Modulation of FGF pathway signaling and vascular differentiation using designed oligomeric assemblies.
Modulation of FGF pathway signaling and vascular differentiation using designed oligomeric assemblies.
复制标题
使用设计的寡聚组件调节 FGF 通路信号传导和血管分化。
DOI：
10.1101/2023.03.14.532666
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
Edman,NatashaI;Redler,RachelL;Phal,Ashish;Schlichthaerle,Thomas;Srivatsan,SanjayR;Etemadi,Ali;An,SeongJ;Favor,Andrew;Ehnes,Devon;Li,Zhe;Praetorius,Florian;Gordon,Max;Yang,Wei;Coventry,Brian;Hicks,DerrickR;Cao,Longxing;
许多生长因子和细胞因子通过与其受体的细胞外结构域结合并驱动受体细胞内酪氨酸激酶结构域的缔合和转磷酸化来发出信号，从而引发下游信号级联。为了能够系统地探索受体的价态和几何形状如何影响信号传导结果，我们设计了具有多达8个亚基的环状同源寡聚体，其使用可以模块化延伸的重复蛋白质构建块。通过将ade novo设计的成纤维细胞生长因子受体（FGFR）结合模块纳入这些支架中，我们产生了一系列合成的信号配体，这些配体表现出有效的化合价和几何结构依赖性Ca 2+释放和促分裂原活化蛋白激酶（MAPK）途径激活。设计的激动剂的高特异性揭示了两种FGFR剪接变体在早期血管发育期间驱动动脉内皮和血管周围细胞命运的不同作用。我们设计的模块化组件应该是广泛有用的解开信号的复杂性，在关键的发展过渡和发展未来的治疗应用。
Many growth factors and cytokines signal by binding to the extracellular domains of their receptors and driving association and transphosphorylation of the receptor intracellular tyrosine kinase domains, initiating downstream signaling cascades. To enable systematic exploration of how receptor valency and geometry affect signaling outcomes, we designed cyclic homo-oligomers with up to 8 subunits using repeat protein building blocks that can be modularly extended. By incorporating ade novo-designed fibroblast growth factor receptor (FGFR)-binding module into these scaffolds, we generated a series of synthetic signaling ligands that exhibit potent valency- and geometry-dependent Ca2+release and mitogen-activated protein kinase (MAPK) pathway activation. The high specificity of the designed agonists reveals distinct roles for two FGFR splice variants in driving arterial endothelium and perivascular cell fates during early vascular development. Our designed modular assemblies should be broadly useful for unraveling the complexities of signaling in key developmental transitions and for developing future therapeutic applications.