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J. Biol. Chem., Vol. 278, Issue 39, 37154-37159, September 26, 2003

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Identification and Characterization of Novel Lysine-independent Apolipoprotein(a)-binding Sites in Fibrin(ogen) C-domains^*

Galina Tsurupa  , Benoît Ho-Tin-Noé  ¶, Eduardo Anglés-Cano ¶ and Leonid Medved  ||

From the Jerome H. Holland Laboratory for the Biomedical Sciences, American Red Cross, Rockville, Maryland 20855 and ^¶INSERM, U460, Centre Hospitalier Universitaire Bichat-Claude Bernard, 75877 Paris 18, France

Accumulation of lipoprotein(a) (Lp(a)) in atherosclerotic plaques is mediated through interaction of fibrin-(ogen) deposits with the apolipoprotein(a) (apo(a)) moiety of Lp(a). It was suggested that because apo(a) competes with plasminogen for binding to fibrin, causing inhibition of fibrinolysis, it could also promote atherothrombosis. Because the fibrin(ogen) C-domains bind plasminogen and tissue-type plasminogen activator with high affinity in a Lys-dependent manner, we hypothesized that they could also bind apo(a). To test this hypothesis, we studied the interaction between the recombinant apo(a) A10 isoform and the recombinant C-fragment (A-(221–610)) corresponding to the C-domain by enzyme-linked immunosorbent assay and surface plasmon resonance. Both methods revealed a high affinity interaction (K_d = 19–21 nM) between the immobilized C-fragment and apo(a), indicating that the former contains an apo(a)-binding site. This affinity was comparable to that of apo(a) for fibrin. At the same time, no interaction was observed between soluble fibrinogen and immobilized apo(a), suggesting that, in the former, this and other apo(a)-binding sites are cryptic. Further experiments with truncated recombinant variants of the C-fragment allowed localization of the apo(a)-binding site to the A-(392–610) region. The presence of -aminocaproic acid only slightly inhibited binding of apo(a) to the C-fragment, indicating the Lys-independent nature of their interaction. In agreement, the influence of plasminogen or tissue-type plasminogen activator on binding of apo(a) to the C-fragment was minimal. These results indicate that the C-domains contain novel high affinity apo(a)-binding sites that may provide a Lys-independent mechanism for bringing Lp(a) to places of fibrin deposition such as injured vessels or atherosclerotic lesions.

Received for publication, May 16, 2003 , and in revised form, July 3, 2003.

^* This work was supported by National Institutes of Health Grant HL-56051 (to L. M.) and by an Adrienne et Pierre Sommer grant from the Fondation de France (to E. A.-C.). 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.

Both authors contributed equally to this work.

^|| To whom correspondence should be addressed: Jerome H. Holland Laboratory, American Red Cross, 15601 Crabbs Branch Way, Rockville, MD 20855. Tel.: 301-738-0719; Fax: 301-738-0740; E-mail: medvedL{at}usa.redcross.org.

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