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Cited by 20Ion channel regulation and functionIon Transport and Channel RegulationErythrocyte Function and Pathophysiology

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Structural insights into the mechanism of phosphate recognition and transport by XPR1

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Zhang, Wenhui, Chen, Yanke, Guan, Zeyuan, Wang, Yong, Tang, Meng, Du, Zhangmeng, Zhang, Jie, Cheng, Meng, Zuo, Jiaqi, Liu, Yan, Wang, Qiang, Liu, Yanjun, Zhang, Delin, Yin, Ping, Ma, Ling, Liu, Zhu·2025·Nature Communications
DOI 10.1038/s41467-024-55471-9PMC PMC11696373

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Abstract

Abstract XPR1 is the only known protein responsible for transporting inorganic phosphate (Pi) out of cells, a function conserved from yeast to mammals. Human XPR1 variants lead to cerebral calcium-phosphate deposition, which are associated with a hereditary neurodegenerative disorder known as primary familial brain calcification (PFBC). Here, we present the cryo-EM structure of human XPR1 in both its Pi-unbound form and various Pi-bound states. XPR1 features 10 transmembrane α-helices that form an ion channel-like architecture. Multiple Pi recognition sites are arranged along the channel, facilitating Pi ion transport. Two arginine residues, subject to pathogenic mutation in PFBC families, line the translocation channel and serve to bind Pi ion. Clinically linked mutations in these arginines impair XPR1’s Pi transport activity. To gain dynamic insights into the channel-like transport mechanism, we conducted molecular dynamics simulations. The simulations reveal that Pi ion undergoes a stepwise transition through the sequential recognition sites during the transport process. Together with functional analyses, our results suggest that the sequential arrangement of Pi recognition sites likely enable XPR1 to use a “relay” process to facilitate Pi ion passage through the channel, and they establish a framework for the interpretation of disease-related mutations and for the development of future therapeutics. One Sentence Summary Combined cryo-EM, molecular dynamics simulations and functional studies demonstrate that human XPR1 employs a channel-like transport mechanism to export inorganic phosphate out of cells

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Metadata

Authors
Zhang, W., Chen, Y., Guan, Z., Wang, Y., Tang, M., Du, Z., Zhang, J., Cheng, M., Zuo, J., Liu, Y., Wang, Q., Liu, Y., Zhang, D., Yin, P., Ma, L., & Liu, Z.
Affiliations
  • Huazhong Agricultural University (CN)
  • Zhejiang University (CN)
Corresponding author
Liu, Zhu
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2025-01-02
Volume
16
Issue
1
Pages
18-18
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-024-55471-9
PMC
PMC11696373
OpenAlex
W4406002903
Cited by
20
References
1
Citations by year
2026: 12 · 2025: 7
FWCI
5.71
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Key Research and Development Program of China
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
  • Health Sciences › Medicine › Physiology (medical) › Erythrocyte Function and Pathophysiology
Keywords
XPR1, inorganic phosphate transport, phosphate recognition, Fahr disease, transmembrane ion channels, arginine mutations, cryo-EM structure, molecular dynamics simulation
MeSH terms
Xenotropic and Polytropic Retrovirus Receptor, Binding Sites, Biological Transport, Humans, Mutation, Phosphates, Cryoelectron Microscopy, Receptors, G-Protein-Coupled, Molecular Dynamics Simulation, HEK293 Cells

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