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J. Biol. Chem., Vol. 281, Issue 19, 13333-13344, May 12, 2006

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Structural and Functional Variations in Human Apolipoprotein E3 and E4^*

Chi-Yuan Chou, Wei-Ping Jen, Yi-Hui Hsieh, Ming-Shi Shiao, and Gu-Gang Chang¹

From the Faculty of Life Sciences, Institute of Biochemistry, Structural Biology Program, National Yang-Ming University and the Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei 112, Taiwan

There are three major apolipoprotein E (apoE) isoforms. Although APOE-3 is considered a longevity gene, APOE-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 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.

Received for publication, October 12, 2005 , and in revised form, March 10, 2006.

^* This work was supported by the National Science Council and Taipei Veterans General Hospital, Taiwan, Republic of China. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Figs. 1S-8S.

¹ To whom correspondence should be addressed: Faculty of Life Sciences, National Yang-Ming University, 155 Li-Nong St., Sec. 2, Taipei 112, Taiwan. Tel.: 886-2-2826-7168; Fax: 886-2-2820-2449; E-mail: ggchang{at}ym.edu.tw.

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