SPECIFICITY OF LIGAND-INDUCED CONFORMATIONAL CHANGE OF LIPOPROTEIN(A)

The conformation of Lp(a) was probed with a set of to-aminocarboxylic acids and other analogs of 6-aminohexanoic acid (6-AHA). Using the vis cosity-corrected sedimentation coefficient, six additional Ligands wer e shown to induce a major conformational change in Lp(a), from a compa ct form to an extended form. These were trans-4-(aminomethyl)cyclohexa necarboxylic acid (t-AMCHA), proline, 4-aminobutyric acid, 8-aminoocta noic acid, N-alpha-acetyllysine, and glycine. Lysine, N-epsilon-acetyl lysine, glutamic acid, and adipic acid were determined not to cause a conformational change. Urea and guanidine hydrochloride were ineffecti ve at inducing this conformational change at concentrations at which t he above ligands did unfold Lp(a). The conformational change was inhib ited by 100 mM NaCl and to a lesser extent by 30 mM sodium glutamate. Despite the fact that these two salts have nearly the same ionic stren gths, the greater inhibition of the unfolding by NaCl is consistent wi th a proposed stabilization of interkringle interactions by chloride i ons. In 100 mM NaCl, which most closely resembles physiological condit ions, only proline, 4-aminobutyric acid, 6-AHA, and t-AMCHA were effec tive ligands. By analyzing the dimensions of the conformation altering ligands, we propose that a critical variable in determining the effec tiveness of a ligand in disrupting Lp(a) is the distance between the c arboxyl and amine functions of the ligand. The optimal distance is app roximately 6 Angstrom, which agrees with the observed 6.6-6.8 Angstrom separation of the cationic and anionic centers of known plasminogen a nd apo(a) lysine binding sites. These studies have implications for th e mechanism of Lp(a) particle assembly.