LIGAND-INDUCED CONFORMATIONAL CHANGE OF LIPOPROTEIN(A)

Lipoprotein(a) undergoes a dramatic, reversible conformational change on binding 6-aminohexanoic acid (6-AHA), as measured by a decrease in the sedimentation rate, the magnitude of which is directly proportiona l 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. R egardless of apo(a) size, binding analysis indicated that 1.4-4 molecu les of 6-AHA bound per Lp(a) particle; the midpoint of the conformatio nal 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 o n kringle IV 10, also undergoes a similar conformational change, the p henomenon 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/f(o) ) of 1.2 that was independent of apo(a) mass, implying constant shape and hydration. For Lp(a) in saturating 6-AHA, f/f(o) ranged from 1.5 t o over 2.1 for the largest apo(a) with 32 K-IV, indicating a linear re lationship between hydrodynamic volume and number of kringles, as expe cted for an extended conformation. However, only the variable portion of apo(a) represented by the K-IV 2 domains, participates in the confo rmational change; the invariant K-IV 3-9 domains remain close to the s urface. These results suggest that apo(a) is maintained in a compact s tate through interactions between weak lysine binding sites and multip le lysines on apoB and/or apo(a), and that these interactions can be d isrupted by 6-AHA, a lysine analog.