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J. Biol. Chem., Vol. 280, Issue 34, 29989-29992, August 26, 2005

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Identification of Vascular Endothelial Growth Factor Receptor-binding Protein in the Venom of Eastern Cottonmouth

A NEW ROLE OF SNAKE VENOM MYOTOXIC LYS⁴⁹-PHOSPHOLIPASE A₂^*

Yasuo Yamazaki, Yukiko Matsunaga, Yuta Nakano, and Takashi Morita

From the Department of Biochemistry, Meiji Pharmaceutical University, 2-522-1, Noshio, Kiyose, Tokyo 204-8588, Japan

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 . 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.

Received for publication, June 6, 2005 , and in revised form, July 13, 2005.

^* This work was supported in part by Scientific Research grants-in-aid from the Ministry of Education, Science, and Culture of Japan (to T. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains the Experimental Procedures and supplemental Figs. 1–5.

To whom correspondence should be addressed. Tel.:/Fax: 81-424-95-8479; E-mail: tmorita{at}my-pharm.ac.jp.

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