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首页> 外文期刊>Molecular and Cellular Biology >Structural Basis for Activation of Fibroblast Growth Factor Signaling by Sucrose Octasulfate
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Structural Basis for Activation of Fibroblast Growth Factor Signaling by Sucrose Octasulfate

机译：蔗糖八硫酸盐激活成纤维细胞生长因子信号转导的结构基础

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Sucrose octasulfate (SOS) is believed to stimulate fibroblast growth factor (FGF) signaling by binding and stabilizing FGFs. In this report, we show that SOS induces FGF-dependent dimerization of FGF receptors (FGFRs). The crystal structure of the dimeric FGF2-FGFR1-SOS complex at 2.6-? resolution reveals a symmetric assemblage of two 1:1:1 FGF2-FGFR1-SOS ternary complexes. Within each ternary complex SOS binds to FGF and FGFR and thereby increases FGF-FGFR affinity. SOS also interacts with the adjoining FGFR and thereby promotes protein-protein interactions that stabilize dimerization. This structural finding is supported by the inability of selectively desulfated SOS molecules to promote receptor dimerization. Thus, we propose that SOS potentiates FGF signaling by imitating the dual role of heparin in increasing FGF-FGFR affinity and promoting receptor dimerization. Hence, the dimeric FGF-FGFR-SOS structure substantiates the recently proposed “two-end” model, by which heparin induces FGF-FGFR dimerization. Moreover, the FGF-FGFR-SOS structure provides an attractive template for the development of easily synthesized SOS-related heparin agonists and antagonists that may hold therapeutic potential.
机译：据信蔗糖八硫酸盐（SOS）通过结合和稳定FGF刺激成纤维细胞生长因子（FGF）信号传导。在此报告中，我们表明SOS诱导FGF受体（FGFRs）的FGF依赖性二聚化。二聚体FGF2-FGFR1-SOS复合物在2.6-π处的晶体结构。分辨率揭示了两个1：1：1 FGF2-FGFR1-SOS三元复合物的对称组装。在每个三元复合物中，SOS与FGF和FGFR结合，从而增加FGF-FGFR亲和力。 SOS还与邻接的FGFR相互作用，从而促进稳定二聚化的蛋白质-蛋白质相互作用。选择性脱硫的SOS分子不能促进受体二聚化支持了这一结构发现。因此，我们建议SOS通过模仿肝素在增加FGF-FGFR亲和力和促进受体二聚作用中的双重作用来增强FGF信号传导。因此，二聚体FGF-FGFR-SOS结构证实了最近提出的“两端”模型，肝素通过该模型诱导FGF-FGFR二聚化。此外，FGF-FGFR-SOS结构为易于合成的SOS相关肝素激动剂和拮抗剂的开发提供了有吸引力的模板，这些激动剂和拮抗剂可能具有治疗潜力。

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