Structural basis for inositol pyrophosphate gating of the phosphate channel XPR1

• 成果类型: Article
• 署名作者: Lu, Yi; Yue, Chen-Xi; Zhang, Li; Yao, Deqiang; Xia, Ying; Zhang, Qing; Zhang, Xinchen; Li, Shaobai; Shen, Yafeng; Cao, Mi; Guo, Chang-Run; Qin, An; Zhao, Jie; Zhou, Lu; Yu, Ye; Cao, Yu
• 署名单位: Shanghai Jiao Tong University; Shanghai Jiao Tong University; China Pharmaceutical University; University of Texas System; University of Texas Southwestern Medical Center; Shanghai Jiao Tong University; Fudan University; Shanghai Jiao Tong University
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-9762
• DOI: 10.1126/science.adp3252
• 发表日期: 2024-11-15
• 关键词: inorganic-phosphate; receptor; calcification; transporters; homeostasis

摘要

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.