Structural differences between apoE3 and apoE4 may be useful in developing therapeutic agents for Alzheimer’s disease
Open accessAbstract
Apolipoproteins E3 and E4, proteins with a molecular mass of 34.15 kDa, differ by a single amino acid change. ApoE4 contains an arginine residue at position 112, whereas apoE3 has a cysteine at this position. ApoE4 is the major risk factor for late-onset Alzheimer’s disease, whereas apoE3, the common isoform, is neutral with respect to this disease. Here, using literature data from both hydrogen-deuterium exchange and site-directed mutations, we suggest structural differences between these two isoforms that are distant from the site of the arginine-to-cysteine change. These structural differences involve sequences from both the N- and C-terminal domains, sequentially far apart but structurally close. In addition, these regions are close to regions that bind lipid and to a region involved in association of apoE monomers to higher molecular weight forms. We discuss the possibility that these regions could be targeted preferentially to affect the function of apoE4 relative to apoE3.
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The APOE3-V236E substitution is the first Alzheimer's disease-associated variant within the C-terminal domain, a region critical for apoE oligomerization and lipidation.
“Notably, the apoE3-V236E substitution is the first AD-associated variant within the C-terminal domain, a region critical for apoE oligomerization and lipidation (10, 36).”
From <i>APOE3</i> -Jacksonville (V236E) variant reduces self-aggregation and risk of dementia (2021) · cites this paper as [36]
ApoE4 domain interaction is predicted to be altered compared with ApoE3 and is thought to promote intermolecular coiled-coil interactions, although other mechanisms are also predicted.
“ApoE4 domain interaction is predicted to be altered compared with ApoE3 and is thought to promote intermolecular coiled-coil interactions although other mechanisms are also predicted (10,25,36).”
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 [36]
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- Authors
- Frieden, C., & Garai, K.
- Affiliations
- Washington University in St. Louis (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-05-21
- Volume
- 109
- Issue
- 23
- Pages
- 8913-8918
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3384159
- OpenAlex
- W2034724732
- Cited by
- 133
- References
- 8
- Citations by year
- 2026: 13 · 2025: 14 · 2024: 11 · 2023: 5 · 2022: 11 · 2021: 10 · 2020: 10 · 2019: 10 · 2018: 5 · 2017: 11 · 2016: 8 · 2015: 6 · 2014: 8 · 2013: 8 · 2012: 3
- FWCI
- 5.36
- Type
- journal article
- Language
- en
- Update notices
- correction (2012-07-16)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (P41GM103422)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- apolipoprotein E, APOE3, APOE ε4, Alzheimer's disease, protein structure, single amino acid substitution, hydrogen-deuterium exchange, site-directed mutagenesis, N-terminal domain, C-terminal domain, lipid binding, oligomerization, therapeutic target
- MeSH terms
- Alzheimer Disease, Humans, Models, Molecular, Protein Conformation, Mutagenesis, Site-Directed, Protein Isoforms, Deuterium Exchange Measurement, Apolipoprotein E3, Apolipoprotein E4, Drug Discovery
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