Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members
Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members
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DOI：
10.1128/mcb.02249-06
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发表时间：
2007-05-01
影响因子：
5.3
通讯作者：
Mohammadi, Moosa
中科院分区：
文献类型：
--
作者：
Goetz, Regina;Beenken, Andrew;Mohammadi, Moosa
独特的成纤维细胞生长因子（FGF），FGF 19，-21，和-23作用于内分泌方式，以调节能量，胆汁酸，葡萄糖，脂质，磷酸盐和维生素D的体内平衡。这些FGF需要Klotho/β Klotho在其靶组织中的存在。在这里，我们展示了单独的FGF 19和与蔗糖八硫酸酯（一种与肝素化学相关的二糖）复合的FGF 23的晶体结构。FGF 19和FGF 23中β链10和12之间的肝素结合区的构象与旁分泌作用FGF所采用的共同构象完全不同。该区域和β 1-β 2环（另一个肝素结合区域）之间的裂缝排除了肝素/硫酸乙酰肝素与FGF 19/23骨架原子之间的直接相互作用。这降低了这些配体的肝素结合亲和力并赋予内分泌功能。Klotho/β Klotho已经进化为肝素/硫酸乙酰肝素促进FGF 19、-21和-23与其同源受体结合的能力差的补偿机制。
Unique among fibroblast growth factors (FGFs), FGF19, -21, and -23 act in an endocrine fashion to regulate energy, bile acid, glucose, lipid, phosphate, and vitamin D homeostasis. These FGFs require the presence of Klotho/beta Klotho in their target tissues. Here, we present the crystal structures of FGF19 alone and FGF23 in complex with sucrose octasulfate, a disaccharide chemically related to heparin. The conformation of the heparin-binding region between beta strands 10 and 12 in FGF19 and FGF23 diverges completely from the common conformation adopted by paracrine-acting FGFs. A cleft between this region and the beta 1-beta 2 loop, the other heparin-binding region, precludes direct interaction between heparin/heparan sulfate and backbone atoms of FGF19/23. This reduces the heparin-binding affinity of these ligands and confers endocrine function. Klotho/beta Klotho have evolved as a compensatory mechanism for the poor ability of heparin/heparan sulfate to promote binding of FGF19, -21, and -23 to their cognate receptors.