| Structural highlights
Disease
S53A1_HUMAN Bilateral striopallidodentate calcinosis. The disease is caused by variants affecting the gene represented in this entry.
Function
S53A1_HUMAN Inorganic ion transporter that mediates phosphate ion export across plasma membrane. Plays a major role in phosphate homeostasis, preventing intracellular phosphate accumulation and possible calcium phosphate precipitation, ultimately preserving calcium signaling. The molecular mechanism of phosphate transport, whether electrogenic, electroneutral or coupled to other ions, remains to be elucidated (By similarity) (PubMed:23791524, PubMed:25938945, PubMed:31043717). Binds inositol hexakisphosphate (Ins6P) and similar inositol polyphosphates, such as 5-diphospho-inositol pentakisphosphate (5-InsP7), important intracellular signaling molecules involved in regulation of phosphate flux (PubMed:27080106).[UniProtKB:Q9Z0U0][1] [2] [3] [4]
Publication Abstract from PubMed
Inorganic phosphate (Pi) has essential metabolic and structural roles in living organisms. The Pi exporter, XPR1/SLC53A1, is critical for cellular Pi homeostasis. When intercellular Pi is high, cells accumulate inositol pyrophosphate (1,5-InsP(8)), a signaling molecule required for XPR1 function. Inactivating XPR1 mutations lead to brain calcifications, causing neurological symptoms including movement disorders, psychosis, and dementia. Here, cryo-electron microscopy structures of dimeric XPR1 and functional characterization delineate the substrate translocation pathway and how InsP(8) initiates Pi transport. Binding of InsP(8) to XPR1, but not the related inositol polyphosphate InsP(6), rigidifies the intracellular SPX domains, with InsP(8) bridging the dimers and SPX and transmembrane domains. Locked in this state, the C-terminal tail is sequestered, revealing the entrance to the transport pathway, thus explaining the obligate roles of the SPX domain and InsP(8). Together, these findings advance our understanding of XPR1 transport activity and expand opportunities for rationalizing disease mechanisms and therapeutic intervention.
, PMID:40113814[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Giovannini D, Touhami J, Charnet P, Sitbon M, Battini JL. Inorganic phosphate export by the retrovirus receptor XPR1 in metazoans. Cell Rep. 2013 Jun 27;3(6):1866-73. PMID:23791524 doi:10.1016/j.celrep.2013.05.035
- ↑ Legati A, Giovannini D, Nicolas G, Lopez-Sanchez U, Quintans B, Oliveira JR, Sears RL, Ramos EM, Spiteri E, Sobrido MJ, Carracedo A, Castro-Fernandez C, Cubizolle S, Fogel BL, Goizet C, Jen JC, Kirdlarp S, Lang AE, Miedzybrodzka Z, Mitarnun W, Paucar M, Paulson H, Pariente J, Richard AC, Salins NS, Simpson SA, Striano P, Svenningsson P, Tison F, Unni VK, Vanakker O, Wessels MW, Wetchaphanphesat S, Yang M, Boller F, Campion D, Hannequin D, Sitbon M, Geschwind DH, Battini JL, Coppola G. Mutations in XPR1 cause primary familial brain calcification associated with altered phosphate export. Nat Genet. 2015 Jun;47(6):579-81. doi: 10.1038/ng.3289. Epub 2015 May 4. PMID:25938945 doi:http://dx.doi.org/10.1038/ng.3289
- ↑ Wild R, Gerasimaite R, Jung JY, Truffault V, Pavlovic I, Schmidt A, Saiardi A, Jessen HJ, Poirier Y, Hothorn M, Mayer A. Control of eukaryotic phosphate homeostasis by inositol polyphosphate sensor domains. Science. 2016 Apr 14. pii: aad9858. PMID:27080106 doi:http://dx.doi.org/10.1126/science.aad9858
- ↑ López-Sánchez U, Nicolas G, Richard AC, Maltête D, Charif M, Ayrignac X, Goizet C, Touhami J, Labesse G, Battini JL, Sitbon M. Characterization of XPR1/SLC53A1 variants located outside of the SPX domain in patients with primary familial brain calcification. Sci Rep. 2019 May 1;9(1):6776. PMID:31043717 doi:10.1038/s41598-019-43255-x
- ↑ Zhu Q, Yaggi MF, Jork N, Jessen HJ, Diver MM. Transport and InsP(8) gating mechanisms of the human inorganic phosphate exporter XPR1. Nat Commun. 2025 Mar 20;16(1):2770. PMID:40113814 doi:10.1038/s41467-025-58076-y
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