Structural and functional variations in human apolipoprotein E3 and E4.
There are three major apolipoprotein E (apoE) isoforms. Although APOE-epsilon3 is considered a longevity gene, APOE-epsilon4 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 3H-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.
Faculty of Life Sciences, Institute of Biochemistry, Structural Biology Program, National Yang-Ming University, Taipei 112, Taiwan.
Chi-Yuan
CY
Chou
Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei 112, Taiwan.
Wei-Ping
WP
Jen
Faculty of Life Sciences, Institute of Biochemistry, Structural Biology Program, National Yang-Ming University, Taipei 112, Taiwan.
Yi-Hui
YH
Hsieh
Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei 112, Taiwan.
Ming-Shi
MS
Shiao
Faculty of Life Sciences, Institute of Biochemistry, Structural Biology Program, National Yang-Ming University, Taipei 112, Taiwan. Electronic address: ggchang@ym.edu.tw.
Gu-Gang
GG
Chang
D000818:Animals; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000737:chemistry* / Q000378:metabolism*; D002460:Cell Line; D017353:Gene Deletion; D006801:Humans; D008297:Male; D051379:Mice; D008958:Models, Molecular; D011487:Protein Conformation; D020033:Protein Isoforms
D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D020033:Protein Isoforms