Synergistic activation of the human phosphate exporter XPR1 by KIDINS220 and inositol pyrophosphate

Peng Zuo, Weize Wang, Zonglin Dai, Jiye Zheng, Shang Yu, Guangxi Wang, Yue Yin, Ling Liang () and Yuxin Yin ()
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Peng Zuo: Peking University Health Science Center
Weize Wang: Peking University Health Science Center
Zonglin Dai: Peking University Health Science Center
Jiye Zheng: Peking University Health Science Center
Shang Yu: Peking University Health Science Center
Guangxi Wang: Peking University Health Science Center
Yue Yin: Peking University Health Science Center
Ling Liang: Peking University Health Science Center
Yuxin Yin: Peking University Health Science Center

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract 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 (InsP6) and phosphate, the complex adopts an outward-open conformation, with InsP6 binding the SPX domain and juxtamembrane regions, indicating active phosphate export. Without phosphate or InsP6, 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 InsP6. Functional mutagenesis shows that InsP6, 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.

Date: 2025
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DOI: 10.1038/s41467-025-58200-y

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