This proposal seeks to enhance the understanding of the structure-function relationship of a very highly conserved region of apolipoprotein E (apoE ) by clarifying in-depth the cellular mechanism by which a conformationally constrained synthetic peptide which mimics this region (amino acids 41-60) enhances the binding and internalization of low density lipoproteins (LDL) to both LDL receptor (LDL-R) positive and negative cells. This will be accomplished by identifying through what on the cell surface this interaction is occuring, localizing the site of binding between this peptide and LDL, tracing t he fate of LDL internalized in the presence of this peptide, studying the effect of this peptide on mutated apolipoproteins, and by optimizing the structure of this synthetic peptide for activity. It is hoped that these studies will point to future possible treatments for patients with familial hypercholesterolemia by providing an alternate route for cellular uptake of LDL independent of the LDL-R or for patients with other hyperlidemias due to apoE or apoB mutations by increasing clearance of lipoproteins.
| Dominguez, S R; Miller-Auer, H; Reardon, C A et al. (1999) Peptide model of a highly conserved, N-terminal domain of apolipoprotein E is able to modulate lipoprotein binding to a member of the class A scavenger receptor family. J Lipid Res 40:753-63 |
