COMPARISON OF THE LYSINE BINDING FUNCTIONS OF LIPOPROTEIN(A) AND PLASMINOGEN

Regions of apoprotein(a) of lipoprotein(a) [L,p(a)] exhibitstriking pr imary sequence homology to the kringles of plasminogen. The kringles o f plasminogen are lysine binding structures and mediate interactions o f plasmin(ogen) with substrates and inhibitors. In the current study, the lysine binding properties of Lp(a) have been compared to those of plasminogen and isolated kringle 4 of plasminogen (K4). An analytical assay was implemented to quantitate the interaction of kringle-contain ing molecules with lysine-Sepharose beads. Radioiodinated ligands, Lp( a), plasminogen, and K4, bound to the beads, and their interactions we re inhibited by lysine analogues in a dose-dependent fashion. A series of omega-aminocarboxylic acids inhibited Lp(a), plasminogen, and K4 b inding to the lysine-Sepharose beads, but marked differences in the ef fectiveness of these compounds were observed with each ligand. In this series of compounds, 6-aminohexanoic acid was the most potent inhibit or of binding to lysine-Sepharose for all three ligands. The pH had li ttle effect on the inhibition of plasminogen binding by these compound s. For Lp(a), a low pH caused a marked decrease in inhibition by the 5 -carbon and 4-carbon omega-amino acids. In addition, tranexamic acid w as 750-fold more potent than lysine in inhibiting plasminogen and 55-f old more potent for K4 binding to the beads. In contrast, the differen tial potency of these compounds on Lp(a) binding was only 3-fold. Thes e results suggest that the kringles of Lp(a) possess lysine binding fu nctions which are similar, but not identical, to those of plasminogen and its K4. To test this conclusion in a biological context, I-125-Lp( a) and I-125-plasminogen binding to monocytoid cells and fibrin clots was compared. The potency of tranexamic acid was much higher than that of lysine for inhibiting plasminogen binding to cells and to fibrin c lots. In contrast, the ratio of tranexamic acid to lysine efficacy was less pronounced for Lp(a) binding to cells and to fibrin. Thus, Lp(a) possesses lysine binding sites which can mediate its interaction with cells and with fibrin, but the fine specificity of these sites in Lp( a) and plasminogen is distinguishable.