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J. Biol. Chem., Vol. 281, Issue 12, 7937-7945, March 24, 2006

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Non-cytotoxic Cobra Cardiotoxin A5 Binds to v3 Integrin and Inhibits Bone Resorption

IDENTIFICATION OF CARDIOTOXINS AS NON-RGD INTEGRIN-BINDING PROTEINS OF THE Ly-6 FAMILY^*

Po-Long Wu, Shao-Chen Lee, Chia-Chen Chuang, Seiji Mori, Nobuaki Akakura, Wen-guey Wu¹, and Yoshikazu Takada²

From the Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 30043, Taiwan and the University of California Davis Medical Center, Sacramento, California 95817

Severe tissue necrosis with a retarded wound healing process is a major symptom of a cobra snakebite. Cardiotoxins (CTXs) are major components of cobra venoms that belong to the Ly-6 protein family and are implicated in tissue damage. The interaction of the major CTX from Taiwan cobra, i.e. CTX A3, with sulfatides in the cell membrane has recently been shown to induce pore formation and cell internalization and to be responsible for cytotoxicity in cardiomyocytes (Wang, C.-H., Liu, J.-H., Lee, S.-C., Hsiao, C.-D., and Wu, W.-g. (2006) J. Biol. Chem. 281, 656-667). We show here that one of the non-cytotoxic CTXs, i.e. CTX A5 or cardiotoxin-like basic polypeptide, from Taiwan cobra specifically bound to v3 integrin and inhibited bone resorption activity. We found that both membrane-bound and recombinant soluble v3 integrins bound specifically to CTX A5 in a dose-dependent manner. Surface plasmon resonance analysis showed that human soluble v3 bound to CTX A5 with an apparent affinity of 0.3 µM. Calf pulmonary artery endothelial cells, which constitutively express v3, showed a CTX A5 binding profile similar to that of membrane-bound and soluble v3 integrins, suggesting that endothelial cells are a potential target for CTX action. We tested whether CTX A5 inhibits osteoclast differentiation and bone resorption, a process known to be involved in v3 binding and inhibited by RGD-containing peptides. We demonstrate that CTX A5 inhibited both activities at a micromolar range by binding to murine v3 integrin in osteoclasts and that CTX A5 co-localized with 3 integrin. Finally, after comparing the integrin binding affinity among CTX homologs, we propose that the amino acid residues near the two loops of CTX A5 are involved in integrin binding. These results identify CTX A5 as a non-RGD integrin-binding protein with therapeutic potential as an integrin antagonist.

Received for publication, December 7, 2005 , and in revised form, January 9, 2006.

^* This work was supported in part by National Science Council Grant NSC94-2311-B-007-023 and Ministry of Economic Affairs Grant 91-EC-17-A-17-S1-0009 (to W.-g. W.) and by National Institutes of Health Grant GM47157 (to Y. T.). 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.

¹To whom correspondence may be addressed. Tel.: 886-3-574-2752; Fax: 886-3-571-5934; E-mail: wgwu{at}life.nthu.edu.tw. ²To whom correspondence may be addressed. Tel.: 916-734-7443; Fax: 916-734-7505; E-mail: ytakada{at}ucdavis.edu.

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