© 1996 American Heart Association, Inc.
Articles |
Lipoprotein(a) Assembly
Quantitative Assessment of the Role of Apo(a) Kringle IV Types 2-10 in Particle Formation
the Department of Biochemistry, Queen's University, Kingston, Ontario, Canada (B.R.G., L.F.M., M.L.K.), and the Department of Medicine, Northwest Lipid Research Laboratories, University of Washington, Seattle (S.M.M.).
Correspondence to Dr M.L. Koschinsky, Department of Biochemistry, Queen's University, Kingston, Ontario, Canada K7L 3N6. E-mail MK11@POST.QUEENSU.CA.
We have developed a system for the quantitative assessment of the efficiency of lipoprotein(a) [Lp(a)] formation in vitro. Amino-terminally truncated derivatives of a 17-kringle form of recombinant apo(a) [r-apo(a)] were transiently expressed in human embryonic kidney cells. Equimolar amounts of r-apo(a) derivatives were incubated with a fourfold molar excess of purified human low density lipoprotein, and r-Lp(a) formation was assessed by densitometric analysis of Western blots. Although r-Lp(a) formation was observed with each r-apo(a) derivative, both the rate and extent of particle formation were greatly lower on removal of kringle IV type 7. Additional substantial decreases in these parameters were observed on removal of kringle IV type 8, thereby suggesting a major role for these two kringles in Lp(a) assembly. We directly demonstrated that the lysine-binding sites (LBSs) within kringle IV types 5-9 are "masked" in the context of the Lp(a) particle and are consequently unavailable for interaction with lysine-Sepharose. Using site-directed mutagenesis, we also demonstrated that the previously described LBS in kringle IV type 10 is not required for r-Lp(a) formation: r-Lp(a) formation using a mutated form of apo(a) that lacks this LBS is comparable in efficiency to that of wild-type r-apo(a) and can be inhibited to a similar extent by 
-amino-n-caproic acid. In summary, the results of our study indicate that apo(a) kringle IV types 7 and 8 are required for maximal efficiency of Lp(a) formation, likely by virtue of their ability to mediate lysine-dependent noncovalent interactions with apoB-100 that precede disulfide bond formation.
Key Words: apolipoprotein(a) • lipoprotein(a) • assembly • kringles
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