Submitted on April 28, 2004
Revised on August 30, 2004
Accepted on September 7, 2004
Structural features of apolipoprotein B synthetic peptides that inhibit lipoprotein(a) assembly
Rebecca J. Sharp, Matthew A. Perugini, Santica M. Marcovina, and Sally P. A. McCormick
Department of Biochemistry, University of Otago, Dunedin, Dunedin 9001
Corresponding Author: BeckSharp{at}xtra.co.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 disulphide 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. Interestingly, 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 since substitutions with arginine result in a more effective inhibitor.
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