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Cited by 134Protein Structure and DynamicsAlzheimer's disease research and treatmentsLipid Membrane Structure and Behavior

A mechanism for lipid binding to apoE and the role of intrinsically disordered regions coupled to domain-domain interactions

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Frieden, Carl, Wang, Hanliu, Ho, Chris M. W.·2017·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1705080114PMC PMC5474821
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Abstract

Significance: Alzheimer’s disease is the most common cause of dementia. It is irreversible, devastating, and costly. Apolipoprotein E4 (ApoE4), a protein whose function in the brain is to transport cholesterol-laden lipid, is a major risk factor for the development of late-onset Alzheimer’s disease relative to the common apoE3 isoform. The two proteins differ by only a single amino acid. There has been no detailed mechanism explaining how apoE functions. Here, we propose a mechanism for lipid binding that involves simple domain–domain movement coupled to the role of intrinsically disordered regions of the protein. This mechanism may lead to the development of small molecular weight compounds that interfere with the role apoE4 plays in the development of Alzheimer’s disease.

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Crossref · 10.1073/pnas.1705080114

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  • ApoE displays low thermodynamic stability and significant conformational plasticity.

    “Several biophysical studies have shown that apoE displays low thermodynamic stability and significant conformational plasticity, and allelic differences as well as single point mutations have been shown to affect protein conformation and to hinder physiological function”

    From Thermodynamic destabilization and aggregation propensity as the mechanism behind the association of apoE3 mutants and lipoprotein glomerulopathy (2018) · cites this paper as [15]

    The Results and Discussion describes intrinsically disordered and flexible regions in apoE3 and says apoE can adopt different conformational forms, supporting significant conformational plasticity. It does not establish that apoE has low thermodynamic stability; the passage says the role of charged residues in stability is unclear. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Allelic differences and single point mutations affect apoE conformation and hinder physiological function.

    “Several biophysical studies have shown that apoE displays low thermodynamic stability and significant conformational plasticity, and allelic differences as well as single point mutations have been shown to affect protein conformation and to hinder physiological function”

    From Thermodynamic destabilization and aggregation propensity as the mechanism behind the association of apoE3 mutants and lipoprotein glomerulopathy (2018) · cites this paper as [15]

    The Results and Discussion (page unavailable) report structural differences between apoE3 and apoE4 associated with their single-amino-acid difference at position 112, and link those differences to lipid-binding specificity. The Abstract (page unavailable) also reports functional differences between the isoforms. The paper does not establish the broader claim that single-point mutations generally hinder apoE’s physiological function; it describes altered function, and reports that a five-mutation form remained biologically active. (LLM, conf=0.84)

    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 [17]

    The Results and Discussion section, under “Lipid Binding,” explicitly says that only monomeric apoE binds lipid. Under “The ApoE Structure,” it reports that apoE forms aggregates at higher concentrations in the absence of lipids, but it does not establish that lipidated apoE is protected from aggregation. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Frieden, C., Wang, H., & Ho, C. M. W.
Affiliations
  • Washington University in St. Louis (US)
  • Drug Design Methodologies LLC, St. Louis, MO 63103
ORCID
Frieden, Carl
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2017-05-30
Volume
114
Issue
24
Pages
6292-6297
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1705080114
PMC
PMC5474821
OpenAlex
W2618913695
Cited by
134
References
6
Citations by year
2026: 16 · 2025: 18 · 2024: 21 · 2023: 19 · 2022: 18 · 2021: 13 · 2020: 13 · 2019: 12 · 2018: 3 · 2017: 1
FWCI
3.24
Type
journal article
Language
en
Open access
Licence
www.pnas.org/site/misc/userlicense.xhtml (vor, 184 d)
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
HHS | National Institutes of Health (NIA RF1AG044331)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
Keywords
apolipoprotein E, APOE ε4, APOE3, lipid binding, intrinsically disordered regions, domain-domain interactions, N-terminal domain, C-terminal domain, hydrogen-deuterium exchange, protein conformational dynamics, Alzheimer's disease risk
MeSH terms
Alzheimer Disease, Binding Sites, Humans, Models, Molecular, Protein Binding, Protein Conformation, Mass Spectrometry, Conserved Sequence, Nuclear Magnetic Resonance, Biomolecular, Protein Isoforms, Deuterium Exchange Measurement, Lipid Metabolism, Apolipoprotein E3, Apolipoprotein E4, Protein Interaction Domains and Motifs, Biophysical Phenomena, Intrinsically Disordered Proteins

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