J. Lipid Res.
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Originally published In Press as doi:10.1194/jlr.M400163-JLR200 on September 16, 2004

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Journal of Lipid Research, Vol. 45, 2227-2234, December 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Structural features of apolipoprotein B synthetic peptides that inhibit lipoprotein(a) assembly

Rebecca J. Sharp*, Matthew A. Perugini{dagger}, Santica M. Marcovina{ddagger} and Sally P. A. McCormick1,*

* Department of Biochemistry, University of Otago, Dunedin, New Zealand
{dagger} Department of Biochemistry and Molecular Biology, University of Melbourne, Victoria, Australia
{ddagger} 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 via an initial noncovalent interaction between apolipoprotein B100 (apoB) and apolipoprotein(a) [apo(a)] that facilitates the formation of a disulfide bond between the two proteins. We previously reported that a lysine-rich, {alpha}-helical peptide spanning human apoB amino acids 4372–4392 was an effective inhibitor of Lp(a) assembly in vitro. To identify the important structural features required for inhibitory action, new variants of the apoB4372-4392 peptide were investigated. Introduction of a central leucine to proline substitution abolished the {alpha}-helical structure of the peptide and disrupted apo(a) binding and inhibition of Lp(a) formation. Substitution of hydrophobic residues in the apoB4372-4392 peptide disrupted apo(a) binding and inhibition of Lp(a) assembly without disrupting the {alpha}-helical structure. Substitution of all four lysine residues in the peptide with arginine decreased the IC50 from 40 µM to 5 µM. Complexing of the arginine-substituted peptide to dimyristoylphosphatidylcholine improved its activity further, yielding an IC50 of 1 µM. We conclude that the {alpha}-helical structure of apoB4372-4392, in combination with hydrophobic residues at the lipid/water interface, is crucial for its interaction with apo(a).

Furthermore, the interaction of apoB4372-4392 with apo(a) is not lysine specific, because substitutions with arginine result in a more effective inhibitor.

Abbreviations: apo(a), apolipoprotein(a); apoB, apolipoprotein B100; CD, circular dichroism; DMPC, dimyristoylphosphatidylcholine; Lp(a), lipoprotein(a)

Supplementary key words apolipoprotein(a) • DMPC vesicles • noncovalent interaction • peptide inhibitor


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