Structural features of synthetic peptides of apolipoprotein E that bind the LDL receptor.
Apolipoprotein (apo) E, via its receptor binding domain contained in residues 140-150, mediates hepatic and peripheral tissue binding of cholesterol-rich lipoproteins. Previously, we reported that a synthetic peptide representing a linear tandem repeat of amino acids 141-155, the 141-155 dimer, binds the low density lipoprotein (LDL) receptor. To define the structural features essential for LDL receptor binding of the 141-155 dimer, a series of modified peptides were synthesized. The secondary structure content of the modified apoE peptides was assessed by circular dichroism (CD) and the receptor activity was studied in cellular LDL receptor binding assays. alpha-Helix content was necessary but not sufficient for receptor activity because both a 129-162 monomer and the 141-155 dimer peptides had comparable CD spectra and helix contents, but only the 141-155 dimer was receptor active. Deletion of the charged amino terminal residues including arg142 and lys143 in the 145-155 or 144-150 dimers had no effect on alpha-helix content, yet abolished their receptor activities. Helical net models of all receptor active peptides indicated that the LDL-receptor binding activity of the 141-155 dimer is dependent on at least two clusters of basic amino acids present on the hydrophilic face of the amphipathic alpha-helix of the 141-155, 141-150, 141-155 (lys143-->ala) and 141-155 (arg150-->ala) dimer peptides.
Dyer
C A
CA
Department of Immunology, Scripps Research Institute, La Jolla, CA 92037.
Cistola
D P
DP
Parry
G C
GC
Curtiss
L K
LK
D000595:Amino Acid Sequence; D001057:Apolipoproteins E / Q000737:chemistry* / Q000378:metabolism; D002942:Circular Dichroism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D046911:Macromolecular Substances; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D011973:Receptors, LDL / Q000378:metabolism*; D012091:Repetitive Sequences, Nucleic Acid; D013696:Temperature
D001057:Apolipoproteins E; D046911:Macromolecular Substances; D011973:Receptors, LDL