A 2-STEP MODEL FOR LIPOPROTEIN(A) FORMATION

Lipoprotein(a) (Lp(a)), a risk factor for coronary artery disease, is a LDL-like particle with apolipoprotein(a) (apo(a)) covalently linked to apolipoprotein B (apoB), the main protein component of LDL. Apo(a) is highly homologous to plasminogen and its gene probably arose by duplication of the plasminogen gene. It has many repeats of kringle- 4-like domain, classified as type 1 through type 10 (T1-T10). T9 is responsible for the covalent linkage between apo(a) and LDL. However, we found that T9 has no affinity for LDL. Therefore, an initial noncovalent interaction between apo(a) and LDL is necessary to bring T9 and LDL together. T6 and possibly T7 of apo(a) were identified as the kringles which mediate this initial interaction. With these findings, a two step model for Lp(a) formation is proposed. This model should be useful in the design of Lp(a) formation inhibitors. These inhibitors are potential anti-hyperlipoprotein(a) drugs.