Human apolipoprotein E (apoE) is a 299-amino-acid protein with a molecular 
weight of 34 kDa. The difference between the apoE3 and apoE4 isoforms is a 
single residue substitution involving a Cys-Arg replacement at residue 112. 
ApoE4 is positively associated with atherosclerosis and late-onset and sporadic 
Alzheimer's disease (AD). ApoE4 and its C-terminal truncated fragments have been 
found in the senile plaques and neurofibrillary tangles in the brain of AD 
patients. However, detail structural information regarding isoform and domain 
interaction remains poorly understood. We prepared full-length, N-, and 
C-terminal truncated apoE3 and apoE4 proteins and studied their structural 
variation. Sedimentation velocity and continuous size distribution analysis 
using analytical ultracentrifugation revealed apoE3(72-299) as consisting of a 
major species with a sedimentation coefficient of 5.9. ApoE4(72-299) showed a 
wider and more complicated species distribution. Both apoE3 and E4 N-terminal 
domain (1-191) existed with monomers as the major component together with some 
tetramer. The oligomerization and aggregation of apoE protein increased when the 
C-terminal domain (192-271) was incorporated. The structural influence of the 
C-terminal domain on apoE is to assist self-association with no significant 
isoform preference. Circular dichroism and fluorescence studies demonstrated 
that apoE4(72-299) possessed a more alpha-helical structure with more 
hydrophobic residue exposure. The structural variation of the N-terminal 
truncated apoE3 and apoE4 protein provides useful information that helps to 
explain the greater aggregation of the apoE4 isoform and thus has implication 
for the involvement of apoE4 in AD.