研究人员呈现了XPR1在多种构象下的冷冻电子显微镜结构，并揭示了细胞内磷酸盐（Pi）出口的跨膜通道和肌醇焦磷酸盐（PP-IP）的双重结合激活模式。一个典型结合位点位于SPX结构域的二聚体界面，第二个位点偏向于PP-IP，位于跨膜结构域与SPX结构域之间。
通过将结构研究与电生理分析相结合，研究人员将XPR1表征为一个由IP/PP-IP激活的磷酸盐通道。其跨膜结构域、SPX结构域和IPs/PP-IP之间的相互作用，调控了其闭合状态和开放状态之间的构象转变。
据介绍，Pi的精确调控对细胞功能至关重要，XPR1在人体中作为唯一的Pi出口蛋白。由PP-IP激活的Pi外排机制尚不清楚。
附：英文原文
Title: Structural basis for inositol pyrophosphate gating of the phosphate channel XPR1
Author: 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
Issue&Volume: 2024-09-26
Abstract: 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.
DOI: adp3252
Source: https://www.science.org/doi/10.1126/science.adp3252