Isoform- and cell type-specific structure of apolipoprotein E lipoparticles as revealed by a novel Forster resonance energy transfer assay
Open accessAbstract
Apolipoprotein E (apoE) has an important role in the pathogenesis of Alzheimer's disease with its three isoforms having distinct effects on disease risk. Here, we assessed the conformational differences between those isoforms using a novel flow cytometry-Forster resonance energy transfer (FRET) assay. We showed that the conformation of intracellular apoE within HEK cells and astrocytes adopts a directional pattern; in other words, E4 adopts the most closed conformation, E2 adopts the most open conformation, and E3 adopts an intermediate conformation. However, this pattern was not maintained upon secretion of apoE from astrocytes. Intermolecular interactions between apoE molecules were isoform-specific, indicating a great diversity in the structure of apoE lipoparticles. Finally, we showed that secreted E4 is the most lipidated isoform in astrocytes, suggesting that increased lipidation acts as a folding chaperone enabling E4 to adopt a closed conformation. In conclusion, this study gives insights into apoE biology and establishes a robust screening system to monitor apoE conformation.
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The single amino acid changes in the different APOE isoforms result in slightly different structures, which have a strikingly large effect on the binding affinities of APOE to lipids, Aβ and receptors.
“The single amino acid changes in the different APOE isoforms result in slightly different structures, which have a strikingly large effect on the binding affinities of APOE to lipids, Aβ and receptors99,111,116,140.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [140]
The paper identifies the single amino acid differences among APOE isoforms and reports differences in their conformation and lipid profiles (Abstract; page not supplied). It does not establish a strikingly large effect on binding affinities: the paper says how those substitutions produce the observed changes requires further study, and whether conformation or lipidation affects interactions with amyloid β or receptors remains largely unknown. (LLM, conf=0.88)
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Cites
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Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies
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- Authors
- Kara, E., Marks, J. D., Fan, Z., Klickstein, J. A., Roe, A. D., Krogh, K. A., Wegmann, S., Maesako, M., Luo, C. C., Mylvaganam, R., Berezovska, O., Hudry, E., & Hyman, B. T.
- Affiliations
- Harvard University (US)
- Massachusetts General Hospital (US)
- Corresponding author
- Hyman, Bradley T.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2017-09
- Volume
- 292
- Issue
- 36
- Pages
- 14720-14729
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC5592654
- OpenAlex
- W2732096011
- Cited by
- 23
- References
- 5
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 2 · 2022: 4 · 2021: 2 · 2020: 3 · 2019: 4 · 2018: 4 · 2017: 1
- FWCI
- 2.33
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- European Molecular Biology Organization (ATLF-815–2014)
- European Commission (LTFCOFUND2013, GA-2013-609409)
- Japan Society for the Promotion of Science
- Kyoto University Education and Research Foundation
- JPB Foundation
- AbbVie
- National Institutes of Health (AG15379, AG044486, 1S10OD012027-01A1, 1S10OD016372-01, 1S10RR020936-01, 1S10RR023440-01A1)
- F-prime
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- apolipoprotein E, APOE isoforms, Alzheimer's disease, FRET assay, flow cytometry, astrocytes, HEK cells, apoE secretion, intermolecular interactions, lipid modification, APOE ε4
- MeSH terms
- Apolipoproteins E, Astrocytes, Flow Cytometry, Humans, Protein Conformation, Protein Isoforms, Fluorescence Resonance Energy Transfer, HEK293 Cells
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