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<p>Glucose-6-phosphate (G6P) transporters are crucial for glucose metabolism by mediating G6P transport from the cytoplasm to endoplasmic reticulum (ER). However, their transport mechanisms remain poorly understood. Here, we elucidate the structural and functional basis of human solute carrier family 37 member 2 (SLC37A2), a G6P transporter implicated in metabolic regulation and macrophage inflammation. We show that SLC37A2 functions as a uniporter, facilitating G6P transport independent of inorganic phosphate gradients. Structures of SLC37A2 in the apo and G6P-bound states reveal a dimeric architecture. Both the ER luminal-open and cytosolic-open structures are captured, showing the structural dynamics during G6P transport. G6P is coordinated by SLC37A2 through interactions with its phosphate and hydroxyl groups. Furthermore, mapping mutations associated with glycogen storage disease type Ib onto SLC37A2 highlights residues essential for transport activity. Together, this work provides structural insights into G6P transport and establishes a framework for understanding related metabolic disorders.</p>

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Structural basis of glucose-6-phosphate transport by human SLC37A2

  • 期刊论文

  • 发表日期：

    2025年11月12日

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  • Qinxuan Lai,
  • Mengzhen Xu,
  • Yongxiang Gao,
  • Zhisen Yang,
  • Linfeng Sun,
  • Xin Liu

摘要

Glucose-6-phosphate (G6P) transporters are crucial for glucose metabolism by mediating G6P transport from the cytoplasm to endoplasmic reticulum (ER). However, their transport mechanisms remain poorly understood. Here, we elucidate the structural and functional basis of human solute carrier family 37 member 2 (SLC37A2), a G6P transporter implicated in metabolic regulation and macrophage inflammation. We show that SLC37A2 functions as a uniporter, facilitating G6P transport independent of inorganic phosphate gradients. Structures of SLC37A2 in the apo and G6P-bound states reveal a dimeric architecture. Both the ER luminal-open and cytosolic-open structures are captured, showing the structural dynamics during G6P transport. G6P is coordinated by SLC37A2 through interactions with its phosphate and hydroxyl groups. Furthermore, mapping mutations associated with glycogen storage disease type Ib onto SLC37A2 highlights residues essential for transport activity. Together, this work provides structural insights into G6P transport and establishes a framework for understanding related metabolic disorders.