Zuo Peng, Wang Weize, Dai Zonglin, Zheng Jiye, Yu Shang, Wang Guangxi, Yin Yue, Liang Ling, Yin Yuxin
Institute of Systems Biomedicine, Department of Pathology, Beijing Key Laboratory of Tumor Systems Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.
Nat Commun. 2025 Mar 24;16(1):2879. doi: 10.1038/s41467-025-58200-y.
Inorganic phosphate (Pi) is essential for life, and its intracellular levels must be tightly regulated to avoid toxicity. XPR1, the sole known phosphate exporter, is critical for maintaining this balance. Here we report cryo-EM structures of the human XPR1-KIDINS220 complex in substrate-free closed and substrate-bound outward-open states, as well as an XPR1 mutant in a substrate-bound inward-facing state. In the presence of inositol hexaphosphate (InsP) and phosphate, the complex adopts an outward-open conformation, with InsP binding the SPX domain and juxtamembrane regions, indicating active phosphate export. Without phosphate or InsP, the complex closes, with transmembrane helix 9 blocking the outward cavity and a C-terminal loop obstructing the intracellular cavity. XPR1 alone remains closed even with phosphate and InsP. Functional mutagenesis shows that InsP, whose levels vary with Pi availability, works with KIDINS220 to regulate XPR1 activity. These insights into phosphate regulation may aid in developing therapies for ovarian cancer.
无机磷酸盐（Pi）对生命至关重要，其细胞内水平必须严格调控以避免毒性。XPR1是唯一已知的磷酸盐转运蛋白，对维持这种平衡至关重要。在此，我们报告了人XPR1-KIDINS220复合物在无底物封闭状态、底物结合外向开放状态以及底物结合内向状态下的冷冻电镜结构，以及一种底物结合内向状态的XPR1突变体。在存在肌醇六磷酸（InsP）和磷酸盐的情况下，复合物呈现外向开放构象，InsP结合SPX结构域和近膜区域，表明磷酸盐的主动输出。在没有磷酸盐或InsP的情况下，复合物关闭，跨膜螺旋9阻塞外向腔，C末端环阻塞细胞内腔。即使有磷酸盐和InsP，单独的XPR1仍保持关闭状态。功能诱变表明，其水平随Pi可用性而变化的InsP与KIDINS220共同作用来调节XPR1活性。这些对磷酸盐调控的见解可能有助于开发卵巢癌治疗方法。
