磷酸通道 XPR1 的焦磷酸肌醇门控结构基础

IF 44.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES Science Pub Date : 2024-11-15 DOI:10.1126/science.adp3252

Yi Lu, Chen-Xi Yue, Li Zhang, Deqiang Yao, Ying Xia, Qing Zhang, Xinchen Zhang, Shaobai Li, Yafeng Shen, Mi Cao, Chang-Run Guo, An Qin, Jie Zhao, Lu Zhou, Ye Yu, Yu Cao

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引用次数: 0

摘要

细胞内磷酸盐（Pi）的精确调节对细胞功能至关重要，XPR1 是人类唯一的 Pi 输出器官。由肌醇焦磷酸盐（PP-IPs）激活的 Pi 外流机制仍不清楚。本研究展示了多种构象的 XPR1 的冷冻电镜结构，揭示了 Pi 输出的跨膜途径和 PP-IPs 的双重结合激活模式。一个典型的结合位点位于 SPX 结构域的二聚体界面上，第二个偏向 PP-IPs 的位点位于跨膜结构域和 SPX 结构域之间。通过将结构研究与电生理分析相结合，我们将 XPR1 定性为一个 IPs/PP-IPs 激活的磷酸盐通道。其 TMD、SPX 结构域和 IPs/PP-IPs 之间的相互作用协调了其关闭态和开放态之间的构象转变。

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Structural basis for inositol pyrophosphate gating of the phosphate channel XPR1.

Precise regulation of intracellular phosphate (Pi) is critical for cellular function, with xenotropic and polytropic retrovirus receptor 1 (XPR1) serving as the sole Pi exporter in humans. The mechanism of Pi efflux, activated by inositol pyrophosphates (PP-IPs), has remained unclear. This study presents cryo-electron microscopy structures of XPR1 in multiple conformations, revealing a transmembrane pathway for Pi export and a dual-binding activation pattern for PP-IPs. A canonical binding site is located at the dimeric interface of Syg1/Pho81/XPR1 (SPX) domains, and a second site, biased toward PP-IPs, is found between the transmembrane and SPX domains. By integrating structural studies with electrophysiological analyses, we characterized XPR1 as an inositol phosphates (IPs)/PP-IPs-activated phosphate channel. The interplay among its transmembrane domains, SPX domains, and IPs/PP-IPs orchestrates the conformational transition between its closed and open states.

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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