Abstract
Vascular endothelial growth factor (VEGF165) and its receptor KDR (kinase insert domain-containing receptor) are central regulators of blood vessel formation. We herein report a KDR-binding protein we have isolated in the venom of eastern cottonmouth (Agkistrodon piscivorus piscivorus). Sequence analysis revealed the isolated KDR-binding protein (designated KDR-bp) is identical to Lys49-phosholipase A2 (Lys49PLA2), an inactive PLA2 homologue with strong myotoxicity, in which Lys49 substitutes Asp49, a key residue for binding the essential cofactor Ca2+. KDR-bp binds to the extracellular domain of KDR with subnanomolar affinity. KDR-bp also binds to a lesser extent with Flt-1 and IgG but not to other receptors with similar immunoglobulin-like domain structures such as platelet-derived growth factor receptor alpha. The interaction between KDR-bp and KDR was blocked by VEGF165, and KDR-bp specifically inhibited VEGF165-stimulated endothelial cell proliferation, indicating KDR-bp is an antagonistic ligand for KDR. Lys49PLA2s from another snake venom were found to exhibit similar receptor binding properties to KDR-bp. This is the first report to demonstrate that an exogenous factor antagonizes VEGF and its receptor system. Our observation offers further insight into the as yet unknown molecular mechanism of myotoxic activity of snake venom Lys49PLA2s. Furthermore, KDR-bp would make a valuable tool for studying the structure and function of KDR, such as that expressed on skeletal muscle cells.
Highlights
Vascular endothelial growth factor (VEGF165) and its receptor KDR are central regulators of blood vessel formation
The interaction between KDR-binding protein (KDR-bp) and KDR was blocked by VEGF165, and KDR-bp inhibited VEGF165-stimulated endothelial cell proliferation, indicating KDR-bp is an antagonistic ligand for KDR
Vascular endothelial growth factor (VEGF165)1 and its receptor system play a central role in the angiogenic process [1]
Summary
We report that myotoxic basic phospholipase A2 (Lys49PLA2) obtained from the venom of eastern cottonmouth binds the extracellular domain of KDR with subnanomolar affinity and results in the blockage of VEGF165. Despite significant homology to active PLA2s, Lys49PLA2s are inactive phospholipolytic enzymes because the Lys substitutes Asp, a key residue for binding of the essential Ca2ϩ-cofactor [11] This is the first report demonstrating that the exogenous factor antagonizes the VEGF receptor by binding to the exterior face of the receptor and, is the first identification of the target molecule of myotoxic basic phospholipase A2 in viper venom.
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