Pellegrini L, Burke D F, von Delft F, Mulloy B, Blundell T L
Department of Biochemistry, University of Cambridge, UK.
Nature. 2000 Oct 26;407(6807):1029-34. doi: 10.1038/35039551.
Fibroblast growth factors (FGFs) are a large family of structurally related proteins with a wide range of physiological and pathological activities. Signal transduction requires association of FGF with its receptor tyrosine kinase (FGFR) and heparan sulphate proteoglycan in a specific complex on the cell surface. Direct involvement of the heparan sulphate glycosaminoglycan polysaccharide in the molecular association between FGF and its receptor is essential for biological activity. Although crystal structures of binary complexes of FGF-heparin and FGF-FGFR have been described, the molecular architecture of the FGF signalling complex has not been elucidated. Here we report the crystal structure of the FGFR2 ectodomain in a dimeric form that is induced by simultaneous binding to FGF1 and a heparin decasaccharide. The complex is assembled around a central heparin molecule linking two FGF1 ligands into a dimer that bridges between two receptor chains. The asymmetric heparin binding involves contacts with both FGF1 molecules but only one receptor chain. The structure of the FGF1-FGFR2-heparin ternary complex provides a structural basis for the essential role of heparan sulphate in FGF signalling.
成纤维细胞生长因子（FGFs）是一个结构相关的蛋白质大家族，具有广泛的生理和病理活性。信号转导需要FGF与其受体酪氨酸激酶（FGFR）以及硫酸乙酰肝素蛋白聚糖在细胞表面形成特定复合物。硫酸乙酰肝素糖胺聚糖多糖直接参与FGF与其受体之间的分子结合对于生物活性至关重要。尽管已经描述了FGF-肝素和FGF-FGFR二元复合物的晶体结构，但FGF信号复合物的分子结构尚未阐明。在此，我们报道了FGFR2胞外结构域以二聚体形式存在的晶体结构，该二聚体形式是由同时结合FGF1和肝素十糖诱导形成的。该复合物围绕一个中央肝素分子组装而成，该肝素分子将两个FGF1配体连接成一个二聚体，该二聚体在两条受体链之间形成桥梁。不对称的肝素结合涉及与两个FGF1分子的接触，但仅与一条受体链接触。FGF1-FGFR2-肝素三元复合物的结构为硫酸乙酰肝素在FGF信号传导中的重要作用提供了结构基础。
