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J. Biol. Chem., Vol. 282, Issue 1, 710-720, January 5, 2007

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Platelet Factor 4 (CXCL4) Seals Blood Clots by Altering the Structure of Fibrin^*

Aymeric A. Amelot¹, Madjid Tagzirt¹, Guylaine Ducouret, René Lai Kuen^¶, and Bernard F. Le Bonniec²

From the INSERM, U765, 75270 Paris Cedex 06, the CNRS, Laboratoire Physicochimie des Polymères et Milieux Disperses, Ecole Supérieure de Physique et de Chimie Industrielles, 75231 Paris Cedex 05, and the ^¶Université Paris Descartes, Service d'Imagerie Cellulaire et Moléculaire, 75270 Paris Cedex 06, France

Platelet factor-4 (PF4/CXCL4) is an orphan chemokine released in large quantities in the vicinity of growing blood clots. Coagulation of plasma supplemented with a matching amount of PF4 results in a translucent jelly-like clot. Saturating amounts of PF4 reduce the porosity of the fibrin network 4.4-fold and decrease the values of the elastic and loss moduli by 31- and 59-fold, respectively. PF4 alters neither the cleavage of fibrinogen by thrombin nor the cross-linking of protofibrils by activated factor XIII but binds to fibrin and dramatically transforms the structure of the ensuing network. Scanning electron microscopy showed that PF4 gives rise to a previously unreported pattern of polymerization where fibrin assembles to form a sealed network. The subunits constituting PF4 form a tetrahedron having at its corners a RPRH motif that mimics (in reverse orientation) the Gly-His-Arg-Pro-amide peptides that co-crystallize with fibrin. Molecular modeling showed that PF4 could be docked to fibrin with remarkable complementarities and absence of steric clashes, allowing the assembly of irregular polymers. Consistent with this hypothesis, as little as 50 µM the QVRPRHIT peptide derived from PF4 affects the polymerization of fibrin.

Received for publication, July 13, 2006 , and in revised form, November 6, 2006.

^* This work was supported in part by grants from INSERM and the Université Paris Descartes of France. 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 Supported by a fellowship from the Ministère de l' Education Nationale, de la Recherche et de la Technologie of France.

² To whom correspondence should be addressed: INSERM U765, Université Paris Descartes, 4 Av. de l'Observatoire, 75270 Paris Cedex 06, France., Tel.: 33-1-53-73-98-28; Fax: 33-1-44-07-17-72; E-mail: bernard.le-bonniec{at}univ-paris5.fr.

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