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Structural basis of phosphate export by human XPR1

Cell Research volume 35, pages 313–316 (2025)Cite this article

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Dear Editor,

Inorganic phosphate (Pi) is an essential macronutrient for life, playing crucial roles in energy metabolism, macromolecule synthesis, cellular signaling, and the formation of bones and teeth. Its homeostasis is orchestrated through a finely tuned equilibrium of import and export processes. In humans, two Na+-dependent phosphate importer families, SLC34 and SLC20, have been established to be instrumental in phosphate import. However, our understanding of the phosphate export process remains limited. The only phosphate exporter proposed thus far in humans is XPR1, also denoted as SLC53A1. XPR1 was initially identified as a cell surface receptor for xenotropic and polytropic mouse leukemia viruses.1,2,3 Later investigations suggest that XPR1 might function as a phosphate exporter, as evidenced by cell-based assays.4 XPR1 mutations are linked to diseases including primary familial brain calcification (PFBC), hypophosphatemic rickets, and severe renal tubular dysfunction, possibly due to disturbance in cellular phosphate homeostasis.5,6 Recent research has underscored its pivotal role in the survival of certain cancers, such as ovarian clear cell carcinoma.7

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Fig. 1: Structural basis of phosphate transport by human XPR1.

Data availability

Atomic coordinates and cryo-EM maps of closed human XPR1 (PDB: 9j97; EMDB: EMD-61254) and open human XPR1 (PDB: 9j98; EMDB: EMD-61255) have been deposited in the Protein Data Bank (http://www.rcsb.org) and the Electron Microscopy Data Bank (https://www.ebi.ac.uk/pdbe/emdb/).

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Acknowledgements

We thank the Cryo-EM Facility and Supercomputer Center of Westlake University for providing data collection and computation support, respectively. This work was supported by the National Science Foundation of China (32122042 and 32071208 to H.S.), the Zhejiang Provincial Natural Science Foundation (DQ24C050001 to H.S.), and the Westlake Education Foundation (to H.S).

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Author notes

  1. These authors contributed equally: Yifei Wang, Yuechan Wang, Hui Yang.

Authors and Affiliations

  1. Zhejiang Key Laboratory of Structural Biology, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China

    Yifei Wang, Yuechan Wang, Hui Yang, Ao Li, Dan Ma & Huaizong Shen

  2. Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang, China

    Yifei Wang, Yuechan Wang, Hui Yang, Ao Li, Dan Ma & Huaizong Shen

  3. Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, Zhejiang, China

    Yifei Wang, Yuechan Wang, Hui Yang, Ao Li, Dan Ma & Huaizong Shen

Authors
  1. Yifei Wang
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  2. Yuechan Wang
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  3. Hui Yang
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  4. Ao Li
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  5. Dan Ma
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  6. Huaizong Shen
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Contributions

The project was conceived by H.S. Molecular cloning, phosphate efflux assay, protein expression profile examination, protein purification, cryo-EM sample preparation, and EM data collection were performed by Yifei W., H.Y. and A.L. Yuechan W. conducted the cryo-EM map reconstruction and model building. All authors contributed to the data analysis. The manuscript was written by H.S.

Corresponding author

Correspondence to Huaizong Shen.

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The authors declare no competing interests.

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Wang, Y., Wang, Y., Yang, H. et al. Structural basis of phosphate export by human XPR1. Cell Res 35, 313–316 (2025). https://doi.org/10.1038/s41422-025-01081-z

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  • DOI: https://doi.org/10.1038/s41422-025-01081-z

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