Catalytically inactive phospholipase A2 homologue binds to vascular endothelial growth factor receptor-2 via C-terminal loop region
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Fujisawa, Daisuke
Yamazaki, Yasuo
Lomonte, Bruno
Morita, Takashi
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Abstract
VEGF (vascular endothelial growth factor) regulates neovascularization
through binding to its receptorKDR(kinase insert domaincontaining
receptor; VEGF receptor-2). We recently identified
a catalytically inactive PLA2 (phospholipase A2) homologue
(KDR-bp) in the venom of eastern cottonmouth (Agkistrodon
piscivorus piscivorus) as a third KDR-binding protein, in addition
to VEGF165 and tissue inhibitor of metalloproteinase-3. KDR-bp
binds to the extracellular domain of KDR with a Kd of 10−8 M,
resulting in specific blockade of endothelial cell growth induced
by VEGF165. Inactive PLA2 homologues are widely distributed
in the venoms of Viperidae snakes and are known to act as
myotoxins. In the present study, we demonstrated that KDRbinding
ability is a common characteristic for inactive PLA2
homologues in snake venom, but not for active PLA2s such
as neurotoxic and platelet aggregation-modulating PLA2s. To
understand better the KDR and KDR-bp interaction, we resolved
the binding region of KDR-bp using eight synthetic peptides designed
based on the structure of KDR-bp. A synthetic peptide
based on the structure of the C-terminal loop region of KDRbp
showed high affinity for KDR, but other peptides did not,
suggesting that the C-terminal loop region of KDR-bp is involved
in the interaction with KDR. The results of the present study
provide insight into the binding of inactive PLA2 homologues
to KDR, and may also assist in the design of novel anti-KDR
molecules for anti-angiogenic therapy.
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Keywords
VEGF receptor, Myotoxin, Phospholipase A2, Snake venom, vascular endothelial growth factor (VEGF)
Citation
http://www.biochemj.org/content/411/3/515
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