Isolated C-terminal tail of FGF23 alleviates hypophosphatemia by inhibiting FGF23-FGFR-Klotho complex formation
Isolated C-terminal tail of FGF23 alleviates hypophosphatemia by inhibiting FGF23-FGFR-Klotho complex formation
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DOI：
10.1073/pnas.0902006107
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发表时间：
2010-01-05
影响因子：
11.1
通讯作者：
Mohammadi, Moosa
中科院分区：
文献类型：
--
作者：
Goetz, Regina;Nakada, Yuji;Mohammadi, Moosa
成纤维细胞生长因子（FGF）23通过以Klotho依赖性方式激活FGF受体（FGFR）1c抑制肾磷酸盐重吸收。FGF 23的磷酸尿活性通过位于FGF核心同源结构域和FGF 23的72个残基长的C末端尾之间的边界处的RXXR基序处的蛋白水解切割而消除。在这里，我们证明了FGFR 1c和Klotho的可溶性胞外域足以在体外与FGF 23形成三元复合物。FGF 23的C末端尾介导FGF 23与在复合FGFR 1c-Klotho界面处产生的从头位点的结合。与该发现一致，FGF 23的分离的72个残基长的C末端尾通过与全长配体竞争结合二元FGFR-Klotho复合物来损害FGF 23信号传导。向健康大鼠注射FGF 23 C-末端尾肽抑制肾磷酸盐排泄并诱导高磷酸盐血症。在归因于高FGF 23的肾磷酸盐消耗的小鼠模型中，FGF 23 C-末端肽减少磷酸盐排泄，导致血清磷酸盐浓度增加。我们的数据表明，RXXR基序处的蛋白水解切割通过双重机制消除FGF 23活性：通过去除驻留在FGF 23的C-末端区域中的二元FGFR-Klotho复合物的结合位点，以及通过产生FGF 23的内源性抑制剂。我们提出来源于FGF 23的C-末端尾部的肽或C-末端尾部的肽模拟物和小分子有机模拟物可用作治疗肾磷酸盐消耗的治疗剂。
Fibroblast growth factor (FGF) 23 inhibits renal phosphate reabsorption by activating FGF receptor (FGFR) 1c in a Klotho-dependent fashion. The phosphaturic activity of FGF23 is abrogated by proteolytic cleavage at the RXXR motif that lies at the boundary between the FGF core homology domain and the 72-residue-long C-terminal tail of FGF23. Here, we show that the soluble ectodomains of FGFR1c and Klotho are sufficient to form a ternary complex with FGF23 in vitro. The C-terminal tail of FGF23 mediates binding of FGF23 to a de novo site generated at the composite FGFR1c-Klotho interface. Consistent with this finding, the isolated 72-residue-long C-terminal tail of FGF23 impairs FGF23 signaling by competing with full-length ligand for binding to the binary FGFR-Klotho complex. Injection of the FGF23 C-terminal tail peptide into healthy rats inhibits renal phosphate excretion and induces hyperphosphatemia. In a mouse model of renal phosphate wasting attributable to high FGF23, the FGF23 C-terminal peptide reduces phosphate excretion, leading to an increase in serum phosphate concentration. Our data indicate that proteolytic cleavage at the RXXR motif abrogates FGF23 activity by a dual mechanism: by removing the binding site for the binary FGFR-Klotho complex that resides in the C-terminal region of FGF23, and by generating an endogenous inhibitor of FGF23. We propose that peptides derived from the C-terminal tail of FGF23 or peptidomimetics and small-molecule organomimetics of the C-terminal tail can be used as therapeutics to treat renal phosphate wasting.