C-terminal Tail of FGF19 Determines Its Specificity toward Klotho Co-receptors
C-terminal Tail of FGF19 Determines Its Specificity toward Klotho Co-receptors
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DOI：
10.1074/jbc.m803319200
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发表时间：
2008-11-28
影响因子：
4.8
通讯作者：
Li, Yang
中科院分区：
文献类型：
--
作者：
Wu, Xinle;Lemon, Bryan;Li, Yang
FGF 19亚家族蛋白（FGF 19、FGF 21和FGF 23）是成纤维细胞生长因子（FGF）的独特成员，以内分泌方式调节能量、胆汁酸、葡萄糖、脂质、磷酸盐和维生素D稳态。它们的活性需要存在α或β Klotho，两种相关的单程跨膜蛋白，作为相关靶组织中的共受体。我们先前表明，FGF 19可以结合α和β Klotho，而FGF 21和FGF 23只能结合β Klotho或α Klotho，分别在体外。为了确定调节FGF 19亚家族成员与Klotho家族蛋白的结合和特异性的机制，构建了FGF 19亚家族成员之间的嵌合蛋白或Klotho家族成员之间的嵌合蛋白以探测这两个家族之间的相互作用。我们的结果表明，具有FGF 21 C-末端尾的FGF 19嵌合体仅与β Klotho相互作用，而具有FGF 23 C-末端尾的嵌合体仅与α Klotho相互作用。FGF信号传导测定也反映了我们观察到的嵌合体特异性的变化。这些结果鉴定了FGF 19的C-末端尾是其识别Klotho家族蛋白所必需的区域。此外，还产生了α和β Klotho之间的嵌合体，以探测Klotho蛋白中对该FGF亚家族的信号传导重要的区域。FGF 23和FGF 21两者分别需要完整的α或β Klotho用于信号传导，而FGF 19可以通过由α Klotho的N末端和β Klotho的C末端组成的Klotho嵌合体进行信号传导。我们的研究结果提供了第一个一瞥的区域，调节这个独特的家庭的FGF和他们的共同受体之间的结合特异性。
FGF19 subfamily proteins (FGF19, FGF21, and FGF23) are unique members of fibroblast growth factors (FGFs) that regulate energy, bile acid, glucose, lipid, phosphate, and vitamin D homeostasis in an endocrine fashion. Their activities require the presence of alpha or beta Klotho, two related single-pass transmembrane proteins, as co-receptors in relevant target tissues. We previously showed that FGF19 can bind to both alpha and beta Klotho, whereas FGF21 and FGF23 can bind only to either beta Klotho or alpha Klotho, respectively in vitro. To determine the mechanism regulating the binding and specificity among FGF19 subfamily members to Klotho family proteins, chimeric proteins between FGF19 subfamily members or chimeric proteins between Klotho family members were constructed to probe the interaction between those two families. Our results showed that a chimera of FGF19 with the FGF21 C-terminal tail interacts only with beta Klotho and a chimera with the FGF23 C-terminal tail interacts only with alpha Klotho. FGF signaling assays also reflected the change of specificity we observed for the chimeras. These results identified the C-terminal tail of FGF19 as a region necessary for its recognition of Klotho family proteins. In addition, chimeras between alpha and beta Klotho were also generated to probe the regions in Klotho proteins that are important for signaling by this FGF subfamily. Both FGF23 and FGF21 require intact alpha or beta Klotho for signaling, respectively, whereas FGF19 can signal through a Klotho chimera consisting of the N terminus of alpha Klotho and the C terminus of beta Klotho. Our results provide the first glimpse of the regions that regulate the binding specificity between this unique family of FGFs and their co-receptors.