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有附件Targeting the extracellular domains D4 and D7 of VEGFR-2 reveals allosteric receptor regulatory sites

yucloud 添加于 2012-8-31 09:22 | 1576 次阅读 | 0 个评论
  •  作 者

    Hyde CAC, Giese A, Stuttfeld E, Abram Saliba J, Villemagne D, Schleier T, Binz HK, Ballmer-Hofer K
  •  摘 要

    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) interacting with either D23, D4 or D7. DARPins interacting with D23 inhibited ligand binding, receptor dimerization, and receptor kinase activation, whilst DARPins specific for D4 or D7 did not prevent ligand binding nor receptor dimerization, but efficiently blocked receptor signaling and functional output. These data show that domains 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.
  •  详细资料

    • 文献种类: Journal Article
    • 期刊名称: Molecular and Cellular Biology
    • 期刊缩写: Mol Cell Biol
    • 期卷页: 2012
    • 地址: Paul Scherrer Institute, Biomolecular Research, Molecular Cell Biology, CH-5232 Villigen PSI, Switzerland
    • ISBN: 0270-7306
  • 学科领域 生物医药 » 药学

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