Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 281, Issue 19, Pages 13333-13344Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M511077200
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There are three major apolipoprotein E ( apoE) isoforms. Although APOE-epsilon 3 is considered a longevity gene, APOE-epsilon 4 is a dual risk factor to atherosclerosis and Alzheimer disease. We have expressed full-length and N- and C-terminal truncated apoE3 and apoE4 tailored to eliminate helix and domain interactions to unveil structural and functional disturbances. The N- terminal truncated apoE4-( 72 - 299) and C-terminal truncated apoE4-( 1 - 231) showed more complicated or aggregated species than those of the corresponding apoE3 counterparts. This isoformic structural variation did not exist in the presence of dihexanoylphosphatidylcholine. The C-terminal truncated apoE-( 1 - 191) and apoE-( 1 - 231) proteins greatly lost lipid binding ability as illustrated by the dimyristoylphosphatidylcholine turbidity clearance. The low density lipoprotein ( LDL) receptor binding ability, determined by a competition binding assay of H-3-LDL to the LDL receptor of HepG2 cells, showed that apoE4 proteins with N- terminal ( apoE4-( 72 - 299)), C-terminal ( apoE4-( 1 - 231)), or complete C-terminal truncation ( apoE4-( 1 - 191)) maintained greater receptor binding abilities than their apoE3 counterparts. The cholesterol-lowering abilities of apoE3-( 72 - 299) and apoE3-( 1 - 231) in apoE- deficient mice were decreased significantly. The structural preference of apoE4 to remain functional in solution may explain the enhanced opportunity of apoE4 isoform to display its pathophysiologic functions in atherosclerosis and Alzheimer disease.
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