STRUCTURAL FEATURES OF SYNTHETIC PEPTIDES OF APOLIPOPROTEIN-E THAT BIND THE LDL RECEPTOR

Apolipoprotein (apo) E, via its receptor binding domain contained in r esidues 140-150, mediates hepatic and peripheral tissue binding of cho lesterol-rich lipoproteins. Previously, we reported that a synthetic p eptide representing a linear tandem repeat of amino acids 141-155, the 141-155 dimer, binds the low density lipoprotein (LDL) receptor. To d efine the structural features essential for LDL receptor binding of th e 141-155 dimer, a series of modified peptides were synthesized. The s econdary structure content of the modified apoE peptides was assessed by circular dichroism (CD) and the receptor activity was studied in ce llular LDL receptor binding assays. alpha-Helix content was necessary but not sufficient for receptor activity because both a 129-162 monome r and the 141-155 dimer peptides had comparable CD spectra and helix c ontents, but only the 141-155 dimer was receptor active. Deletion of t he charged amino terminal residues including arg(142) and lys(143) in the 145-155 or 144-150 dimers had no effect on alpha-helix content, ye t abolished their receptor activities. Helical net models of all recep tor active peptides indicated that the LDL-receptor binding activity o f the 141-155 dimer is dependent on at least two clusters of basic ami no acids present on the hydrophilic face of the amphipathic alpha-heli x of the 141-155, 141-150, 141-155 (lys(143)-->ala) and 141-155 (arg(1 50)-->ala) dimer peptides.