C-terminal heparin-binding peptide of snake venom VEGF specifically blocks VEGF-stimulated endothelial cell proliferation.
Vascular endothelial growth factor-A165 (VEGF-A165) exhibits diverse biological effects through binding to its receptor KDR (VEGFR-2). Heparin-like molecules are known to modulate their interaction. There have been reports that VEGF-A lacking the C-terminal heparin binding region significantly reduced mitogenic activity. Recently, we found novel heparin-binding VEGFs from snake venoms, designated VEGF-Fs, which specifically recognize kinase domain containing receptor (KDR). The C-terminal heparin-binding region is almost completely absent in VEGF-Fs when compared with other heparin-binding VEGFs, despite their heparin-binding potential. In this congress, we report that the C-terminal heparin-binding region of VEGF-F specifically/preferentially interacts with the VEGF-bondable heparin/heparan sulfate, but not with those associated with bFGF or TFPI. We also present the identification of a VEGF receptor-binding protein from the venom of eastern cottonmouth (Agkistrodon piscivorus piscivorus). Sequence analysis revealed the isolated KDR-binding protein (designated KDR-bp) is identical to Lys49PLA2, an inactive PLA2 homologue with strong myoxicity. KDR-bp binds to the extracellular domain of KDR with subnanomolar affinity. The interaction between KDR-bp and KDR was blocked by VEGF-A165, and KDR-bp specifically inhibited VEGF-A165-stimulated endothelial cell proliferation, indicating KDR-bp is an antagonistic ligand for KDR. This is the first observation demonstrating that an exogenous factor antagonizes the VEGF receptor, furthermore, it is the first identification of the target molecule of the myotoxic PLA2 from viper venom.
Yamazaki
Yasuo
Y
Department of Biochemistry, Meiji Pharmaceutical University, Tokyo, Japan.
Tokunaga
Yuko
Y
Takani
Koji
K
Morita
Takashi
T
D000818:Animals; D001665:Binding Sites; D049109:Cell Proliferation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects; D006493:Heparin / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D010446:Peptide Fragments; D012910:Snake Venoms / Q000737:chemistry*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000378:metabolism
D010446:Peptide Fragments; D012910:Snake Venoms; D042461:Vascular Endothelial Growth Factor A; D006493:Heparin; D040301:Vascular Endothelial Growth Factor Receptor-2