9j51
CryoEM structure of human XPR1 in complex with phosphate in state A
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 PubMedXPR1 is the sole protein known to transport inorganic phosphate (Pi) out of cells, a function conserved across species from yeast to mammals. Human XPR1 variants lead to cerebral calcium-phosphate deposition and primary familial brain calcification (PFBC), a hereditary neurodegenerative disorder. Here, we present the cryo-EM structure of human XPR1 in both its Pi-unbound and various Pi-bound states. XPR1 features 10 transmembrane alpha-helices forming an ion channel-like structure, with multiple Pi recognition sites along the channel. Pathogenic mutations in two arginine residues, which line the translocation channel, disrupt Pi transport. Molecular dynamics 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 this sequential arrangement allows XPR1 to facilitate Pi ion passage via a "relay" process, and they establish a framework for the interpretation of disease-related mutations and for the development of future therapeutics. Structural insights into the mechanism of phosphate recognition and transport by XPR1.,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 Nat Commun. 2025 Jan 2;16(1):18. doi: 10.1038/s41467-024-55471-9. PMID:39747008[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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