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Vol. 283, Issue 2, 843-853, 1997

Biochemical Characterization of the Binding of Echistatin to Integrin alpha vbeta 3 Receptor

C. Chandra Kumar, Huiming-Nie, Christine Prorock Rogers, Mike Malkowski, Eugene Maxwell, Joseph J. Catino and Lydia Armstrong

Department of Tumor Biology, Schering Research Institute, Kenilworth, New Jersey

Echistatin is a 49-amino-acid peptide belonging to the family of disintegrins that are derived from snake venoms and are potent inhibitors of platelet aggregation and cell adhesion. Integrin alpha vbeta 3 receptor plays a critical role in several physiological processes such as tumor-induced angiogenesis, tumor cell metastasis, osteoporosis and wound repair. In this study, we have characterized the binding of echistatin to purified integrin alpha vbeta 3 receptor and the form expressed on human embryonic kidney 293 cells. We show that both purified and membrane-bound integrin alpha vbeta 3 binds to echistatin with a high affinity, which can be competed efficiently by linear and cyclic peptides containing the RGD sequence. Previous studies have shown that alpha vbeta 3 binds to vitronectin in a nondissociable manner, whereas an RGD-containing peptide derived from vitronectin binds in a dissociable manner with a Kd of 9.4 × 10-7 M. Our studies indicate that radiolabeled echistatin binds to alpha vbeta 3 in a nondissociable manner, similar to native echistatin. However, echistatin does not support the adhesion of 293 cells expressing alpha vbeta 3 receptor because of poor binding to plastic dishes and is a potent antagonist of the adhesion of these cells to vitronectin. These studies demonstrate that echistatin binding to alpha vbeta 3 is of high affinity and irreversible similar to vitronectin and provides an alternate ligand for high-throughput screening for alpha vbeta 3 antagonists.

Copyright © by The American Society for Pharmacology and Experimental Therapeutics


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