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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Publication Details

Journal
Science
Published
2024-09-26
DOI
https://doi.org/10.1126/science.adp3252
Citations
30
Primary Topic
Trace Elements in Health
Type
article
Field-Weighted Citation Impact
9.29
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article

Structural basis for inositol pyrophosphate gating of the phosphate channel XPR1

Lu Zhou, Ying Xia, Ye Yu, Xinchen Zhang et al.
30 citations
Science
Trace Elements in Health
9.29
article

Structural basis for inositol pyrophosphate gating of the phosphate channel XPR1

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

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.

ScienceVol. 386(6723)
China Pharmaceutical University (CN), Shanghai Jiao Tong University (CN), Fudan University (CN), Renji Hospital (CN), Shanghai Ninth People's Hospital (CN), The University of Texas Southwestern Medical Center (US)
Clean water and sanitation
Openalex Percentile: Top 1%
Trace Elements in Health
9.29
DOISourceOpenAlex
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