Structural Basis for Inositol Pyrophosphate Gating of the Phosphate Channel XPR1

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

SCIENCE（2024）

Shanghai Jiao Tong Univ | Fudan Univ

Cited 5|Views23

Abstract

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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