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-Structure paper
| タイトル | KIDINS220 and InsP8 safeguard the stepwise regulation of phosphate exporter XPR1. |
|---|---|
| ジャーナル・号・ページ | Mol Cell, Vol. 85, Issue 17, Page 3209-33224.e8, Year 2025 |
| 掲載日 | 2025年9月4日 |
著者 | Xiaojie Wang / Zhongjian Bai / Ciara Wallis / Huanchen Wang / Yaoyao Han / Ruitao Jin / Mingguang Lei / Tian Yang / Chunfang Gu / Henning Jessen / Stephen Shears / Yadong Sun / Ben Corry / Yixiao Zhang / ![]() |
| PubMed 要旨 | XPR1 is emerging as the only known inorganic phosphate (Pi) exporter in humans, critical for Pi homeostasis, with its activity stimulated by inositol pyrophosphate InsP8 and regulated by neuronal ...XPR1 is emerging as the only known inorganic phosphate (Pi) exporter in humans, critical for Pi homeostasis, with its activity stimulated by inositol pyrophosphate InsP8 and regulated by neuronal scaffold protein KIDINS220. Our structural studies reveal that InsP8 specifically activates XPR1 in a stepwise manner, involving profound SYG1/PHO/XPR1 (SPX) domain movements. Each XPR1 subunit functions with four gating states, in which Pi permeates a constriction site via a "knock-kiss-kick" process. By contrast, KIDINS220 delicately stabilizes XPR1 in a closed conformation through multiple mechanisms, one of which involves trapping the XPR1 α1 helix-critical for InsP8 binding-within an interaction hub. InsP8 serves as a key to release KIDINS220's restraint, reinforcing a "key-to-locks" mechanism to safeguard the stepwise activation. Additionally, our study provides direct structural insights into XPR1-associated neuronal disorders and highlights the evolutionary conservation and divergence among XPR1 orthologs, offering a comprehensive understanding of Pi homeostasis across species. |
リンク | Mol Cell / PubMed:40858110 / PubMed Central |
| 手法 | EM (単粒子) |
| 解像度 | 3.12 - 7.52 Å |
| 構造データ | EMDB-61859, PDB-9jxd: EMDB-61860, PDB-9jxe: EMDB-61861, PDB-9jxf: EMDB-61862, PDB-9jxg: EMDB-61863, PDB-9jxh: EMDB-61864, PDB-9jxi: EMDB-61865, PDB-9jxj: EMDB-61866, PDB-9jxk: EMDB-61867, PDB-9jxl: EMDB-61868, PDB-9jxm: EMDB-61869, PDB-9jxn: EMDB-61870, PDB-9jxo: EMDB-61871, PDB-9jxp: ![]() EMDB-61872: Cryo-EM structure of XPR1-KIDINS220 complex ![]() EMDB-61873: Local refinement of SPX and ARs in XPR1-KIDINS220 complex ![]() EMDB-61874: Local refinement of additional KIDINS220 TM-helix in XPR1-KIDINS220 complex EMDB-61875, PDB-9jxq: ![]() EMDB-61876: Cryo-EM structure of XPR1-KIDINS220-InsP8 complex EMDB-61877, PDB-9jxr: ![]() EMDB-61878: Cryo-EM structure of Drosophila melanogaster PXo ![]() EMDB-61879: Cryo-EM structure of PHO1 |
| 化合物 | ![]() ChemComp-I8P: ![]() ChemComp-HOH: ![]() ChemComp-PO4: |
| 由来 |
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キーワード | TRANSPORT PROTEIN / phosphate channel;phosphate exporter;PFBC / phosphate channel |
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