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Journal of Lipid Research, Vol. 45, 63-70, January 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Mutation of lysine residues in apolipoprotein B-100 causes defective lipoprotein[a] formation

Catherine Y. Y. Liu^*, Ric Broadhurst, Santica M. Marcovina and Sally P. A. McCormick^1,*

^* Department of Biochemistry, University of Otago, Dunedin, New Zealand
AgResearch Ruakura, Hamilton, New Zealand
Department of Medicine, Northwest Lipid Research Laboratories, University of Washington, Seattle, WA 98103

¹ To whom correspondence should be addressed. e-mail: sally.mccormick{at}stonebow.otago.ac.nz

Lipoprotein[a] (Lp[a]) is assembled by a two-step process involving an initial lysine-dependent binding between apolipoprotein B-100 (apoB-100) and apolipoprotein[a] (apo[a]) that facilitates the formation of a disulphide bond between apoB-100Cys4,326 and apo[a]Cys4,057. Previous studies of transgenic mice expressing apoB-95 (4,330 amino acids) and apoB-97 (4,397 amino acids) have shown that apoB-100 amino acids 4,330–4,397 are important for the initial binding to apo[a]. Furthermore, a lysine-rich peptide spanning apoB-100 amino acids 4,372–4,392 has recently been shown to bind apo[a] and inhibit Lp[a] assembly in vitro. This suggests that a putative apo[a] binding site exists in the apoB-4,372–4,392 region. The aim of our study was to establish whether the apoB-4,372–4,392 sequence was important for Lp[a] assembly in the context of the full-length apoB-100. Transgenic mice were created that expressed a mutant human apoB-100, apoB-100K₄S₄, in which all four lysine residues in the 4,372–4,392 sequence were mutated to serines. The apoB-100K₄S₄ mutant showed a reduced capacity to form Lp[a] in vitro compared with wild-type human apoB-100. Double transgenic mice expressing both apoB-100K₄S₄ and apo[a] contained significant amounts of free apo[a] in the plasma, indicating a less-efficient assembly of Lp[a] in vivo.

Taken together, these results clearly show that the apoB-4,372–4,392 sequence plays a role in Lp[a] assembly.

Abbreviations: apo[a], apolipoprotein[a]; apoB-100, apolipoprotein B-100; FPLC, fast protein liquid chromatography; Lp[a], lipoprotein[a]; YAC, yeast artificial chromosome

Supplementary key words apolipoprotein[a] • assembly • coronary heart disease • lysine • site-directed mutagenesis • transgenic mice • yeast artificial chromosome

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