Synergistic activation of the human phosphate exporter XPR1 by KIDINS220 and inositol pyrophosphate
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-fre...
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Nature Portfolio
2025-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-58200-y |
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| author | Peng Zuo Weize Wang Zonglin Dai Jiye Zheng Shang Yu Guangxi Wang Yue Yin Ling Liang Yuxin Yin |
| author_facet | Peng Zuo Weize Wang Zonglin Dai Jiye Zheng Shang Yu Guangxi Wang Yue Yin Ling Liang Yuxin Yin |
| author_sort | Peng Zuo |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-e43e732f452241ef80e37d65fd1e00b2 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-e43e732f452241ef80e37d65fd1e00b22025-08-20T03:40:48ZengNature PortfolioNature Communications2041-17232025-03-0116111310.1038/s41467-025-58200-ySynergistic activation of the human phosphate exporter XPR1 by KIDINS220 and inositol pyrophosphatePeng Zuo0Weize Wang1Zonglin Dai2Jiye Zheng3Shang Yu4Guangxi Wang5Yue Yin6Ling Liang7Yuxin Yin8Institute of Systems Biomedicine, Department of Pathology, Beijing Key Laboratory of Tumor Systems Biology, School of Basic Medical Sciences, Peking University Health Science CenterInstitute of Systems Biomedicine, Department of Pathology, Beijing Key Laboratory of Tumor Systems Biology, School of Basic Medical Sciences, Peking University Health Science CenterInstitute of Systems Biomedicine, Department of Pathology, Beijing Key Laboratory of Tumor Systems Biology, School of Basic Medical Sciences, Peking University Health Science CenterDepartment of Biophysics, School of Basic Medical Sciences, Peking University Health Science CenterDepartment of Biophysics, School of Basic Medical Sciences, Peking University Health Science CenterInstitute of Systems Biomedicine, Department of Pathology, Beijing Key Laboratory of Tumor Systems Biology, School of Basic Medical Sciences, Peking University Health Science CenterDepartment of Pharmacology, School of Basic Medical Sciences, Peking University Health Science CenterInstitute of Systems Biomedicine, Department of Pathology, Beijing Key Laboratory of Tumor Systems Biology, School of Basic Medical Sciences, Peking University Health Science CenterInstitute of Systems Biomedicine, Department of Pathology, Beijing Key Laboratory of Tumor Systems Biology, School of Basic Medical Sciences, Peking University Health Science CenterAbstract 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.https://doi.org/10.1038/s41467-025-58200-y |
| spellingShingle | Peng Zuo Weize Wang Zonglin Dai Jiye Zheng Shang Yu Guangxi Wang Yue Yin Ling Liang Yuxin Yin Synergistic activation of the human phosphate exporter XPR1 by KIDINS220 and inositol pyrophosphate Nature Communications |
| title | Synergistic activation of the human phosphate exporter XPR1 by KIDINS220 and inositol pyrophosphate |
| title_full | Synergistic activation of the human phosphate exporter XPR1 by KIDINS220 and inositol pyrophosphate |
| title_fullStr | Synergistic activation of the human phosphate exporter XPR1 by KIDINS220 and inositol pyrophosphate |
| title_full_unstemmed | Synergistic activation of the human phosphate exporter XPR1 by KIDINS220 and inositol pyrophosphate |
| title_short | Synergistic activation of the human phosphate exporter XPR1 by KIDINS220 and inositol pyrophosphate |
| title_sort | synergistic activation of the human phosphate exporter xpr1 by kidins220 and inositol pyrophosphate |
| url | https://doi.org/10.1038/s41467-025-58200-y |
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