Specificity of ligand-induced conformational change of lipoprotein(a).
The conformation of Lp(a) was probed with a set of omega-aminocarboxylic acids and other analogs of 6-aminohexanoic acid (6-AHA). Using the viscosity-corrected sedimentation coefficient, six additional ligands were shown to induce a major conformational change in Lp(a), from a compact form to an extended form. These were trans-4-(aminomethyl)cyclohexanecarboxylic acid (t-AMCHA), proline, 4-aminobutyric acid, 8-aminooctanoic acid, Nalpha-acetyllysine, and glycine. Lysine, Nepsilon-acetyllysine, glutamic acid, and adipic acid were determined not to cause a conformational change. Urea and guanidine hydrochloride were ineffective at inducing this conformational change at concentrations at which the above ligands did unfold Lp(a). The conformational change was inhibited by 100 mM NaCl and to a lesser extent by 20 mM sodium glutamate. Despite the fact that these two salts have nearly the same ionic strengths, the greater inhibition of the unfolding by NaCl is consistent with a proposed stabilization of interkringle interactions by chloride ions. In 100 mM NaCl, which most closely resembles physiological conditions, only proline, 4-aminobutyric acid, 6-AHA, and t-AMCHA were effective ligands. By analyzing the dimensions of the conformation altering ligands, we propose that a critical variable in determining the effectiveness of a ligand in disrupting Lp(a) is the distance between the carboxyl and amine functions of the ligand. The optimal distance is approximately 6 A, which agrees with the observed 6.6-6.8 A separation of the cationic and anionic centers of known plasminogen and apo(a) lysine binding sites. These studies have implications for the mechanism of Lp(a) particle assembly.
Fless
G M
GM
Departments of Medicine and Pathology, University of Chicago, 5841 South Maryland Avenue, Chicago, Illinois 60637, USA.
Santiago
J Y
JY
Furbee
J
J
Meredith
S C
SC
D015119:Aminocaproic Acid / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D008024:Ligands; D017270:Lipoprotein(a) / Q000737:chemistry* / Q000187:drug effects; D008239:Lysine / Q000031:analogs & derivatives / Q000494:pharmacology; D008956:Models, Chemical; D008970:Molecular Weight; D009994:Osmolar Concentration; D010316:Particle Size; D011392:Proline / Q000494:pharmacology; D011487:Protein Conformation; D011489:Protein Denaturation; D012492:Salts / Q000494:pharmacology; D014148:Tranexamic Acid / Q000494:pharmacology; D014461:Ultracentrifugation
D008024:Ligands; D017270:Lipoprotein(a); D012492:Salts; D018698:Glutamic Acid; D014148:Tranexamic Acid; D011392:Proline; D008239:Lysine; D015119:Aminocaproic Acid