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J. Biol. Chem., Vol. 278, Issue 34, 32251-32258, August 22, 2003

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Identification of a Novel Binding Site for Platelet Integrins _IIb3 (GPIIbIIIa) and ₅₁ in the C-domain of Fibrinogen^*

Nataly P. Podolnikova  , Valentin P. Yakubenko , George L. Volkov , Edward F. Plow  and Tatiana P. Ugarova  ¶

From the Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Department of Molecular Cardiology, Lerner Research Institute, Cleveland, Ohio 44195 and the Palladin Institute of Biochemistry, Kiev 01601, Ukraine

The interactions of platelets with fibrinogen mediate a variety of responses including adhesion, platelet aggregation, and fibrin clot retraction. Whereas it was assumed that interactions of the platelet integrin _IIb3 with the AGDV sequence in the C-domain of fibrinogen and/or RGD sites in the A chains are involved in clot retraction and adhesion, recent data demonstrated that fibrinogen lacking these sites still supported clot retraction. These findings suggested that an unknown site in fibrinogen and/or other integrins participate in clot retraction. Here we have identified a sequence within C that mediates binding of fibrinogen to platelets. Synthetic peptide duplicating the 365–383 sequence in C, designated P3, efficiently inhibited clot retraction in a dose-dependent manner. Furthermore, P3 supported platelet adhesion and was an effective inhibitor of platelet adhesion to fibrinogen fragments. Analysis of overlapping peptides spanning P3 and mutant recombinant C-domains demonstrated that the P3 activity is contained primarily within 370–383. Integrins _IIb3 and ₅₁ were implicated in recognition of P3, since platelet adhesion to the peptide was blocked by function-blocking monoclonal antibodies against these receptors. Direct evidence that _IIb3 and ₅₁ bind P3 was obtained by selective capture of these integrins from platelet lysates using a P3 affinity matrix. Thus, these data suggest that the P3 sequence in the C-domain of fibrinogen defines a previously unknown recognition specificity of _IIb3 and ₅₁ and may function as a binding site for these integrins.

Received for publication, January 14, 2003 , and in revised form, April 30, 2003.

^* This work was supported by the American Heart Association Established Investigator Award (to T. P. U.), National Institutes of Health Grants HL 63199 (to T. P. U.) and HL 54924 (to E. F. P.), and a predoctoral fellowship (to N. P. P.) from the American Heart Association. 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.

^¶ To whom correspondence should be addressed: Cleveland Clinic, 9500 Euclid Ave., Mail Code NB-50, Cleveland, OH 44195. Tel.: 216-445-8209; Fax: 216-445-8204; E-mail: ugarovt{at}ccf.org.

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