Liu Yang, Ma Jinghong, Beenken Andrew, Srinivasan Lakshmi, Eliseenkova Anna V, Mohammadi Moosa
Department of Biochemistry & Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
Department of Biochemistry & Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, USA.
Structure. 2017 Sep 5;25(9):1325-1336.e3. doi: 10.1016/j.str.2017.06.016. Epub 2017 Jul 27.
The epithelial fibroblast growth factor 9 (FGF9) subfamily specifically binds and activates the mesenchymal "c" splice isoform of FGF receptors 1-3 (FGFR1-3) to regulate organogenesis and tissue homeostasis. The unique N and C termini of FGF9 subfamily ligands mediate a reversible homodimerization that occludes major receptor binding sites within the ligand core region. Here we provide compelling X-ray crystallographic, biophysical, and biochemical data showing that homodimerization controls receptor binding specificity of the FGF9 subfamily by keeping the concentration of active FGF9 monomers at a level, which is sufficient for a normal FGFR "c" isoform binding/signaling, but is insufficient for an illegitimate FGFR "b" isoform binding/signaling. We show that deletion of the N terminus or alanine substitutions in the C terminus of FGF9 skews the delicate ligand equilibrium toward active FGF9 monomers causing off-target binding and activation of FGFR b isoforms. Our study is the first to implicate ligand homodimerization in the regulation of ligand-receptor specificity.
上皮成纤维细胞生长因子9（FGF9）亚家族特异性结合并激活成纤维细胞生长因子受体1 - 3（FGFR1 - 3）的间充质“c”剪接异构体，以调节器官发生和组织稳态。FGF9亚家族配体独特的N端和C端介导可逆的同二聚化，这种同二聚化会封闭配体核心区域内的主要受体结合位点。在此，我们提供了令人信服的X射线晶体学、生物物理学和生物化学数据，表明同二聚化通过将活性FGF9单体的浓度维持在足以实现正常FGFR“c”异构体结合/信号传导，但不足以实现非法FGFR“b”异构体结合/信号传导的水平，来控制FGF9亚家族的受体结合特异性。我们表明，FGF9的N端缺失或C端的丙氨酸取代会使微妙的配体平衡偏向活性FGF9单体，导致FGFR b异构体的脱靶结合和激活。我们的研究首次表明配体同二聚化参与配体 - 受体特异性的调节。
