Self-association of human apolipoprotein E3 and E4 in the presence and absence of phospholipid
Open accessAbstract
Human apolipoprotein E (apoE) exists as three main isoforms, differing by single amino acid substitutions, with the apoE4 isoform strongly linked to the incidence of late onset Alzheimer's disease. We have expressed and purified apoE3 and apoE4 from Escherichia coli and compared their hydrodynamic properties by gel permeation liquid chromatography, capillary electrophoresis, circular dichroism, and sedimentation methods. Sedimentation velocity experiments, employing a new method for determining the size distribution of polydisperse macromolecules in solution (Schuck, P. (2000) Biophys. J. 78, 1606-1619), provide direct evidence for the heterogeneous solution structures of apoE3 and apoE4. In a lipid-free environment, apoE3 and apoE4 exist as a slow equilibrium mixture of monomer, tetramer, octamer, and a small proportion of higher oligomers. Both sedimentation velocity and equilibrium experiments indicate that apoE4 has a greater propensity to self-associate. We also demonstrate that apoE3 and apoE4 oligomers dissociate significantly in the presence of dihexanoylphosphatidylcholine micelles (20 mm) and to a lesser extent at submicellar concentrations (4 mm). The alpha-helical content for both isoforms was almost identical (50%) in the presence and absence of dihexanoylphosphatidylcholine. These results reveal that apoE oligomers undergo phospholipid-induced dissociation to folded monomers, suggesting the monomeric form prevails on the lipoprotein surface in vivo.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
ApoE is prone to aggregation and forms oligomeric structures in solution.
“Furthermore, apoE has been shown to be prone to aggregation and to form oligomeric structures in solution (21,22).”
From Thermodynamic destabilization and aggregation propensity as the mechanism behind the association of apoE3 mutants and lipoprotein glomerulopathy (2018) · cites this paper as [38]
ApoE lipidation shifts the monomer-oligomer equilibrium towards monomer.
“ApoE lipidation is known to shift the monomeroligomer equilibrium towards monomer (18,24,35)”
From APOE Isoform-Dependent Self-Association Measured by a Split-Luciferase Complementation Assay: Differential Effects of Disease-Risk and Protective Variants (2026) · cites this paper as [35]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Apolipoprotein E: Structure-Function Relationships
Weisgraber, K. H. (1994) · Advances in Protein Chemistry · doi:10.1016/s0065-3233(08)60642-7 · Cited by 830 · see citing works
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
Proposed nomenclature of apoE isoproteins, apoE genotypes, and phenotypes
Zannis, V. I., Breslow, J. L., Utermann, G., Mahley, R. W., Weisgraber, K. H., Havel, R. J., Goldstein, J. L., Brown, M. S., Schonfeld, G., Hazzard, W. R., et al. (1982) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)38094-9 · Cited by 436 · 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
Aggerbeck, L. P., Wetterau, J. R., Weisgraber, K. H., Wu, C. S., & Lindgren, F. T. (1988) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)68779-4 · Cited by 229 · 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
Flagged first, then by citations
Research works printed but not linked: 10
- [1]1. Shore, V.G. ∙ Shore, B. Biochemistry. 1973; 12:502-507 Crossref Scopus (245) PubMed Google Scholar
- [2]2. Eisenberg, S. J. Lipid Res. 1984; 25:1017-1058 Full Text (PDF) PubMed Google Scholar
- [3]3. Mahley, R.W. Science. 1988; 240:622-630 Crossref Scopus (3592) PubMed Google Scholar
- [4]4. Weisgraber, K.H. Adv. Protein Chem. 1994; 45:249-302 Crossref PubMed Google Scholar
- [5]5. Weisgraber, K.H. ∙ Rall, Jr., S.C. ∙ Mahley, R.W. J. Biol. Chem. 1981; 256:9077-9083 Full Text (PDF) PubMed Google Scholar
- [6]6. Rall, Jr., S.C. ∙ Weisgraber, K.H. ∙ Mahley, R.W. J. Biol. Chem. 1982; 257:4171-4178 Full Text (PDF) PubMed Google Scholar
- [7]7. Zannis, V.I. ∙ Breslow, J.L. ∙ Utermann, G. ... J. Lipid Res. 1982; 23:911-914 Full Text (PDF) PubMed Google Scholar
- [8]8. Utermann, G. ∙ Jaeschke, M. ∙ Menzel, J. FEBS Lett. 1975; 56:352-355 Crossref Scopus (203) PubMed Google Scholar
- [9]9. Corder, E.H. ∙ Saunders, A.M. ∙ Strittmatter, W.J. ... Science. 1993; 261:921-923 Crossref Scopus (7510) PubMed Google Scholar
- [10]10. Wetterau, J.R. ∙ Aggerbeck, L.P. ∙ Rall, Jr., S.C. ... J. Biol. Chem. 1988; 263:6240-6248
Cited by
Sorted by citations
Direct Transcriptional Effects of Apolipoprotein E
Theendakara, V., Peters-Libeu, C. A., Spilman, P., Poksay, K. S., Bredesen, D. E., & Rao, R. V. (2016) · The Journal of Neuroscience · doi:10.1523/jneurosci.3562-15.2016 · Cited by 152 · see citing works
Amino-terminal domain stability mediates apolipoprotein E aggregation into neurotoxic fibrils
Hatters, D. M., Zhong, N., Rutenber, E., & Weisgraber, K. H. (2006) · Journal of Molecular Biology · doi:10.1016/j.jmb.2006.06.080 · Cited by 105 · see citing works
Sakamoto, T., Tanaka, M., Vedhachalam, C., Nickel, M., Nguyen, D., Dhanasekaran, P., Phillips, M. C., Lund-Katz, S., & Saito, H. (2008) · Biochemistry · doi:10.1021/bi701923h · Cited by 54 · see citing works
Georgiadou, D., Stamatakis, K., Efthimiadou, E. K., Kordas, G., Gantz, D., Chroni, A., & Stratikos, E. (2013) · Journal of Lipid Research · doi:10.1194/jlr.m030965 · Cited by 37 · see citing works
Clément-Collin, V., Barbier, A., Dergunov, A. D., Visvikis, A., Siest, G., Desmadril, M., Takahashi, M., & Aggerbeck, L. P. (2006) · Biophysical Chemistry · doi:10.1016/j.bpc.2005.07.009 · Cited by 32 · see citing works
Georgiadou, D., Chroni, A., Vezeridis, A., Zannis, V. I., & Stratikos, E. (2011) · PLoS ONE · doi:10.1371/journal.pone.0027037 · Cited by 24 · see citing works
Katsarou, M., Stratikos, E., & Chroni, A. (2018) · Journal of Lipid Research · doi:10.1194/jlr.m088732 · Cited by 22 · see citing works
Andrieieva, D., Falltrick, I., Chiang, C.-Y., Beaumont, B., Guen, Y. L., Liu, C., Pergolesi, S., Ma, C.-T., Jackson, M. R., Hyman, B. T., et al. (2026) · doi:10.64898/2026.05.09.26352797 · Cited by 2 · see citing works
Georgiadou, D., & Chroni, A. (2026) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2025.149644 · Cited by 2 · see citing works
- Authors
- Perugini, M. A., Schuck, P., & Howlett, G. J.
- Affiliations
- The University of Melbourne (AU)
- National Institutes of Health (US)
- Corresponding author
- Howlett, Geoffrey J.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2000-11
- Volume
- 275
- Issue
- 47
- Pages
- 36758-36765
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2076775566
- Cited by
- 118
- References
- 7
- Citations by year
- 2026: 4 · 2025: 1 · 2023: 3 · 2022: 1 · 2021: 1 · 2020: 5 · 2019: 8 · 2018: 5 · 2017: 5 · 2016: 11 · 2015: 5 · 2014: 4 · 2013: 5 · 2012: 6
- FWCI
- 3.09
- 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 › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
- Keywords
- apolipoprotein E, APOE3, APOE ε4, self-association, oligomerization, solution structure, alpha-helical content, Alzheimer's disease
- MeSH terms
- Apolipoproteins E, Chromatography, Gel, Circular Dichroism, Humans, Micelles, Phospholipid Ethers, Phospholipids, Protein Conformation, Electrophoresis, Capillary, Apolipoprotein E3, Apolipoprotein E4
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
