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PreprintCited 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 human XPR1

Open access
Liu, Zhu, Zhang, Wenhui, Chen, Yanke, Guan, Zeyuan, Du, Zhangmeng, Cheng, Meng, Zhang, Jie, Zuo, Jiaqi, Cheng, Peng, Wang, Qiang, Liu, Yanjun, Zhang, Delin, Yin, Ping·2024·Nature Communications
DOI 10.21203/rs.3.rs-3282549/v1PMC PMC11696373

Preprint — published as 10.1038/s41467-024-55471-9 · Paper page

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Abstract

XPR1 is the only known protein that transports inorganic phosphate (Pi) out of cells, and the function is conserved across species from yeast to mammals 1-4. Human XPR1 variants lead to cerebral calcium-phosphate deposition, which are associated with a neurodegenerative disorder known as primary familial brain calcification (PFBC)5. Here, we present the Cryo-EM structure of human XPR1 bound to Pi ions. XPR1 contains 10 transmembrane α-helices, forming an ion channel-like architecture that recognizes and transports Pi ions. Two arginine residues, subject to pathogenic mutation in PFBC families, line the translocation channel and serve to bind Pi ions. Clinically linked mutations of these arginine residues impair the Pi transport activity of XPR1. To track the movement of Pi ions within the translocation channel, we capture a mutant XPR1 in an alternative conformation. It reveals a rearrangement of intrahelical hydrogen bonds between a channel-lining tryptophan and two Pi-binding residues. This rearrangement links Pi recognition and transport, by means of flipping the tryptophan residue to propel Pi through the translocation channel. Our results provide mechanistic understanding of how XPR1 recognizes and transports phosphate ions across cell membrane, and they establish a framework for interpreting disease-related mutations and for the development of future therapeutics.

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Research works printed but not linked: 66

  1. Giovannini D, Touhami J, Charnet P, Sitbon M, Battini JL (2013) Inorganic Phosphate Export by the Retrovirus Receptor XPR1 in Metazoans. Cell Rep 3:1866–1873 · DOI
  2. Hurlimann BC, Stadler-Waibel M, Werner TP, Freimoser FM (2007) Pho91 is a vacuolar phosphate phosphate and polyphosphate Saccharomyces cerevisiae. Mol Biol Cell 18:4438–4445 · DOI
  3. Ma B et al (2021) A plasma membrane transporter coordinates phosphate reallocation and grain filling in cereals. Nat Genet 53:906–915 · DOI
  4. Xu C et al (2023) A phosphate-sensing organelle regulates phosphate and tissue homeostasis. Nature 617:798–806 · DOI
  5. Legati A et al (2015) Mutations in XPR1 cause primary familial brain calcification associated with altered phosphate export. Nat Genet 47:579–581 · DOI
  6. Kavanaugh MP, CELL-SURFACE RECEPTORS FOR GIBBON APE LEUKEMIA-VIRUS, AND AMPHOTROPIC MURINE RETROVIRUS ARE INDUCIBLE SODIUM-DEPENDENT PHOSPHATE SYMPORTERS et al (1994) Proc Natl Acad Sci USA 91:7071–7075 · DOI
  7. Olah Z, Lehel C, Anderson WB, Eiden MV, Wilson CA (1994) THE CELLULAR RECEPTOR FOR GIBBON APE LEUKEMIA-VIRUS IS A NOVEL HIGH-AFFINITY SODIUM-DEPENDENT PHOSPHATE TRANSPORTER. J Biol Chem 269:25426–25431 · DOI
  8. Hilfiker H et al (1998) Characterization of a murine type II sodium-phosphate cotransporter expressed in mammalian small intestine. Proc Natl Acad Sci USA 95:14564–14569 · DOI
  9. Murer H, Hernando N, Forster I, Biber J (2000) Proximal tubular phosphate reabsorption: Molecular mechanisms. Physiol Rev 80:1373–1409 · DOI
  10. Forster IC, Hernando N, Biber J, Murer H (2013) Phosphate transporters of the SLC20 and SLC34 families. Mol Aspects Med 34:386–395 · DOI
  11. Chande S, Bergwitz C (2018) Role of phosphate sensing in bone and mineral metabolism. Nat Reviews Endocrinol 14:637–655 · DOI
  12. Prie D, Friedlander G (2010) Genetic Disorders of Renal Phosphate Transport. N Engl J Med 362:2399–2409 · DOI
  13. Manghat P, Sodi R, Swaminathan R (2014) Phosphate homeostasis and disorders. Ann Clin Biochem 51:631–656 · DOI
  14. Tailor CS, Nouri A, Lee CG, Kozak C, Kabat D (1999) Cloning and characterization of a cell surface receptor for xenotropic and polytropic murine leukemia viruses. Proc Natl Acad Sci USA 96:927–932 · DOI
  15. Pedersen BP et al (2013) Crystal structure of a eukaryotic phosphate transporter. Nature 496:533–536 · DOI
  16. Tsai JY et al (2020) Structure of the sodium-dependent phosphate transporter reveals insights into human solute carrier SLC20. Sci Adv 6
  17. Liu Y et al (2021) Key computational findings reveal proton transfer as driving the functional cycle in the phosphate transporter PiPT. Proc Natl Acad Sci USA 118
  18. Lopez-Sanchez U et al (2020) Interplay between primary familial brain calcification-associated SLC20A2 and XPR1 phosphate transporters requires inositol polyphosphates for control of cellular phosphate homeostasis. J Biol Chem 295:9366–9378 · DOI
  19. Jennings ML (2023) Role of transporters in regulating mammalian intracellular inorganic phosphate. Front Pharmacol 14 · DOI
  20. Balck A et al (2021) Genotype-Phenotype Relations in Primary Familial Brain Calcification: Systematic MDSGene Review. Mov Disord 36:2468–2480 · DOI
  21. Yao XP et al (2017) Analysis of gene expression and functional characterization of XPR1: a pathogenic gene for primary familial brain calcification. Cell Tissue Res 370:267–273 · DOI
  22. Anheim M et al (2016) XPR1 mutations are a rare cause of primary familial brain calcification. J Neurol 263:1559–1564 · DOI
  23. Sobrido MJ, Coppola G, Oliveira J, Hopfer S, Geschwind DH (2014) Primary Familial Brain Calcification. GeneReviews http://www.ncbi.nlm.nih.gov/books/NBK1421/)
  24. Xu X et al (2023) The Pathology of Primary Familial Brain Calcification: Implications for Treatment. Neurosci Bull 39:659–674 · DOI
  25. Ramos EM et al (2018) Primary brain calcification: an international study reporting novel variants and associated phenotypes. Eur J Hum Genet 26:1462–1477 · DOI
  26. Mailer RK et al (2021) Xenotropic and polytropic retrovirus receptor 1 regulates procoagulant platelet polyphosphate. Blood 137:1392–1405 · DOI
  27. Bondeson DP et al (2022) Phosphate dysregulation via the XPR1-KIDINS220 protein complex is a therapeutic vulnerability in ovarian cancer. Nat Cancer · DOI
  28. Quintans B, Oliveira J, Sobrido M-J (2018) Primary familial brain calcifications. Handb Clin Neurol 147:307–317 · DOI
  29. Akasu-Nagayoshi Y et al (2022) PHOSPHATE exporter XPR1/SLC53A1 is required for the tumorigenicity of epithelial ovarian cancer. Cancer Sci 113:2034–2043 · DOI
  30. Li XY et al (2020) Control of XPR1-dependent cellular phosphate efflux by InsP(8) is an exemplar for functionally-exclusive inositol pyrophosphate signaling. Proc Natl Acad Sci USA 117:3568–3574 · DOI
  31. Moritoh Y et al (2021) The enzymatic activity of inositol hexakisphosphate kinase controls circulating phosphate in mammals. Nat Commun 12 · DOI
  32. Li XY et al (2024) Homeostatic coordination of cellular phosphate uptake and efflux requires an organelle-based receptor for the inositol pyrophosphate IP8. Cell Rep 43
  33. Wild R et al (2016) Control of eukaryotic phosphate homeostasis by inositol polyphosphate sensor domains. Science 352:986–990 · DOI
  34. Guan Z et al (2023) The cytoplasmic synthesis and coupled membrane translocation of eukaryotic polyphosphate by signal-activated VTC complex. Nat Commun 14:718 · DOI
  35. Guan ZY et al (2022) Mechanistic insights into the regulation of plant phosphate homeostasis by the rice SPX2-PHR2 complex. Nat Commun 13
  36. Zhou J et al (2021) Mechanism of phosphate sensing and signaling revealed by rice SPX1-PHR2 complex structure. Nat Commun 12 · DOI
  37. Wege S et al (2016) The EXS Domain of PHO1 Participates in the Response of Shoots to Phosphate Deficiency via a Root-to-Shoot Signal. Plant Physiol 170:385–400 · DOI
  38. Wang Y, Ribot C, Rezzonico E, Poirier Y (2004) Structure and expression profile of the Arabidopsis PHO1 gene family indicates a broad role in inorganic phosphate homeostasis. Plant Physiol 135:400–411 · DOI
  39. Holm L, Sander C, PROTEIN-STRUCTURE COMPARISON BY (1993) ALIGNMENT OF DISTANCE MATRICES. J Mol Biol 233:123–138 · DOI · Paper page
  40. Chovancova E et al (2012) CAVER 3.0: A Tool for the Analysis of Transport Pathways in Dynamic Protein Structures. PLoS Comput Biol 8 · DOI
  41. Sun LF et al (2012) Crystal structure of a bacterial homologue of glucose transporters GLUT1-4. Nature 490:361–366 · DOI
  42. Popova Y, Thayumanavan P, Lonati E, Agrochao M, Thevelein JM (2010) Transport and signaling through the phosphate-binding site of the yeast Pho84 phosphate transceptor. Proc Natl Acad Sci USA 107:2890–2895 · DOI
  43. Lopez-Sanchez U et al (2019) Characterization of XPR1/SLC53A1 variants located outside of the SPX domain in patients with primary familial brain calcification. Sci Rep 9 · DOI
  44. Guo XX et al (2019) Spectrum of SLC20A2, PDGFRB, PDGFB, and XPR1 mutations in a large cohort of patients with primary familial brain calcification. Hum Mutat 40:392–403 · DOI
  45. Orimo K et al (2023) A Japanese family with idiopathic basal ganglia calcification carrying a novel XPR1 variant. J Neurol Sci 451 · DOI
  46. Poirier Y, Thoma S, Somerville C, Schiefelbein J (1991) A MUTANT OF ARABIDOPSIS DEFICIENT IN XYLEM LOADING OF PHOSPHATE. Plant Physiol 97:1087–1093 · DOI
  47. Stefanovic A et al (2011) Over-expression of PHO1 in Arabidopsis leaves reveals its role in mediating phosphate efflux. Plant J 66:689–699 · DOI
  48. Quistgaard EM, Low C, Guettou F, Nordlund P (2016) Understanding transport by the major facilitator superfamily (MFS): structures pave the way. Nat Rev Mol Cell Biol 17:123–132 · DOI
  49. Drew D, North RA, Nagarathinam K, Tanabe M (2021) Structures and General Transport Mechanisms by the Major Facilitator Superfamily (MFS). Chem Rev 121:5289–5335 · DOI
  50. Shears SB (2015) Inositol pyrophosphates: why so many phosphates? Adv Biol Regul 57:203–216 · DOI
  51. Nagpal L, He S, Rao F, Snyder SH (2024) Inositol Pyrophosphates as Versatile Metabolic Messengers. Annu Rev Biochem 93:317–338 · DOI
  52. Zheng SQ et al (2017) MotionCor2: anisotropic correction of beam-induced motion for improved cryo-electron microscopy. Nat Methods 14:331–332 · DOI
  53. Rohou A, Grigorieff N (2015) CTFFIND4: Fast and accurate defocus estimation from electron micrographs. J Struct Biol 192:216–221 · DOI
  54. Punjani A, Rubinstein JL, Fleet DJ, Brubaker M (2017) A. cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination. Nat Methods 14:290–296 · DOI · Paper page
  55. Zhong ED, Bepler T, Berger B, Davis JH (2021) CryoDRGN: reconstruction of heterogeneous cryo-EM structures using neural networks. Nat Methods 18:176–185 · DOI
  56. Zivanov J et al (2018) New tools for automated high-resolution cryo-EM structure determination in RELION-3. Elife 7 · DOI
  57. Kucukelbir A, Sigworth FJ, Tagare HD (2014) Quantifying the local resolution of cryo-EMEM density maps. Nat Methods 11:63–65 · DOI
  58. Brown A et al (2015) Tools for macromolecular model building and refinement into electron cryo-microscopy reconstructions. Acta Crystallogr Sect D-Structural Biology 71:136–153 · DOI
  59. Afonine PV et al (2018) Real-space refinement in PHENIX for cryo-EM and crystallography. Acta Crystallogr Sect D-Structural Biology 74:531–544 · DOI
  60. Williams CJ et al (2018) MolProbity: More and better reference data for improved all-atom structure validation. Protein Sci 27:293–315 · DOI · Paper page
  61. Jo S, Kim T, Iyer VG, Im W (2008) Software news and updates - CHARNIM-GUI: A web-based grraphical user interface for CHARMM. J Comput Chem 29:1859–1865 · DOI · Paper page
  62. Huang J et al (2017) CHARMM36m: an improved force field for folded and intrinsically disordered proteins. Nat Methods 14:71–73 · DOI
  63. Olsson MHM, Sondergaard CR, Rostkowski M, Jensen JH (2011) PROPKA3: Consistent Treatment of Internal and Surface Residues in Empirical pKa Predictions. J Chem Theory Comput 7:525–537 · DOI
  64. Páll S, Abraham MJ, Kutzner C, Hess B, Lindahl E (2015) Tackling exascale software challenges in molecular dynamics simulations with GROMACS. 2nd International Conference on Exascale Applications and Software (EASC). 3–27
  65. Bonomi M et al (2019) Promoting transparency and reproducibility in enhanced molecular simulations. Nat Methods 16:670–673 · DOI
  66. Briones R, Biau C, Kutzner C, de Groot BL, Aponte-Santamaría C (2019) GROmaρs: A GROMACS-Based Toolset to Analyze Density Maps Derived from Molecular Dynamics Simulations. Biophys J 116:4–11 · DOI

Metadata

Authors
Liu, Z., Zhang, W., Chen, Y., Guan, Z., Du, Z., Cheng, M., Zhang, J., Zuo, J., Cheng, P., Wang, Q., Liu, Y., Zhang, D., & Yin, P.
Affiliations
  • Huazhong Agricultural University (CN)
  • Huazhong Agricultural University
Corresponding author
Liu, Zhu
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2024-08-29
Volume
16
Issue
1
Pages
18-18
ISSN
2041-1723 (ISSN-L)
DOI
10.21203/rs.3.rs-3282549/v1
PMC
PMC11696373
OpenAlex
W4406002903
Cited by
20
References
1
Citations by year
2026: 12 · 2025: 7 · 2024: 1
FWCI
5.67
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 Natural Science Foundation of China (32371300, 32071226)
  • Zhejiang University
  • Huazhong Agricultural University
  • University of Science and Technology of China
  • National Postdoctoral Program for Innovative Talents
  • National Key Research and Development Program of China
  • Fundamental Research Funds for the Central Universities (2662023PY001)
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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