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J. Biol. Chem., Vol. 282, Issue 37, 26928-26938, September 14, 2007

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Aegyptin, a Novel Mosquito Salivary Gland Protein, Specifically Binds to Collagen and Prevents Its Interaction with Platelet Glycoprotein VI, Integrin 21, and von Willebrand Factor^*

Eric Calvo, Fuyuki Tokumasu, Osvaldo Marinotti^¶, Jean-Luc Villeval^||, José M. C. Ribeiro, and Ivo M. B. Francischetti¹

From the Vector Biology Section, and Biochemical and Biophysical Parasitology Section, Laboratory of Malaria and Vector Research, NIAID, National Institutes of Health, Bethesda, Maryland 20892-8132, the ^¶Department of Molecular Biology and Biochemistry, University of California, Irvine, California 92697-3900, and ^||INSERM, U790, Université Paris XI, Institut Gustave Roussy, 94805 Villejuif, France

Blood-sucking arthropods have evolved a number of inhibitors of platelet aggregation and blood coagulation. In this study we have molecularly and functionally characterized aegyptin, a member of the family of 30-kDa salivary allergens from Aedes aegypti, whose function remained elusive thus far. Aegyptin displays a unique sequence characterized by glycine, glutamic acid, and aspartic acid repeats and was shown to specifically block collagen-induced human platelet aggregation and granule secretion. Plasmon resonance experiments demonstrate that aegyptin binds to collagen types I–V (K_d 1 nM) but does not interact with vitronectin, fibronectin, laminin, fibrinogen, and von Willebrand factor (vWf). In addition, aegyptin attenuates platelet adhesion to soluble or fibrillar collagen. Furthermore, aegyptin inhibits vWf interaction with collagen type III under static conditions and completely blocks platelet adhesion to collagen under flow conditions at high shear rates. Notably, aegyptin prevents collagen but not convulxin binding to recombinant glycoprotein VI. These findings suggest that aegyptin recognizes specific binding sites for glycoprotein VI, integrin 21, and vWf, thereby preventing collagen interaction with its three major ligands. Aegyptin is a novel tool to study collagen-platelet interaction and a prototype for development of molecules with antithrombotic properties.

Received for publication, July 10, 2007 , and in revised form, July 24, 2007.

^* This work was supported by the Division of Intramural Research, NIAID, National Institutes of Health. 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.

¹ To whom correspondence should be addressed: Vector Biology Section, NIAID, National Institutes of Health, 12735 Twinbrook Pkwy. Rm. 2E-28, Bethesda, MD 20892-8132. Tel.: 301-402-2748; Fax: 301-480-2571; E-mail: ifrancischetti{at}niaid.nih.gov.

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