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Volume 272, Number 38, Issue of September 19, 1997 pp. 23616-23622
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Transgenic Mice Expressing Human ApoB95 and ApoB97
EVIDENCE THAT SEQUENCES WITHIN THE CARBOXYL-TERMINAL PORTION OF HUMAN apoB100 ARE IMPORTANT FOR THE ASSEMBLY OF LIPOPROTEIN(a)

(Received for publication, June 11, 1997, and in revised form, July 2, 1997)

Sally P. A. McCormick ^§ , Jennifer K. Ng , Candace M. Cham , Stacy Taylor , Santica M. Marcovina , Jere P. Segrest ^** , Robert E. Hammer and Stephen G. Young ^§§§

From the  Gladstone Institute of Cardiovascular Disease, ^§ Cardiovascular Research Institute, ^§§ Department of Medicine, University of California, San Francisco, California 94141-9100, the  Department of Medicine, Northwest Lipid Research Laboratories, University of Washington, Seattle, Washington 98103, the ^** Department of Medicine, University of Alabama Medical Center, Birmingham, Alabama 35294-0012, and the  Department of Biochemistry, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75235

The structural features of apolipoprotein (apo) B that are important for its covalent linkage to apo(a) to form lipoprotein(a) (Lp(a)) are incompletely understood. Although apoB100 cysteine 4326 is required for the disulfide linkage with apo(a), other structural features, aside from a single free cysteine residue, must be important for apoB's initial interaction with apo(a) and for facilitating the formation of the disulfide bond. To determine if sequences carboxyl-terminal to cysteine 4326 affect the efficiency of Lp(a) formation, we used "pop-in, pop-out" gene targeting in a human apoB yeast artificial chromosome to introduce nonsense mutations into exon 29 of the apoB gene. The mutant yeast artificial chromosomes, which coded for the truncated versions of human apoB, apoB95, and apoB97, were then used to express these mutant forms of apoB in transgenic mice. As judged by in vitro assays of Lp(a) formation, apoB95 (4330 amino acids) formed a small amount of Lp(a) but did so slowly. In contrast, apoB97 (4397 amino acids) formed Lp(a) rapidly, although not quite as rapidly as the full-length apoB100 (4536 amino acids). These results were supported by an analysis of double-transgenic mice expressing both human apo(a) and either apoB95 or apoB97. In mice expressing both apoB95 and apo(a), there was only a trace amount of Lp(a) in the plasma, and most of the apo(a) was free, whereas in mice expressing both apoB97 and apo(a), virtually all of the apo(a) was bound to apoB97 in the form of Lp(a). These results show that sequences carboxyl-terminal to apoB95 (amino acids 4331-4536) are not absolutely required for Lp(a) formation, but this segment of the apoB molecule, particularly residues 4331-4397, is necessary for the efficient assembly of Lp(a).

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