Polypeptide segments, composed of a helixes with specific surface topography termed amphipathic helixes, have been proposed as the basic lipid-associating domains of apolipoproteins from the plasma lipoproteins. A computer search for proteins having sequences that could form amphipathic helixes indicated that amyloid A, a pathologically occurring protein usually associated with “secondary” amyloidosis, also contained amphipathic helixes. In studies reported here, amyloid A is shown to associate spontaneously with phospholipid vesicles with the following results: (a) the formation of a protein- lipid complex isolated by equilibrium density gradient ultracentrifugation, (b) a 100% increase in a α helicity as measured by circular dichroism, (c) a 9-nm shift in the fluorescence maximum due to the single tryptophan residue located in the amphipathic region, indicating the tryptophan is moving from a polar to a nonpolar environment, and (d) the formation of stacked disk-like protein-lipid complexes as visualized by negative stain electron microscopy. The temperature dependence of the circular dichroic spectrum of the amyloid Aphospholipid complex suggests that the complex is formed by insertion of protein between the fatty acyl chains of the lipid. These findings suggest that the amphipathic helix is an important structural unit in lipid-associating proteins and that this unit can be recognized on the basis of its amino acid sequence. In addition, these studies have implications for the origin and function of amyloid A protein.
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