温州医科大学Moosa Mohammadi等研究人员合作揭示FGF荷尔蒙信号的结构基础。相关论文于2023年6月7日在线发表在《自然》杂志上。

研究人员表示，α/βKlotho核心受体同时参与成纤维细胞生长因子（FGF）激素（FGF19、FGF21和FGF23）及其同源的细胞表面FGF受体（FGFR1-4），从而稳定内分泌的FGF-FGFR复合物。然而，这些激素仍然需要硫酸肝素（HS）蛋白多糖作为额外的核心受体来诱导FGFR二聚化/激活，从而激发其基本的代谢活动。

为了揭示支撑HS核心受体作用的分子机制，研究人员解析了三种不同的1:2:1:1的FGF23-FGFR-αKlotho-HS四元复合物冷冻电镜结构，其特点是FGFR1（FGFR1c）、FGFR3（FGFR3c）或FGFR4的'c'剪接异构体作为受体组件。这些结构得到了基于细胞的受体互补和异源二聚体实验的支持，并揭示了一个单一的HS链使FGF23及其在1:1:1的FGF23-FGFR-αKlotho三元复合物中的初级FGFR能够共同招募一个单独的次级FGFR分子，导致不对称的受体二聚化和激活。然而，αKlotho并不直接参与招募二级受体/二聚化。

结果还表明，受体二聚化的不对称模式适用于仅以HS依赖的方式发出信号的旁分泌FGF。这些结构和生化数据颠覆了目前对称的FGFR二聚化模式，为合理发现FGF信号调节剂作为人类代谢性疾病和癌症的治疗药物提供了蓝图。

附：英文原文

Title: Structural basis for FGF hormone signalling

Author: Chen, Lingfeng, Fu, Lili, Sun, Jingchuan, Huang, Zhiqiang, Fang, Mingzhen, Zinkle, Allen, Liu, Xin, Lu, Junliang, Pan, Zixiang, Wang, Yang, Liang, Guang, Li, Xiaokun, Chen, Gaozhi, Mohammadi, Moosa

Issue&Volume: 2023-06-07

Abstract: α/βKlotho coreceptors simultaneously engage fibroblast growth factor (FGF) hormones (FGF19, FGF21 and FGF23)1,2 and their cognate cell-surface FGF receptors (FGFR1–4) thereby stabilizing the endocrine FGF–FGFR complex3,4,5,6. However, these hormones still require heparan sulfate (HS) proteoglycan as an additional coreceptor to induce FGFR dimerization/activation and hence elicit their essential metabolic activities6. To reveal the molecular mechanism underpinning the coreceptor role of HS, we solved cryo-electron microscopy structures of three distinct 1:2:1:1 FGF23–FGFR–αKlotho–HS quaternary complexes featuring the ‘c’ splice isoforms of FGFR1 (FGFR1c), FGFR3 (FGFR3c) or FGFR4 as the receptor component. These structures, supported by cell-based receptor complementation and heterodimerization experiments, reveal that a single HS chain enables FGF23 and its primary FGFR within a 1:1:1 FGF23–FGFR–αKlotho ternary complex to jointly recruit a lone secondary FGFR molecule leading to asymmetric receptor dimerization and activation. However, αKlotho does not directly participate in recruiting the secondary receptor/dimerization. We also show that the asymmetric mode of receptor dimerization is applicable to paracrine FGFs that signal solely in an HS-dependent fashion. Our structural and biochemical data overturn the current symmetric FGFR dimerization paradigm and provide blueprints for rational discovery of modulators of FGF signalling2 as therapeutics for human metabolic diseases and cancer.

DOI: 10.1038/s41586-023-06155-9

Source: https://www.nature.com/articles/s41586-023-06155-9