Ligand-induced conformational change of lipoprotein(a).
Lipoprotein(a) undergoes a dramatic, reversible conformational change on binding 6-amino-hexanoic acid (6-AHA), as measured by a decrease in the sedimentation rate, the magnitude of which is directly proportional to apo(a) mass. A similar reversible transition from a compact to an extended form has been shown to occur in plasminogen on occupation of a weak lysine binding site. The magnitude of the change in Lp(a) with large apo(a) is about 2.5 times that seen for plasminogen, however. Regardless of apo(a) size, binding analysis indicated that 1.4-4 molecules of 6-AHA bound per Lp(a) particle; the midpoint of the conformational change occurs at 6-AHA concentrations of 100-200 mM. Since rhesus Lp(a), which lacks both kringle V and the strong lysine binding site on kringle IV 10, also undergoes a similar conformational change, the phenomenon may be attributable to weak sites, possibly located in K-IV 5-8. Compact Lp(a), i.e., native Lp(a), had a frictional ratio (f/f0) of 1.2 that was independent of apo(a) mass, implying constant shape and hydration. For Lp(a) in saturating 6-AHA, f/f0 ranged from 1.5 to over 2.1 for the largest apo(a) with 32 K-IV, indicating a linear relationship between hydrodynamic volume and number of kringles, as expected for an extended conformation. However, only the variable portion of apo(a) represented by the K-IV 2 domains, participates in the conformational change; the invariant K-IV 3-9 domains remain close to the surface. These results suggest that apo(a) is maintained in a compact state through interactions between weak lysine binding sites and multiple lysines on apoB and/or apo(a), and that these interactions can be disrupted by 6-AHA, a lysine analog.
Fless
G M
GM
Department of Medicine, University of Chicago, Illinois 60637, USA.
Furbee
J
J
Snyder
M L
ML
Meredith
S C
SC
D015119:Aminocaproic Acid / Q000378:metabolism; D001054:Apolipoproteins A / Q000737:chemistry; D006801:Humans; D008024:Ligands; D017270:Lipoprotein(a) / Q000737:chemistry* / Q000378:metabolism; D008970:Molecular Weight; D011485:Protein Binding; D011487:Protein Conformation
D001054:Apolipoproteins A; D008024:Ligands; D017270:Lipoprotein(a); D015119:Aminocaproic Acid