Structure and function of human XPR1 in phosphate export
Abstract Xenotropic and polytropic retrovirus receptor 1 (XPR1) functions as a phosphate exporter and is pivotal in maintaining human phosphate homeostasis. It has been identified as a causative gene for primary familial brain calcification. Here we present the cryogenic electron microscopy (cryo-EM...
Saved in:
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-03-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-58195-6 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850063905864286208 |
|---|---|
| author | Long Chen Jin He Mingxing Wang Ji She |
| author_facet | Long Chen Jin He Mingxing Wang Ji She |
| author_sort | Long Chen |
| collection | DOAJ |
| description | Abstract Xenotropic and polytropic retrovirus receptor 1 (XPR1) functions as a phosphate exporter and is pivotal in maintaining human phosphate homeostasis. It has been identified as a causative gene for primary familial brain calcification. Here we present the cryogenic electron microscopy (cryo-EM) structure of human XPR1 (HsXPR1). HsXPR1 exhibits a dimeric structure in which only TM1 directly constitutes the dimer interface of the transmembrane domain. Each HsXPR1 subunit can be divided spatially into a core domain and a scaffold domain. The core domain of HsXPR1 forms a pore-like structure, along which two phosphate-binding sites enriched with positively charged residues are identified. Mutations of key residues at either site substantially diminish the transport activity of HsXPR1. Phosphate binding at the central site may trigger a conformational change at TM9, leading to the opening of the extracellular gate. In addition, our structural analysis reveals a new conformational state of HsXPR1 in which the cytoplasmic SPX domains form a V-shaped structure. Altogether, our results elucidate the overall architecture of HsXPR1 and shed light on XPR1-mediated phosphate export. |
| format | Article |
| id | doaj-art-ccb6528b1f9d417c8fe89c31455ee30e |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-ccb6528b1f9d417c8fe89c31455ee30e2025-08-20T02:49:27ZengNature PortfolioNature Communications2041-17232025-03-011611810.1038/s41467-025-58195-6Structure and function of human XPR1 in phosphate exportLong Chen0Jin He1Mingxing Wang2Ji She3MOE Key Laboratory for Cellular Dynamics, Hefei National Research Center for Interdisciplinary Sciences at the Microscale, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of ChinaMOE Key Laboratory for Cellular Dynamics, Hefei National Research Center for Interdisciplinary Sciences at the Microscale, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of ChinaMOE Key Laboratory for Cellular Dynamics, Hefei National Research Center for Interdisciplinary Sciences at the Microscale, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of ChinaMOE Key Laboratory for Cellular Dynamics, Hefei National Research Center for Interdisciplinary Sciences at the Microscale, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of ChinaAbstract Xenotropic and polytropic retrovirus receptor 1 (XPR1) functions as a phosphate exporter and is pivotal in maintaining human phosphate homeostasis. It has been identified as a causative gene for primary familial brain calcification. Here we present the cryogenic electron microscopy (cryo-EM) structure of human XPR1 (HsXPR1). HsXPR1 exhibits a dimeric structure in which only TM1 directly constitutes the dimer interface of the transmembrane domain. Each HsXPR1 subunit can be divided spatially into a core domain and a scaffold domain. The core domain of HsXPR1 forms a pore-like structure, along which two phosphate-binding sites enriched with positively charged residues are identified. Mutations of key residues at either site substantially diminish the transport activity of HsXPR1. Phosphate binding at the central site may trigger a conformational change at TM9, leading to the opening of the extracellular gate. In addition, our structural analysis reveals a new conformational state of HsXPR1 in which the cytoplasmic SPX domains form a V-shaped structure. Altogether, our results elucidate the overall architecture of HsXPR1 and shed light on XPR1-mediated phosphate export.https://doi.org/10.1038/s41467-025-58195-6 |
| spellingShingle | Long Chen Jin He Mingxing Wang Ji She Structure and function of human XPR1 in phosphate export Nature Communications |
| title | Structure and function of human XPR1 in phosphate export |
| title_full | Structure and function of human XPR1 in phosphate export |
| title_fullStr | Structure and function of human XPR1 in phosphate export |
| title_full_unstemmed | Structure and function of human XPR1 in phosphate export |
| title_short | Structure and function of human XPR1 in phosphate export |
| title_sort | structure and function of human xpr1 in phosphate export |
| url | https://doi.org/10.1038/s41467-025-58195-6 |
| work_keys_str_mv | AT longchen structureandfunctionofhumanxpr1inphosphateexport AT jinhe structureandfunctionofhumanxpr1inphosphateexport AT mingxingwang structureandfunctionofhumanxpr1inphosphateexport AT jishe structureandfunctionofhumanxpr1inphosphateexport |