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Cited by 57Alzheimer's disease research and treatmentsLipid Membrane Structure and BehaviorCholesterol and Lipid Metabolism

Dissociation of Apolipoprotein E Oligomers to Monomer Is Required for High-Affinity Binding to Phospholipid Vesicles

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Kanchan Garai, Berevan A. Baban, Carl Frieden·2011·Biochemistry
DOI 10.1021/bi1020106PMC PMC3088999
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Abstract

The apolipoprotein apoE plays a key role in cholesterol and lipid metabolism. There are three isoforms of this protein, one of which, apoE4, is the major risk factor for Alzheimer's disease. At micromolar concentrations all lipid-free apoE isoforms exist primarily as monomers, dimers, and tetramers. However, the molecular weight form of apoE that binds to lipid has not been clearly defined. We have examined the role of self-association of apoE with respect to interactions with phospholipids. Measurements of the time dependence of turbidity clearance of small unilamellar vesicles of dimyristoyl-sn-glycero-3-phosphocholine (DMPC) upon addition of apoE show that higher molecular weight oligomers bind poorly if at all. The kinetic data can be described by a reaction model in which tetramers and dimers of apoE must first dissociate to monomers which then bind to the liposome surface in a fast and reversible manner. A slow but not readily reversible conformational conversion of the monomer then occurs. Prior knowledge of the rate constants for the association-dissociation process allows us to determine the rate constant of the conformational conversion. This rate constant is isoform dependent and appears to correlate with the stability of the apoE isoforms with the rate of dissociation of the apoE oligomers to monomers being the rate-limiting process for lipidation. Differences in the lipidation kinetics between the apoE isoforms arise from their differences in the self-association behavior leading to the conclusion that self-association behavior may influence biological functions of apoE in an isoform-dependent manner.

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  • An antibody against non-lipidated APOE, which is the version most likely to oligomerize, has shown promise in multiple Alzheimer disease mouse models.

    “Along this line, an antibody against non-lipidated APOE, which is the version most likely to oligomerize, has shown promise in multiple AD mouse models136–139.”

    From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [136]

    The Abstract (page unavailable) reports that lipid-free apoE forms monomers, dimers, and tetramers, supporting the oligomerization part of the sentence. The paper studies apoE binding to phospholipid vesicles; it does not report an antibody treatment or results in Alzheimer disease mouse models. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Only the monomer of ApoE is able to bind lipids, and lipidated ApoE appears to be protected from aggregation.

    “However only the monomer of ApoE is able to bind lipids and lipidated ApoE appears to be protected from aggregation highlighting this as an important element of ApoE biology for further study (17,18).”

    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 [18]

    The Discussion section, “Only monomer binds to lipids” (page unavailable), says monomers bind tightly and oligomer dissociation is necessary to form final lipoprotein particles. It also allows that dimers or higher oligomers may bind, so the claim that only monomers can bind lipids is too absolute. The paper discusses self-association of lipid-free apoE but does not establish that lipidated apoE is protected from aggregation. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Dissociation of apoE oligomers to monomers appears to be required for lipid binding to the protein.

    “Imperatively, the aggregation propensity of apoE likely influences its lipidation capacity (22), as dissociation of apoE oligomers to monomers appears to be required for lipid binding to the protein (46).”

    From <i>APOE3</i> -Jacksonville (V236E) variant reduces self-aggregation and risk of dementia (2021) · cites this paper as [46]

  • Dissociation to monomer is thought to be required for high-affinity lipid binding and may influence downstream receptor interactions, making the non-covalent oligomeric pool the relevant target for understanding isoform-dependent differences in ApoE lipidation and cholesterol transport.

    “This form of self-association is functionally significant because dissociation to monomer is thought to be required for high-affinity lipid binding (18) and may influence downstream receptor interactions, making the non-covalent oligomeric pool the relevant target for understanding isoform-dependent differences in ApoE lipidation and cholesterol transport.”

    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 [18]

  • 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 [18]

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Authors
Garai, K., Baban, B. A., & Frieden, C.
Affiliations
Washington University in St. Louis (US)
Corresponding author
Carl Frieden
ORCID
Venue
Biochemistry
Publisher
American Chemical Society (ACS)
Published
2011-02-28
Volume
50
Issue
13
Pages
2550-2558
ISSN
  • 0006-2960 (ISSN-L)
  • 1520-4995
DOI
10.1021/bi1020106
PMC
PMC3088999
OpenAlex
W2020581548
Cited by
57
References
11
Citations by year
2026: 4 · 2025: 2 · 2024: 5 · 2023: 2 · 2022: 3 · 2021: 5 · 2020: 6 · 2019: 4 · 2018: 2 · 2017: 2 · 2016: 6 · 2014: 6 · 2013: 2 · 2012: 5
FWCI
3.49
Type
journal article
Language
en
Open access
Locations
  • Biochemistry (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Hope Center for Neurological Disorders
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK 13332, R01DK013332)
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
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Keywords
apolipoprotein E, APOE ε4, APOE isoforms, protein self-association, oligomer dissociation, lipid modification, phospholipid vesicles, distributed model predictive control, conformational conversion, binding kinetics, cholesterol metabolism
MeSH terms
Apolipoproteins E, Circular Dichroism, Dimyristoylphosphatidylcholine, Fluorescent Dyes, Humans, Kinetics, Osmolar Concentration, Protein Binding, Protein Denaturation, Dimerization, Protein Isoforms, Fluorescence Resonance Energy Transfer, Mutant Proteins, Apolipoprotein E4, Unilamellar Liposomes, Protein Stability

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