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首页> 外文期刊>Molecular and Cellular Biology >Targeting Extracellular Domains D4 and D7 of Vascular Endothelial Growth Factor Receptor 2 Reveals Allosteric Receptor Regulatory Sites
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Targeting Extracellular Domains D4 and D7 of Vascular Endothelial Growth Factor Receptor 2 Reveals Allosteric Receptor Regulatory Sites

机译：靶向血管内皮生长因子受体2的胞外域D4和D7揭示了变构受体调控位点

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Vascular endothelial growth factors (VEGFs) activate three receptor tyrosine kinases, VEGFR-1, -2, and -3, which regulate angiogenic and lymphangiogenic signaling. VEGFR-2 is the most prominent receptor in angiogenic signaling by VEGF ligands. The extracellular part of VEGF receptors consists of seven immunoglobulin homology domains (Ig domains). Earlier studies showed that domains 2 and 3 (D23) mediate ligand binding, while structural analysis of dimeric ligand/receptor complexes by electron microscopy and small-angle solution scattering revealed additional homotypic contacts in membrane-proximal Ig domains D4 and D7. Here we show that D4 and D7 are indispensable for receptor signaling. To confirm the essential role of these domains in signaling, we isolated VEGFR-2-inhibitory “designed ankyrin repeat proteins” (DARPins) that interact with D23, D4, or D7. DARPins that interact with D23 inhibited ligand binding, receptor dimerization, and receptor kinase activation, while DARPins specific for D4 or D7 did not prevent ligand binding or receptor dimerization but effectively blocked receptor signaling and functional output. These data show that D4 and D7 allosterically regulate VEGFR-2 activity. We propose that these extracellular-domain-specific DARPins represent a novel generation of receptor-inhibitory drugs for in vivo applications such as targeting of VEGFRs in medical diagnostics and for treating vascular pathologies.
机译：血管内皮生长因子（VEGF）激活三种受体酪氨酸激酶VEGFR-1，-2和-3，它们调节血管生成和淋巴管生成信号。 VEGFR-2是VEGF配体在血管生成信号中最突出的受体。 VEGF受体的细胞外部分由七个免疫球蛋白同源结构域（Ig结构域）组成。较早的研究表明，结构域2和3（D23）介导配体结合，而通过电子显微镜和小角度溶液散射对二聚体配体/受体复合物进行结构分析，发现膜近端Ig结构域D4和D7中存在其他同型接触。在这里，我们显示D4和D7对于受体信号传导是必不可少的。为了确认这些域在信号传导中的重要作用，我们分离了与D23，D4或D7相互作用的VEGFR-2抑制性“设计的锚蛋白重复蛋白”（DARPins）。与D23相互作用的DARPin抑制了配体结合，受体二聚化和受体激酶活化，而对D4或D7特异的DARPins并未阻止配体结合或受体二聚化，但有效地阻断了受体信号传导和功能输出。这些数据表明D4和D7变构调节VEGFR-2活性。我们建议这些细胞外域特异性DARPins代表新一代的受体抑制药物，用于 in vivo 应用，例如在医学诊断中靶向VEGFRs和治疗血管病变。

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