Effects of Polymorphism on the Lipid Interaction of Human Apolipoprotein E
Open accessAbstract
ApoE exists as three common isoforms, apoE2, apoE3, and apoE4; apoE2 and apoE3 preferentially bind to high density lipoproteins, whereas apoE4 prefers very low density lipoproteins (VLDL). To understand the molecular basis for the different lipoprotein distributions of these isoforms in human plasma, we examined the lipid-binding properties of the apoE isoforms and some mutants using lipid emulsions. With both large (120 nm) and small (35 nm) emulsion particles, the binding affinity of apoE4 was much higher than that of apoE2 and apoE3, whereas the maximal binding capacities were similar among the three isoforms. The 22-kDa N-terminal fragment of apoE4 displayed a much higher binding capacity than did apoE2 and apoE3. The apoE4(E255A) mutant, which has no electrostatic interaction between Arg61 and Glu255, showed binding behavior similar to that of apoE3, indicating that N- and C-terminal domain interaction in apoE4 is responsible for its high affinity for lipid. In addition, the apoE3(P267A) mutant, which is postulated to contain a long alpha-helix in the C-terminal domain, had significantly decreased binding capacities for both sizes of emulsion particle, suggesting that the apoE4 preference for VLDL is not due to a stabilized long alpha-helical structure. Isothermal titration calorimetry measurements showed that there is no significant difference in thermodynamic parameters for emulsion binding among the apoE isoforms. However, fluorescence measurements of 8-anilino-1-naphthalenesulfonic acid binding to apoE indicated that apoE4 has more exposed hydrophobic surface compared with apoE3 mainly due to the different tertiary organization of the C-terminal domain. The less organized structure in the C-terminal domain of apoE4 leads to the higher affinity for lipid, contributing to its preferential association with VLDL. In fact, we found that apoE4 binds to VLDL with higher affinity compared with apoE3.
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ApoE4 binds to lipid particles with higher affinity than does apoE3 and shows preference for VLDL, whereas apoE2 and apoE3 mainly bind to HDL.
“ApoE4 binds to lipid particles with higher affinity than does apoE3 and shows preference for VLDL, whereas apoE2 and apoE3 mainly bind to HDL [ 42].”
From ApoE Plasma Levels and Risk of Cardiovascular Mortality in Old Age (2006) · cites this paper as [42]
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- Authors
- Saito, H., Dhanasekaran, P., Baldwin, F., Weisgraber, K. H., Phillips, M. C., & Lund-Katz, S.
- Affiliations
- National Institute of Health Sciences (JP)
- Children's Hospital of Philadelphia (US)
- University of California, San Francisco (US)
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2003-10
- Volume
- 278
- Issue
- 42
- Pages
- 40723-40729
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1994509415
- Cited by
- 89
- References
- 10
- Citations by year
- 2026: 3 · 2025: 4 · 2023: 3 · 2022: 1 · 2021: 2 · 2020: 5 · 2019: 3 · 2018: 2 · 2017: 2 · 2015: 3 · 2014: 4 · 2013: 2 · 2012: 2
- FWCI
- 2.42
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (AG-20235, R01AG020235)
- National Heart, Lung, and Blood Institute (R01HL056083, HL-56083)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- apolipoprotein E, protein isoforms, APOE ε4, APOE2, APOE3, lipid binding, VLDL, high-density lipoprotein, C-terminal domain, N-terminal domain, hydrophobic surface exposure, binding affinity, lipid emulsions, protein-lipid interactions
- MeSH terms
- Anilino Naphthalenesulfonates, Apolipoproteins E, Calorimetry, Dose-Response Relationship, Drug, Fluorescent Dyes, Humans, Kinetics, Mutation, Polymorphism, Genetic, Protein Binding, Spectrometry, Fluorescence, Temperature, Thermodynamics, Time Factors, Protein Structure, Tertiary, Protein Isoforms, Lipid Metabolism
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