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TitleSynergistic activation of the human phosphate exporter XPR1 by KIDINS220 and inositol pyrophosphate.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 2879, Year 2025
Publish dateMar 24, 2025
AuthorsPeng Zuo / Weize Wang / Zonglin Dai / Jiye Zheng / Shang Yu / Guangxi Wang / Yue Yin / Ling Liang / Yuxin Yin /
PubMed AbstractInorganic 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 ...Inorganic 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) and phosphate, the complex adopts an outward-open conformation, with InsP binding the SPX domain and juxtamembrane regions, indicating active phosphate export. Without phosphate or InsP, 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. Functional mutagenesis shows that InsP, 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.
External linksNat Commun / PubMed:40128258 / PubMed Central
MethodsEM (single particle)
Resolution3.03 - 3.8 Å
Structure data

60704

9ine

EMDB-60704, PDB-9ine:
Cryo-EM structure of human XPR1 in closed state in the presence of KIDINS220-1-432
Method: EM (single particle) / Resolution: 3.32 Å

60705

9inf

EMDB-60705, PDB-9inf:
Cryo-EM structure of human XPR1 in closed state in the presence of KIDINS220-1-432 and 10 mM KH2PO4
Method: EM (single particle) / Resolution: 3.36 Å

60707

9inh

EMDB-60707, PDB-9inh:
Cryo-EM structure of human XPR1 in complex with InsP6 in outward-facing state (SPX visible)-in the presence of KIDINS220-1-432 and 10 mM KH2PO4
Method: EM (single particle) / Resolution: 3.68 Å

60861

9itg

EMDB-60861, PDB-9itg:
Cryo-EM structure of human XPR1-E622A/F623A mutant in complex with InsP6 in inward-facing state in the presence of 10 mM KH2PO4
Method: EM (single particle) / Resolution: 3.03 Å

60897

9iuc

EMDB-60897, PDB-9iuc:
Cryo-EM structure of human XPR1 in complex with InsP6 in closed state - in the presence of KIDINS220-1-432 without substrate KH2PO4
Method: EM (single particle) / Resolution: 3.8 Å

Chemicals

ChemComp-CLR:
CHOLESTEROL

ChemComp-3PE:
1,2-Distearoyl-sn-glycerophosphoethanolamine / phospholipid*YM

ChemComp-LPE:
1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHOCHOLINE

ChemComp-PLM:
PALMITIC ACID

ChemComp-ACD:
ARACHIDONIC ACID

ChemComp-HOH:
WATER

ChemComp-IHP:
INOSITOL HEXAKISPHOSPHATE

ChemComp-PO4:
PHOSPHATE ION

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

ChemComp-1T9:
(2S,3R,4E)-3-hydroxy-2-(octanoylamino)octadec-4-en-1-yl dihydrogen phosphate

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / SLC53A1 / transporter / phosphate

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