Regulation of Receptor Binding Specificity of FGF9 by an Autoinhibitory Homodimerization.
Regulation of Receptor Binding Specificity of FGF9 by an Autoinhibitory Homodimerization.
复制标题
DOI：
10.1016/j.str.2017.06.016
复制
发表时间：
2017-09-05
期刊：
影响因子：
--
通讯作者：
Mohammadi M
中科院分区：
文献类型：
--
作者：
Liu Y;Ma J;Beenken A;Srinivasan L;Eliseenkova AV;Mohammadi M
上皮FGF 9亚家族特异性结合并激活FGF受体1-3的间充质“c”剪接同种型以调节器官发生和组织稳态。FGF 9亚家族配体的独特N和C末端介导可逆的同源二聚化，其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，显示同源二聚化通过将活性FGF 9单体的浓度保持在足以用于正常FGFR“c”同种型结合/信号传导但不足以用于非法FGFR“B”同种型结合/信号传导的水平来控制FGF 9亚家族的受体结合特异性。我们表明，FGF 9的N-末端的缺失或C-末端的丙氨酸取代使微妙的配体平衡偏向活性FGF 9单体，导致FGFR“B”亚型的脱靶结合和活化。我们的研究是第一个牵连配体同源二聚化的配体受体特异性的调节。Liu等人表明，FGF 9配体的受体结合特异性受可逆的同源二聚化控制，其将单体活性配体的浓度维持在可引起FGF 9对FGFR受体的“B”剪接同种型的非法结合和活化的阈值以下。
The epithelial FGF9 subfamily specifically binds and activates the mesenchymal ‘c’ splice isoform of FGF receptor 1–3 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 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 towards 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. Liu et al. show that receptor binding specificity of FGF9 ligand is controlled by a reversible homodimerization, which maintains the concentration of monomeric active ligands below the threshold that can cause illegitimate binding and activation of ‘b’ splice isoforms of FGFR receptor by FGF9.
登录
查看更多内容
影响因子：
3.9
作者：
Abdel-Rahman, Wael M.;Kalinina, Juliya;Peltomaki, Paivi
通讯作者：
Peltomaki, Paivi
影响因子：
19.6
作者：
Cancilla, B;Ford-Perriss, MD;Bertram, JF
通讯作者：
Bertram, JF
影响因子：
4.6
作者：
Lin, Yongshun;Liu, Guoqin;Wang, Fen
通讯作者：
Wang, Fen
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
11.2
作者：
Hendrix, ND;Wu, R;Cho, KR
通讯作者：
Cho, KR