Lipid-peptide association and activation of lecithin:cholesterol acyltransferase. Effect of alpha-helicity.
A series of apolipopeptides, in which single proline substitutions were made at various sites in the 20-residue sequence, have been synthesized and tested. These peptides have nearly the same hydrophobic content, but very different helical contents, in a structure-making solvent. The affinity of these peptides for phospholipids was evaluated on the basis of their intrinsic tryptophan fluorescence and equilibrium dialysis against model high density lipoproteins. Proline substitutions at one end of the peptide had little or no effect on the fluorescence, circular dichroism, affinity for model high density lipoproteins, or activation of human plasma lecithin:cholesterol acyltransferase. By contrast, there was a dramatic change in all of these variables as the site of substitution was moved progressively closer to the middle of the peptide. All of these data suggested that a helix breaker that is substituted at the midpoint of a helical surface-associating peptide will greatly reduce its affinity for phospholipid surfaces. These results demonstrate that helicity and hydrophobicity are independent determinants of the affinity of an apolipopeptide for a phospholipid surface.
D000595:Amino Acid Sequence; D001053:Apolipoproteins / Q000378:metabolism* / Q000494:pharmacology; D002942:Circular Dichroism; D004134:Dimyristoylphosphatidylcholine / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D050356:Lipid Metabolism; D008055:Lipids / Q000494:pharmacology; D008075:Lipoproteins, HDL / Q000378:metabolism; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000378:metabolism*; D010713:Phosphatidylcholines / Q000494:pharmacology; D011392:Proline; D011487:Protein Conformation; D013050:Spectrometry, Fluorescence; D013329:Structure-Activity Relationship
D001053:Apolipoproteins; D008055:Lipids; D008075:Lipoproteins, HDL; D010713:Phosphatidylcholines; D011392:Proline; D007862:Phosphatidylcholine-Sterol O-Acyltransferase; C028694:1-palmitoyl-2-oleoylphosphatidylcholine; D004134:Dimyristoylphosphatidylcholine