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<p>Phosphate homeostasis is essential for fundamental cellular processes, including energy metabolism, signal transduction, and nucleic acid synthesis. Although XPR1 family proteins are conserved phosphate exporters throughout eukaryotes, their structural mechanisms in organisms other than mammals and plants remain largely unexplored. Here, we presented high-resolution cryo-electron microscopy (cryo-EM) structures of <i>Schizosaccharomyces pombe</i> Xpr1 (SpXpr1) in both the apo and inositol hexakisphosphate (InsP6)-bound states. While SpXpr1 shares conserved phosphate coordination sites with its human and plant orthologs, SpXpr1 employs a unique dual gating mechanism: (1) an intracellular gate formed by the N-loop of the SPX domain, stabilized by a preceding N-helix and an extended TM10 helix and (2) an extracellular ECL<sub>plug</sub> occluding the exit. We further showed that InsP6 binding induces allosteric destabilization of the N-loop gate, facilitating phosphate release. Functional validation through phosphate efflux assays in <i>Homo sapiens</i> <i>XPR1</i> (<i>HsXPR1</i>)-knockout cells and whole-cell patch-clamp recordings confirmed the structural observations. Our findings elucidated a unique gating mechanism of SpXpr1 and offer evolutionary perspectives on phosphate regulation across eukaryotes.</p>

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Structural insights into the gating mechanism of the fission yeast phosphate exporter SpXpr1

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月15日

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  • Hui Yang,
  • Yuechan Wang,
  • Chenxi Yue,
  • Xinran Li,
  • Yifei Wang,
  • Ye Yu,
  • Huaizong Shen

摘要

Phosphate homeostasis is essential for fundamental cellular processes, including energy metabolism, signal transduction, and nucleic acid synthesis. Although XPR1 family proteins are conserved phosphate exporters throughout eukaryotes, their structural mechanisms in organisms other than mammals and plants remain largely unexplored. Here, we presented high-resolution cryo-electron microscopy (cryo-EM) structures of Schizosaccharomyces pombe Xpr1 (SpXpr1) in both the apo and inositol hexakisphosphate (InsP6)-bound states. While SpXpr1 shares conserved phosphate coordination sites with its human and plant orthologs, SpXpr1 employs a unique dual gating mechanism: (1) an intracellular gate formed by the N-loop of the SPX domain, stabilized by a preceding N-helix and an extended TM10 helix and (2) an extracellular ECLplug occluding the exit. We further showed that InsP6 binding induces allosteric destabilization of the N-loop gate, facilitating phosphate release. Functional validation through phosphate efflux assays in Homo sapiens XPR1 (HsXPR1)-knockout cells and whole-cell patch-clamp recordings confirmed the structural observations. Our findings elucidated a unique gating mechanism of SpXpr1 and offer evolutionary perspectives on phosphate regulation across eukaryotes.