Abstract
The four peptide analogs of the amphipathic helix whose interactions with dimyristoyl phosphatidylcholine were described in the preceding paper were compared with apolipoproteins (apo) A-I and A-II in ability to displace native apolipoprotein from high density lipoprotein (HDL) and in ability to activate lecithin:cholesterol acyltransferase. The rank order of the ability of the four peptide analogs to displace apo-A-I from intact HDL was 18A-Pro-18A greater than 18A greater than des-Val10-18A greater than reverse-18A, the same order suggested in the preceding paper for relative lipid affinities. Modified HDL from which 40% of the apo-A-I had been displaced by 18A was indistinguishable from unmodified HDL in its ability to act as a lecithin:cholesterol acyltransferase substrate. This suggests that the easily displaced apo-A-I molecules in polydisperse HDL are relatively ineffectual as lecithin:cholesterol acyltransferase activators and/or 18A replaces the lecithin:cholesterol acyltransferase activity lost. The peptide analog 18A-Pro-18A was found to be a powerful activator of lecithin:cholesterol acyltransferase when incubated with unilamellar egg phosphatidylcholine (PC) vesicles, reaching 140% of the activity of apo-A-I at a 1:1.75 peptide-to-egg PC ratio. In another experiment, it was found that discoidal egg PC complexes of 18A-Pro-18A, 18A, and des-Val10-18A, formed by cholate dialysis, had 30-45% of the activity of apo-A-I/egg PC discoidal complexes, also formed by cholate dialysis, at the same peptide/lipid weight ratio. Examination of the structures formed when the 18A-Pro-18A peptide was incubated with unilamellar egg PC vesicles indicated that the ability of 18A-Pro-18A to exceed apo-A-I in lecithin:cholesterol acyltransferase activating ability is due to the spontaneous conversion by 18A-Pro-18A of egg PC vesicles to small protein annulus-bilayer disc structures. Apo-A-I, apo-A-II, nor any of the other three peptide analogs of the amphipathic helix studied were able to convert a significant fraction of egg PC unilamellar vesicles to discoidal structures.
Highlights
The four peptide analogs of the amphipathic helix (DMPC’) and four systematically different synthetic peptide whose interactions with dimyristoylphosphatidylcho- analogs of the amphipathic helix were studied (Table I)
The line weredescribed in the preceding paper were com- two analogs whose sequences most strongly mimicked native pared withapolipoproteinsA-I and A-I1 in ability amphipathic sequences, 18A and18A-Pro-l8A, most todisplace native apolipoproteinfromhighdensity strongly mimicked apolipoprotein A-I in interactions with lipoprotein (HDL) andinability to activate leci- DMPC
Therank orderof the affinity than 18A, presumably due to the cooperativity proability of the fourpeptide analogs to displace apo-A-I vided by the presence of two covalently linked lipid-associatfrom intact high density lipoprotein (HDL) was 18A-Pro-18A> 18A > des-Val’O- ing domains
Summary
By 1 8 A was indistinguishable fromunmodified HDL in In the present paper, the four peptide analogs are compared its ability to actas a 1ecithin:cholesterol acyltransfer- with apolipoproteins A-I and A-I1in ability to displace native ase substrate This suggests that the displaced apolipoproteins from high density lipoprotein (HDL) and in apo-A-I molecules in polydisperse HDL a r e relatively ability to activate 1ecithin:cholesterol acyltransferase. Vesicles, esterhas been suggested [3] to result in the trapping of reaching 140% of the activity of apo-A-I at a 1:1.75 cholesterol in HDL, lowering the concentration of chopeptide-to-egg PC ratio.In another experimenti,t was lesterol in peripheral cell membranes This putative process found that discoidal egg PC complexes of 18A-Pro- has been referred to as reverse cholesterol transport. The cholesterol-free bottom fractions (free protein) and the fractioncontainingcholesterol(HDL) were pooled and dialyzed againstTris
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