Department of Pharmacology, New York University School of Medicine, 550, First Avenue, New York, NY 10016, USA.
Structure. 2012 Jan 11;20(1):77-88. doi: 10.1016/j.str.2011.10.022.
Uncontrolled fibroblast growth factor (FGF) signaling can lead to human malignancies necessitating multiple layers of self-regulatory control mechanisms. Fibroblast growth factor receptor (FGFR) autoinhibition mediated by the alternatively spliced immunoglobulin (Ig) domain 1 (D1) and the acid box (AB)-containing linker between D1 and Ig domain 2 (D2) serves as the first line of defense to minimize inadvertent FGF signaling. In this report, nuclear magnetic resonance and surface plasmon resonance spectroscopy are used to demonstrate that the AB subregion of FGFR electrostatically engages the heparan sulfate (HS)-binding site on the D2 domain in cis to directly suppress HS-binding affinity of FGFR. Furthermore, the cis electrostatic interaction sterically autoinhibits ligand-binding affinity of FGFR because of the close proximity of HS-binding and primary ligand-binding sites on the D2 domain. These data, together with the strong amino acid sequence conservation of the AB subregion among FGFR orthologs, highlight the universal role of the AB subregion in FGFR autoinhibition.
不受控制的成纤维细胞生长因子 (FGF) 信号传导可能导致人类恶性肿瘤，需要多层次的自我调节控制机制。成纤维细胞生长因子受体 (FGFR) 通过选择性剪接的免疫球蛋白 (Ig) 结构域 1 (D1) 和 D1 与 Ig 结构域 2 (D2) 之间的酸盒 (AB) 连接子介导的自身抑制作用是第一道防线，可以最大程度地减少意外的 FGF 信号传导。在本报告中，使用核磁共振和表面等离子体共振光谱法证明 FGFR 的 AB 亚区通过静电相互作用与 D2 结构域上的肝素硫酸 (HS) 结合位点在顺式中相互作用，直接抑制 FGFR 与 HS 的结合亲和力。此外，由于 D2 结构域上 HS 结合和主要配体结合位点非常接近，这种顺式静电相互作用会阻碍 FGFR 的配体结合亲和力，从而使 FGFR 自身抑制。这些数据以及 FGFR 同源物中 AB 亚区的强氨基酸序列保守性，突出了 AB 亚区在 FGFR 自身抑制中的普遍作用。
