Structural and functional variations in human apolipoprotein E3 and E4.
Open accessAbstract
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.
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The polymorphism at position 112 brings about alterations in the thermodynamic properties of the molecule that may underlie functional changes linked with disease predisposition.
“This polymorphic variation brings about alterations in the thermodynamic properties of the molecule that may underlie functional changes linked with disease predisposition [61], [65], [71], [72], [73], [74].”
From Biophysical Analysis of Apolipoprotein E3 Variants Linked with Development of Type III Hyperlipoproteinemia (2011) · cites this paper as [61]
The paper identifies the position-112 Cys-to-Arg difference between apoE3 and apoE4 and reports isoform-specific structural and functional differences. Its concluding passage links apoE4’s potential structural stability to pathophysiologic functions, but our copy does not establish that the position-112 substitution alters thermodynamic properties specifically. (LLM, conf=0.82)
Experimental — accuracy not yet measuredFunctional differences between apoE4 and apoE3 have been attributed to altered inter-domain interactions brought about by the polymorphism at position 112 of the N-terminal domain.
“Specifically, functional differences between apoE4 and apoE3 have been attributed to altered inter-domain interactions brought about by the polymorphism at position 112 of the N-terminal domain.”
From Biophysical Analysis of Apolipoprotein E3 Variants Linked with Development of Type III Hyperlipoproteinemia (2011) · cites this paper as [61]
The introduction identifies the Cys112-to-Arg112 difference between apoE3 and apoE4, and the Discussion links their functional differences to a possible domain–domain interaction (page unavailable in our copy). But the paper says this interaction may assist apoE4 stability and that the proposed Arg61–Glu255 interaction cannot explain its observations; it does not establish that the position-112 change causes the functional differences through altered inter-domain interactions. (LLM, conf=0.82)
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- Authors
- Chou, C.-Y., Jen, W.-P., Hsieh, Y.-H., Shiao, M.-S., & Chang, G.-G.
- Affiliations
- National Yang Ming University (TW)
- Taipei Veterans General Hospital (TW)
- Corresponding author
- Chang, Gu-Gang
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2006-05
- Volume
- 281
- Issue
- 19
- Pages
- 13333-13344
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2046783287
- Cited by
- 46
- References
- 8
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 1 · 2021: 3 · 2020: 1 · 2019: 3 · 2017: 1 · 2015: 2 · 2014: 4 · 2013: 1 · 2012: 6
- FWCI
- 3.74
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- apolipoprotein E, APOE3, APOE ε4, protein truncation, protein aggregation, lipid binding, LDL receptor binding, cholesterol lowering, ApoE-deficient mice, atherosclerosis, Alzheimer's disease
- MeSH terms
- Animals, Apolipoproteins E, Cell Line, Humans, Male, Models, Molecular, Protein Conformation, Gene Deletion, Protein Isoforms, Mice, Apolipoprotein E3, Apolipoprotein E4
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