Structural insights into the mechanism of phosphate recognition and transport by XPR1
Abstract XPR1 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 dis...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55471-9 |
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| author | Wenhui Zhang Yanke Chen Zeyuan Guan Yong Wang Meng Tang Zhangmeng Du Jie Zhang Meng Cheng Jiaqi Zuo Yan Liu Qiang Wang Yanjun Liu Delin Zhang Ping Yin Ling Ma Zhu Liu |
| author_facet | Wenhui Zhang Yanke Chen Zeyuan Guan Yong Wang Meng Tang Zhangmeng Du Jie Zhang Meng Cheng Jiaqi Zuo Yan Liu Qiang Wang Yanjun Liu Delin Zhang Ping Yin Ling Ma Zhu Liu |
| author_sort | Wenhui Zhang |
| collection | DOAJ |
| description | Abstract XPR1 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 α-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. |
| format | Article |
| id | doaj-art-6ccfef41a01e4b2d91c33a8d5ae5203c |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-6ccfef41a01e4b2d91c33a8d5ae5203c2025-01-05T12:38:12ZengNature PortfolioNature Communications2041-17232025-01-0116111010.1038/s41467-024-55471-9Structural insights into the mechanism of phosphate recognition and transport by XPR1Wenhui Zhang0Yanke Chen1Zeyuan Guan2Yong Wang3Meng Tang4Zhangmeng Du5Jie Zhang6Meng Cheng7Jiaqi Zuo8Yan Liu9Qiang Wang10Yanjun Liu11Delin Zhang12Ping Yin13Ling Ma14Zhu Liu15National Key Laboratory of Crop Genetic Improvement, Hubei Hongshan Laboratory, Huazhong Agricultural UniversityNational Key Laboratory of Crop Genetic Improvement, Hubei Hongshan Laboratory, Huazhong Agricultural UniversityNational Key Laboratory of Crop Genetic Improvement, Hubei Hongshan Laboratory, Huazhong Agricultural UniversityCollege of Life Sciences, Zhejiang UniversityNational Key Laboratory of Crop Genetic Improvement, Hubei Hongshan Laboratory, Huazhong Agricultural UniversityNational Key Laboratory of Crop Genetic Improvement, Hubei Hongshan Laboratory, Huazhong Agricultural UniversityNational Key Laboratory of Crop Genetic Improvement, Hubei Hongshan Laboratory, Huazhong Agricultural UniversityNational Key Laboratory of Crop Genetic Improvement, Hubei Hongshan Laboratory, Huazhong Agricultural UniversityNational Key Laboratory of Crop Genetic Improvement, Hubei Hongshan Laboratory, Huazhong Agricultural UniversityNational Key Laboratory of Crop Genetic Improvement, Hubei Hongshan Laboratory, Huazhong Agricultural UniversityNational Key Laboratory of Crop Genetic Improvement, Hubei Hongshan Laboratory, Huazhong Agricultural UniversityNational Key Laboratory of Crop Genetic Improvement, Hubei Hongshan Laboratory, Huazhong Agricultural UniversityNational Key Laboratory of Crop Genetic Improvement, Hubei Hongshan Laboratory, Huazhong Agricultural UniversityNational Key Laboratory of Crop Genetic Improvement, Hubei Hongshan Laboratory, Huazhong Agricultural UniversityNational Key Laboratory of Crop Genetic Improvement, Hubei Hongshan Laboratory, Huazhong Agricultural UniversityNational Key Laboratory of Crop Genetic Improvement, Hubei Hongshan Laboratory, Huazhong Agricultural UniversityAbstract XPR1 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 α-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.https://doi.org/10.1038/s41467-024-55471-9 |
| spellingShingle | Wenhui Zhang Yanke Chen Zeyuan Guan Yong Wang Meng Tang Zhangmeng Du Jie Zhang Meng Cheng Jiaqi Zuo Yan Liu Qiang Wang Yanjun Liu Delin Zhang Ping Yin Ling Ma Zhu Liu Structural insights into the mechanism of phosphate recognition and transport by XPR1 Nature Communications |
| title | Structural insights into the mechanism of phosphate recognition and transport by XPR1 |
| title_full | Structural insights into the mechanism of phosphate recognition and transport by XPR1 |
| title_fullStr | Structural insights into the mechanism of phosphate recognition and transport by XPR1 |
| title_full_unstemmed | Structural insights into the mechanism of phosphate recognition and transport by XPR1 |
| title_short | Structural insights into the mechanism of phosphate recognition and transport by XPR1 |
| title_sort | structural insights into the mechanism of phosphate recognition and transport by xpr1 |
| url | https://doi.org/10.1038/s41467-024-55471-9 |
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