人類XPR1結構揭示磷酸鹽輸出機制
作者：小柯機器人 發布時間：2024/8/25 18:33:14
本期文章：《自然》：Online/在線發表
中國科學院物理研究所姜道華團隊近期取得重要工作進展，他們通過研究人類XPR1結構揭示了磷酸鹽輸出機制。相關研究成果2024年8月21日在線發表于《自然》雜志上。
據介紹，無機磷酸鹽（Pi）是所有生物體的基本常量營養素，其穩態對許多生物活動至關重要。作為迄今為止唯一已知的人類Pi輸出者，XPR1在細胞Pi穩態中起著不可或缺的作用。XPR1的功能障礙與神經退行性疾病有關。然而，XPR1介導的Pi外排和細胞內肌醇多磷酸鹽（InsPP）傳感器SPX結構域調節的機制仍然知之甚少。
研究人員以Pi結合的閉合、開放和InsP6結合形式展示了人類XPR1的冷凍電鏡結構，揭示了XPR1門控和InsPP調控的結構基礎。XPR1由N端SPX結構域、二聚體形成核心結構域和Pi轉運結構域組成。在運輸結構域內，三個基本簇負責Pi的結合和運輸，保守的W573充當門控的分子開關。
此外，SPX結構域與InsP6結合，并通過釋放限制Pi進入的C末端環來促進Pi流出。
總之，這一研究為真菌、植物和動物中XPR1同源物對Pi穩態的機制理解提供了一個概念框架。
附：英文原文
Title: Human XPR1 structures reveal phosphate export mechanism
Author: Yan, Rui, Chen, Huiwen, Liu, Chuanyu, Zhao, Jun, Wu, Di, Jiang, Juquan, Gong, Jianke, Jiang, Daohua
Issue&Volume: 2024-08-21
Abstract: Inorganic phosphate (Pi) is a fundamental macronutrient for all living organisms, the homeostasis of which is critical for numerous biological activities1,2,3. As the only known human Pi exporter to date, XPR1 has an indispensable role in cellular Pi homeostasis4,5. Dysfunction of XPR1 is associated with neurodegenerative disease6,7,8. However, the mechanisms underpinning XPR1-mediated Pi efflux and regulation by the intracellular inositol polyphosphate (InsPP) sensor SPX domain remain poorly understood. Here we present cryo-electron microscopy structures of human XPR1 in Pi-bound closed, open and InsP6-bound forms, revealing the structural basis for XPR1 gating and regulation by InsPPs. XPR1 consists of an N-terminal SPX domain, a dimer-formation core domain and a Pi transport domain. Within the transport domain, three basic clusters are responsible for Pi binding and transport, and a conserved W573 acts as a molecular switch for gating. In addition, the SPX domain binds to InsP6 and facilitates Pi efflux by liberating the C-terminal loop that limits Pi entry. This study provides a conceptual framework for the mechanistic understanding of Pi homeostasis by XPR1 homologues in fungi, plants and animals.
DOI: 10.1038/s41586-024-07852-9
Source: https://www.nature.com/articles/s41586-024-07852-9
期刊信息
Nature：《自然》，創刊于1869年。隸屬于施普林格·自然出版集團，最新IF：69.504
官方網址：http://www.nature.com/
投稿鏈接：http://www.nature.com/authors/submit_manuscript.html
