Modulation of Apolipoprotein E Structure by Domain Interaction
Open accessAbstract
Interaction of the amino- and carboxyl-terminal domains in apolipoprotein (apo) E, referred to as domain interaction, is predicted to be more pronounced in apoE4 than in apoE3 and to underlie the association of apoE4 with Alzheimer and cardiovascular diseases. However, direct physical proof for the domain interaction concept is lacking. To address this issue, fluorescence resonance energy transfer and electron paramagnetic resonance spectroscopy were used to probe the spatial proximity of the two domains of apoE. Both methods demonstrated that the two domains are closer in both lipid-free and phospholipid-bound apoE4 than in apoE3 as a result of domain interaction. In addition, as shown by electron paramagnetic resonance, the domains of apoE4 move apart to resemble more closely the distance in apoE3 when the isoforms are bound to triglyceride-rich emulsion particles. These results demonstrate that domain interaction is a structural property of apoE4 and that apoE adopts different conformations when complexed to different lipids.
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Thermal stability may be a particularly sensitive indicator of structural perturbation in the helical bundle and domain-domain interaction regions.
“suggests that thermal stability may be a particularly sensitive indicator of structural perturbation in these regions 22,24,33,41,51 .”
From Utilizing a cell culture based novel cellular thermal shift assay to understand the isoform-dependent thermal stability of ApoE variants (2026) · cites this paper as [22]
The passage headed “Influence of Binding to Phospholipid on Domain Interaction” reports conformational changes measured by spin-label spectroscopy, and the Discussion describes changes in distance between domains. A separate passage mentions prior denaturation studies, but none says thermal stability is a particularly sensitive indicator of structural perturbation. Searches for thermal stability, melting temperature, and thermal unfolding did not locate that point in our copy; page numbers were unavailable. (LLM, conf=0.74)
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- Authors
- Hatters, D. M., Budamagunta, M. S., Voss, J. C., & Weisgraber, K. H.
- Affiliations
- Gladstone Institutes (US)
- University of California, Davis (US)
- Corresponding author
- Weisgraber, Karl H.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2005-10
- Volume
- 280
- Issue
- 40
- Pages
- 34288-34295
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1976725721
- Cited by
- 88
- References
- 6
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 5 · 2023: 4 · 2021: 2 · 2020: 2 · 2019: 7 · 2018: 2 · 2017: 2 · 2016: 1 · 2015: 3 · 2014: 4 · 2013: 1 · 2012: 8
- FWCI
- 3.81
- 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 (R01AG029246, R01AG020235, P01AG022074)
- 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, APOE ε4, APOE3, domain interactions, protein structure, lipid binding, protein conformation, Alzheimer's disease, cardiovascular disease
- MeSH terms
- Apolipoproteins E, Electron Spin Resonance Spectroscopy, Lipids, Microscopy, Models, Structural, Protein Binding, Protein Conformation, Mutagenesis, Site-Directed, Protein Structure, Tertiary, Protein Isoforms, Fluorescence Resonance Energy Transfer, Apolipoprotein E3, Apolipoprotein E4
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