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Cryo-EM structure of human XPR1 in closed state in the presence of KIDINS220-1-432 and 10 mM KH2PO4
Structural highlights
DiseaseS53A1_HUMAN Bilateral striopallidodentate calcinosis. The disease is caused by variants affecting the gene represented in this entry. FunctionS53A1_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 PubMedInorganic phosphate (Pi) is essential for life, and its intracellular levels must be tightly regulated to avoid toxicity. XPR1, the sole known phosphate exporter, is critical for maintaining this balance. Here we report cryo-EM structures of the human XPR1-KIDINS220 complex in substrate-free closed and substrate-bound outward-open states, as well as an XPR1 mutant in a substrate-bound inward-facing state. In the presence of inositol hexaphosphate (InsP(6)) and phosphate, the complex adopts an outward-open conformation, with InsP(6) binding the SPX domain and juxtamembrane regions, indicating active phosphate export. Without phosphate or InsP(6), the complex closes, with transmembrane helix 9 blocking the outward cavity and a C-terminal loop obstructing the intracellular cavity. XPR1 alone remains closed even with phosphate and InsP(6). Functional mutagenesis shows that InsP(6), whose levels vary with Pi availability, works with KIDINS220 to regulate XPR1 activity. These insights into phosphate regulation may aid in developing therapies for ovarian cancer. Synergistic activation of the human phosphate exporter XPR1 by KIDINS220 and inositol pyrophosphate.,Zuo P, Wang W, Dai Z, Zheng J, Yu S, Wang G, Yin Y, Liang L, Yin Y Nat Commun. 2025 Mar 24;16(1):2879. doi: 10.1038/s41467-025-58200-y. PMID:40128258[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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