Precise regulation of intracellular phosphate (Pi) is critical for cellular function, with 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 by PP-IPs. A canonical binding site is located at the dimeric interface of 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 characterize XPR1 as an IPs/PP-IPs-activated phosphate channel. The interplay among its TMDs, SPX domains, and IPs/PP-IPs orchestrates the conformational transition between its closed and open states.

中文翻译：

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磷酸盐通道 XPR1 的肌醇焦磷酸门控的结构基础


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 输出源。由肌醇焦磷酸盐 （PP-IPs） 激活的 Pi 外排的机制尚不清楚。本研究展示了 XPR1 的多种构象的冷冻电子显微镜结构，揭示了 Pi 输出的跨膜途径和 PP-IP 的双重结合激活模式。一个经典结合位点位于 SPX 结构域的二聚体界面，第二个位点偏向 PP-IPs，位于跨膜和 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 表征为 IPs/PP-IPs 激活的磷酸盐通道。其 TMD、SPX 结构域和 IPs/pp-ip 之间的相互作用协调了其关闭状态和开放状态之间的构象转换。