Neutral lipid transport in mammals is complicated involving many types of apolipoprotein. The exchangeable apolipoproteins mediate the transfer of hydrophobic lipids between tissues and particles, and bind to cell surface receptors. Amphipathic α-helices form a common structural motif that facilitates their lipid binding and exchangeability. ApoLp-III, the only exchangeable apolipoprotein found in insects, is a model amphipathic α-helix bundle protein and its three dimensional structure and function mimics that of the mammalian proteins apoE and apoAI. Even the intracellular exchangeable lipid droplet protein TIP47/perilipin 3 contains an α-helix bundle domain with high structural similarity to that of apoE and apoLp-III. Here, we investigated the interaction of apoLp-III from Locusta migratoria with lipid monolayers. Consistent with earlier work we find that insertion of apoLp-III into fluid lipid monolayers is highest for diacylglycerol. We observe a preference for saturated and more highly ordered lipids, suggesting a new mode of interaction for amphipathic α-helix bundles. X-ray reflectivity shows that apoLp-III unfolds at a hydrophobic interface and flexible loops connecting the amphipathic α-helices stay in solution. X-ray diffraction indicates that apoLp-III insertion into diacylglycerol monolayers induces additional ordering of saturated acyl-chains. These results thus shed important new insight into the protein-lipid interactions of a model exchangeable apolipoprotein with significant implications for its mammalian counterparts.
The interactions between proteins and biological membranes play an important role in many aspects of biochemistry. Thus, the ability to monitor the structural dynamics of membrane proteins is of great interest. In general, hydrophobic peptides are disordered and tend to aggregate in aqueous environments. For example, the amyloid-b (Ab) peptide, a major component of the insoluble plaques associated with Alzheimer's disease, is intrinsically disordered under physiological conditions. However, Ab adopts a-helical structure in membrane mimicking environments. This is not surprising as the hydrophobic region derives from the transmembrane (TM) region of the amyloid precursor protein. More interesting is the fact that low concentrations of organic solvents or surfactants promote aggregation and formation of b-sheet structure. The ability to simultaneously monitor lipid association and study its effect on the secondary structure of amyloidogenic proteins would be of great interest. Recent studies have shown a significantly enhanced amide I mode in the deep-UV resonance Raman (dUVRR) spectra of transmembrane proteins is a marker for lipid association. Positively charged hydrophobic peptides, including the hydrophobic Ab(25-40) fragment of Ab, spontaneously insert into anionic lipid bilayers. The application of dUVRR spectroscopy to monitor lipid-association, insertion and folding of these peptides will be presented.
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