人类XPR1结构揭示磷酸盐输出机制
作者：小柯机器人 发布时间：2024/8/25 18:33:14
本期文章：《自然》：Online/在线发表
中国科学院物理研究所姜道华团队近期取得重要工作进展，他们通过研究人类XPR1结构揭示了磷酸盐输出机制。相关研究成果2024年8月21日在线发表于《自然》杂志上。
据介绍，无机磷酸盐（Pi）是所有生物体的基本常量营养素，其稳态对许多生物活动至关重要。作为迄今为止唯一已知的人类Pi输出者，XPR1在细胞Pi稳态中起着不可或缺的作用。XPR1的功能障碍与神经退行性疾病有关。然而，XPR1介导的Pi外排和细胞内肌醇多磷酸盐（InsPP）传感器SPX结构域调节的机制仍然知之甚少。
研究人员以Pi结合的闭合、开放和InsP6结合形式展示了人类XPR1的冷冻电镜结构，揭示了XPR1门控和InsPP调控的结构基础。XPR1由N端SPX结构域、二聚体形成核心结构域和Pi转运结构域组成。在运输结构域内，三个基本簇负责Pi的结合和运输，保守的W573充当门控的分子开关。
此外，SPX结构域与InsP6结合，并通过释放限制Pi进入的C末端环来促进Pi流出。
总之，这一研究为真菌、植物和动物中XPR1同源物对Pi稳态的机制理解提供了一个概念框架。
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》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html
