Apo E: The role of conserved residues in defining function
Open accessAbstract
The amino acid sequences of apolipoprotein E (apoE) from 63 different mammalian species have been downloaded from the protein database. The sequences were compared to human apoE4 to determine conserved and non‐conserved sequences of amino acids. ApoE4 is the major risk factor for the development of late onset Alzheimer's disease while apoE3, which differs from apoE4 by a single amino acid change at position 112, poses little or no risk for the development of this disease. Thus, the two proteins appear to be structurally and functionally different. Seven highly conserved regions, representing approximately 47 amino acids (of 299) have been found. These regions are distributed throughout the protein and reflect ligand binding sites as well as regions proposed to be involved in the propagation of the cysteine–arginine change at position 112 to distant regions of the protein in the N‐ and C‐terminal domains. Highly non‐conserved regions are at the N‐ and C‐terminal ends of the apoE protein.
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ApoE-knockout is a more suitable model than ApoE4 mutants to study dyslipidemia because the E4 allele manifests an isoform-specific structural conformation that produces allele-specific effects.
“To answer this question, ApoE-knockout is a more suitable model than ApoE4 mutants to study dyslipidemia because the E4 allele manifests an isoform-specific structural conformation that produces allele-specific effects.”
From Dyslipidemia-Induced Mitochondrial Dysfunctions in the Brains Does Not Reach Pathological Levels in the ApoE-Knockout Mice (2026) · cites this paper as [29]
The Introduction and Discussion describe structural and functional differences between apoE isoforms, but the Discussion treats the nature of their conformational differences as an open question. The paper does not compare ApoE-knockout and ApoE4-mutant models or recommend either for studying dyslipidemia. (LLM, conf=0.84)
Experimental — accuracy not yet measuredSome ApoE4 mouse phenotypes are believed to arise from an allele-specific conformation of ApoE4.
“Some of these phenotypes are believed to arise from an allele-specific conformation of ApoE4: a unique arginine at position 112 (cysteine in the other two isoforms) shifts the hinge region of the protein, enabling the N-terminal domain (residues 1–167) to directly interact with the C-terminal domain (residues 206–299) [29].”
From Dyslipidemia-Induced Mitochondrial Dysfunctions in the Brains Does Not Reach Pathological Levels in the ApoE-Knockout Mice (2026) · cites this paper as [29]
The Introduction identifies arginine at position 112 as distinctive to ApoE4, and “The allosteric pathway” proposes that a change there propagates a structural difference toward the C-terminal domain. The Discussion also describes N- and C-terminal interactions. Our copy does not connect this mechanism to the cited mouse phenotypes or say that arginine 112 shifts a hinge region to enable those interactions. (LLM, conf=0.84)
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Cites
Human apolipoprotein E. The complete amino acid sequence
Rall, S. C., Weisgraber, K. H., & Mahley, R. W. (1982) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)34702-1 · Cited by 741 · see citing works
Three-Dimensional Structure of the LDL Receptor-Binding Domain of Human Apolipoprotein E
Wilson, C., Wardell, M. R., Weisgraber, K. H., Mahley, R. W., & Agard, D. A. (1991) · Science · doi:10.1126/science.2063194 · Cited by 678 · see citing works
Apolipoprotein E structure: insights into function
Hatters, D. M., Peters-Libeu, C. A., & Weisgraber, K. H. (2006) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2006.06.008 · Cited by 583 · see citing works
The receptor-binding domain of human apolipoprotein E. Binding of apolipoprotein E fragments.
Innerarity, T. L., Friedlander, E. J., Rall, S. C., Weisgraber, K. H., & Mahley, R. W. (1983) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)44180-9 · Cited by 276 · see citing works
Westerlund, J. A., & Weisgraber, K. H. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)82318-3 · Cited by 164 · see citing works
Interaction of the N-Terminal Domain of Apolipoprotein E4 with Heparin
Dong, J., Peters-Libeu, C. A., Weisgraber, K. H., Segelke, B. W., Rupp, B., Capila, I., Hernáiz, M. J., LeBrun, L. A., & Linhardt, R. J. (2001) · Biochemistry · doi:10.1021/bi002417n · Cited by 99 · see citing works
Characterization of the Heparin Binding Sites in Human Apolipoprotein E
Saito, H., Dhanasekaran, P., Nguyen, D., Baldwin, F., Weisgraber, K. H., Wehrli, S., Phillips, M. C., & Lund-Katz, S. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m213207200 · Cited by 90 · see citing works
Apolipoprotein E and Alzheimer's disease: the protective effects of ApoE2 and E3
Rebeck, G. W., Kindy, M., & LaDu, M. J. (2002) · Journal of Alzheimer's Disease · doi:10.3233/jad-2002-4304 · Cited by 89 · see citing works
Basak, J. M., Kim, J., Pyatkivskyy, Y., Wildsmith, K. R., Jiang, H., Parsadanian, M., Patterson, B. W., Bateman, R. J., & Holtzman, D. M. (2012) · Molecular Neurodegeneration · doi:10.1186/1750-1326-7-14 · Cited by 27 · see citing works
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Research works printed but not linked: 1
- Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261:921-923.
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Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies
Yamazaki, Y., Zhao, N., Caulfield, T. R., Liu, C.-C., & Bu, G. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-019-0228-7 · Cited by 1,425 · see citing works
TREM2-Ligand Interactions in Health and Disease
Kober, D. L., & Brett, T. J. (2017) · Journal of Molecular Biology · doi:10.1016/j.jmb.2017.04.004 · Cited by 284 · see citing works
Hsu, C.-H., Chu, P.-W., Chen, Y.-Y., Ho, M.-H., Liao, E.-C., & Chen, S.-K. (2026) · Neurochemical Research · doi:10.1007/s11064-026-04842-3
- Authors
- Frieden, C.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Frieden, Carl
- ORCID
- Frieden, Carl
- Venue
- Protein Science
- Publisher
- Wiley
- Published
- 2014-12-09
- Volume
- 24
- Issue
- 1
- Pages
- 138-144
- ISSN
- 0961-8368 (ISSN-L)
- 1469-896X
- PMC
- PMC4282419
- OpenAlex
- W1559890486
- Cited by
- 29
- References
- 9
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 2 · 2023: 5 · 2022: 1 · 2021: 3 · 2020: 2 · 2019: 3 · 2017: 7 · 2015: 1
- FWCI
- 1.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Protein Science (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (RF1AG044331)
- BrightFocus Foundation
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- apolipoprotein E, APOE ε4, APOE3, conserved residues, sequence conservation, late-onset Alzheimer's disease, ligand binding sites, protein structure-function relationship, N-terminal domain, C-terminal domain, interspecies sequence comparison
- MeSH terms
- Alzheimer Disease, Amino Acid Sequence, Anticoagulants, Apolipoproteins E, Binding Sites, Heparin, Humans, Models, Molecular, Molecular Sequence Data, Protein Binding, Receptors, LDL, Amyloid beta-Peptides, Conserved Sequence, Apolipoprotein E3, Apolipoprotein E4
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