Identification of a second Klotho interaction site in the C terminus of FGF23
Identification of a second Klotho interaction site in the C terminus of FGF23
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DOI：
10.1016/j.celrep.2020.108665
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发表时间：
2021-01-26
期刊：
影响因子：
8.8
通讯作者：
DiMarchi, Richard D.
中科院分区：
文献类型：
--
作者：
Agrawal, Archita;Ni, Pu;DiMarchi, Richard D.
FGF 23与FGFR/KL受体复合物相互作用以传播细胞信号传导，其中其C末端C26肽对于接合共受体KL至关重要。我们确定了一个独特的肽序列C28驻留在FGF 23的C端，调节其与KL的相互作用。C28可以独立地作为FGF 23拮抗剂发挥作用，我们报告了一种优化的肽拮抗剂，其效力大大增强。如体外和体内研究所示，FGF 23可以使用两个C-末端位点中的任一个来发挥生物学效应。两个KL相互作用位点的缺失使蛋白失活。我们的结论是，FGF 23的C末端是一个双齿配体拥有两个独立的KL相互作用位点。这第二个KL-缔合位点的鉴定提供了FGF 23受体信号传导的分子基础的另一个视角，并提出了与其结构作用机制和偏倚生物信号传导的潜力有关的问题。
FGF23 interacts with a FGFR/KL-receptor complex to propagate cellular signaling, where its C-terminal C26 peptide is critical for engaging the co-receptor KL. We identify a distinct peptide sequence C28 residing in the FGF23 C terminus that regulates its interaction with KL. C28 can independently function as an FGF23 antagonist, and we report an optimized peptide antagonist of much enhanced potency. FGF23 can use either of the two C-terminal sites to exert biological effects, as shown by in vitro and in vivo studies. The loss of both KL-interaction sites inactivates the protein. We conclude that the C terminus of FGF23 is a bidentate ligand possessing two independent KL-interaction sites. The identification of this second KL-association site provides an additional perspective in the molecular basis of FGF23-receptor signaling and raises questions pertaining to its structural mechanism of action and the potential for biased biological signaling.