The apolipoprotein B3304–3317 peptide as an inhibitor of the lipoprotein (a):apolipoprotein B-containing lipoprotein interaction

Author:

Trieu V N1,Olsson U2,McConathy W J1

Affiliation:

1. Departments of Medicine and Biochemistry, University of North Texas Health Science Center at Fort Worth, Fort Worth, TX 76107, U.S.A.

2. Wallenberg Laboratory, Göteborgs University, Göteborg, Sweden

Abstract

Lipoprotein (a) [Lp(a)] is a risk factor for coronary artery disease. It is characterized by apolipoprotein (a) [apo(a)] disulphide linked to apolipoprotein B (apoB), by Cys4057 of apo(a) and possibly Cys3734 of apoB. We call this the covalent apo(a):apoB-Lp interaction, to distinguish it from the non-covalent Lp(a):apoB-Lp interaction, mediated by the proline-binding kringle-4-like domain(s) of Lp(a). The Lp(a):apoB-Lp interaction was inhibited by an apoB peptide spanning residues 3304-3317. This peptide was found by a computerized search for sites on apoB similar to the plasminogen's kringle-4-binding site of alpha 2-antiplasmin. It probably constitutes part of the Lp(a)-binding site on apoB because: (1) it corresponds to the alpha 2-antiplasmin minimum binding domain for plasminogen's kringle-4; (2) the competitive nature of inhibition [KI = (1.5 +/- 0.7) x 10(-4) M, n = 5] suggested that it and apoB-Lp bound to Lp(a) by the same mechanism at the same site; and (3) it specifically bound Lp(a) and not apoB-Lp, and the bound Lp(a) was dissociated by inhibitors of the Lp(a):apoB-Lp interaction, 6-aminohexanoic acid and L-proline. Inhibition was independent of its proline residue, suggesting that proline in the context of a peptide is not a ligand for the kringle(s) which mediated the binding of Lp(a) to apoB-Lp.

Publisher

Portland Press Ltd.

Subject

Cell Biology,Molecular Biology,Biochemistry

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1. Biogenesis of Lp(a) in transgenic mouse hepatocytes;Clinical Genetics;2008-04-23

2. Analysis of the mechanism of lipoprotein(a) assembly;Clinical Genetics;2008-04-23

3. Inhibitors of lipoprotein(a) assembly;Bioorganic & Medicinal Chemistry;2003-11

4. A Synthetic Peptide That Inhibits Lipoprotein(a) Assembly;Arteriosclerosis, Thrombosis, and Vascular Biology;2003-03

5. An Analysis of the Interaction between Mouse Apolipoprotein B100 and Apolipoprotein(a);Journal of Biological Chemistry;2000-09

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