美国华盛顿大学David Baker等研究人员合作发现，设计的寡聚物组装体可调节FGF通路信号和血管分化。相关论文于2024年6月10日在线发表于国际学术期刊《细胞》。
为了能够系统地探索受体价位和几何形状如何影响信号转导结果，研究人员利用可模块化扩展的重复蛋白质构件设计了多达8个亚基的环状同源寡聚体。通过将全新设计的成纤维细胞生长因子受体（FGFR）结合模块整合到这些支架中，研究人员生成了一系列合成信号配体，这些配体表现出强效的价位和几何依赖性Ca2+释放，和丝裂原活化蛋白激酶（MAPK）通路激活。
所设计激动剂的高度特异性揭示了两种表皮生长因子受体（FGFR）剪接变体，在早期血管发育过程中驱动动脉内皮和血管周围细胞命运的不同作用。研究人员设计的模块化组装体在揭示关键发育转变过程中，信号传导的复杂性和开发未来的治疗应用方面具有广泛的用途。
据悉，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结合和转磷酸化，从而启动下游信号级联。
附：英文原文
Title: Modulation of FGF pathway signaling and vascular differentiation using designed oligomeric assemblies
Author: Natasha I. Edman, Ashish Phal, Rachel L. Redler, Thomas Schlichthaerle, Sanjay R. Srivatsan, Devon Duron Ehnes, Ali Etemadi, Seong J. An, Andrew Favor, Zhe Li, Florian Praetorius, Max Gordon, Thomas Vincent, Silvia Marchiano, Leslie Blakely, Chuwei Lin, Wei Yang, Brian Coventry, Derrick R. Hicks, Longxing Cao, Neville Bethel, Piper Heine, Analisa Murray, Stacey Gerben, Lauren Carter, Marcos Miranda, Babak Negahdari, Sangwon Lee, Cole Trapnell, Ying Zheng, Charles E. Murry, Devin K. Schweppe, Benjamin S. Freedman, Lance Stewart, Damian C. Ekiert, Joseph Schlessinger, Jay Shendure, Gira Bhabha, Hannele Ruohola-Baker, David Baker
Issue&Volume: 2024-06-10
Abstract: 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 a de 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.
DOI: 10.1016/j.cell.2024.05.025
Source: https://www.cell.com/cell/fulltext/S0092-8674(24)00534-8