangyun Wang

  3. Key Laboratory of Biomacromolecules, Chinese Academy of Sciences, Beijing, China

    Fahui Li, Linhua Tai, Xiaoyu Sun, Zhenyu Lv, Wenqin Tang, Ziyi Zhao, Shaohua Ma, Shichen Tang, Quanchang Gu, Xiaolei Zhu, Xiaohong Liu & Jiangyun Wang

  4. iHuman Institute, ShanghaiTech University, Shanghai, China

    Tianxin Wang

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Contributions

J.W. organized the project. J.W., F.L., L.T. and X.L. guided all the structural analyses. J.W. and F.L. designed all the mutants for functional analyses. F.L., Q.G., Z.Z., S.M., S.T. and T.W. developed the FFAR2/3 constructs and optimized protein expression. F.L. performed protein expression. F.L., X.S. and D.G. prepared samples for cryo-EM. F.L. prepared the cryo-EM grids and collected the cryo-EM data. L.T. performed cryo-EM map calculation, model building, and structure refinement. W.T. performed the MD simulations. Z.L., X.Z. and M.Y. performed the functional assays. J.W. and F.L. wrote the manuscript. All the authors have read and commented on the manuscript.

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Correspondence to Jiangyun Wang.

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The authors declare no competing interests.

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Li, F., Tai, L., Sun, X. et al. Molecular recognition and activation mechanism of short-chain fatty acid receptors FFAR2/3. Cell Res 34, 323–326 (2024). https://doi.org/10.1038/s41422-023-00914-z

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