Apolipoprotein/lipid interactions: studies with synthetic polypeptides.
The understanding of complex interactions which occur in the serum lipoproteins has been greatly aided by using peptide synthesis to obtain fragments of the apolipoproteins which are unobtainable by other means. The results from lipid-binding studies with these synthetic materials have generally supported the amphipathic helical hypothesis of Segrest et al. for the interaction of phospholipid with the apolipoprotein. However, CD results from these same experiments suggest that the amphipathic helices may not be as large as originally proposed. The contribution of other protein structural features, e.g. beta-sheets and beta-turns, to lipid binding has not been systematically investigated. The importance of hydrophobicity to lipid-protein interaction is strongly supported by the experimental data. Indeed, there is preliminary evidence that the hydrophobic residues positioned beneath the paired acidic and basic residues on the amphipathic helix are extremely critical to the interaction with phospholipid. The role of charged residues in binding is less clear and needs further investigation. The importance of the structural features previously mentioned can be elucidated through the synthesis of appropriately substituted peptides. However, the final proof of the protein structural features involved in protein-lipid interaction must await x-ray diffraction analysis and detailed NMR measurements. As more peptides are synthesized and studied, the authors feel that the complexities of lipid transport and metabolism will be better understood. The surface properties of peptide fragments of the apoproteins are presently being investigated and could lead to important findings on the exchange of apoproteins between lipoprotein classes. The interactions of synthetic peptides with the enzymes which control lipid synthesis and degradation have increased the understanding of protein-protein and protein-lipid interactions which control these important processes. The ability of a synthetic peptide to accelerate lipolysis in an apoC-II deficient lipoprotein offers the potential for treating these patients with synthetic material to reduce their hypertriglyceridemia. The ability to model the amphipathic helix opens new vistas for the study of the role of hydrophobicity, peptide length, helix potential, and charged residues in lipid binding. The observation of Pownall et al. and Yokayama et al. that phospholipid-cholesterol complexes of these model peptides can serve as substrates for LCAT suggests several exciting avenues for further study of cholesterol metabolism and transport. As these studies increase knowledge of lipid transport, the potential exists to intervene therapeutically with potent synthetic lipid-binding peptides to reduce serum cholesterol or to remove cholesterol from arterial lesions.
D000595:Amino Acid Sequence; D016632:Apolipoprotein A-I; D016633:Apolipoprotein A-II; D053302:Apolipoprotein C-I; D053304:Apolipoprotein C-II; D053305:Apolipoprotein C-III; D001053:Apolipoproteins / Q000097:blood*; D001054:Apolipoproteins A; D001056:Apolipoproteins C; D006801:Humans; D008055:Lipids / Q000097:blood*; D008956:Models, Chemical; D010446:Peptide Fragments / Q000138:chemical synthesis*; D011485:Protein Binding; D011487:Protein Conformation
D016632:Apolipoprotein A-I; D016633:Apolipoprotein A-II; D053302:Apolipoprotein C-I; D053304:Apolipoprotein C-II; D053305:Apolipoprotein C-III; D001053:Apolipoproteins; D001054:Apolipoproteins A; D001056:Apolipoproteins C; D008055:Lipids; D010446:Peptide Fragments