Atomistic Insights into Structural Differences between E3 and E4 Isoforms of Apolipoprotein E
Open accessAbstract
Among various isoforms of Apolipoprotein E (ApoE), the E4 isoform (ApoE4) is considered to be the strongest risk factor for Alzheimer's disease, whereas the E3 isoform (ApoE3) is neutral to the disease. Interestingly, the sequence of ApoE4 differs from its wild-type ApoE3 by a single amino acid C112R in the 299-amino-acid-long sequence. Hence, the puzzle remains: how a single-amino-acid difference between the ApoE3 and ApoE4 sequences can give rise to structural dissimilarities between the two isoforms, which can potentially lead to functional differences with significant pathological consequences. The major obstacle in addressing this question has been the lack of a 3D atomistic structure of ApoE4 to date. In this work, we resolve the issue by computationally modeling a plausible atomistic 3D structure of ApoE4. Our microsecond-long atomistic simulations elucidate key structural differences between monomeric ApoE3 and ApoE4, which renders ApoE4 thermodynamically less stable, less structured, and topologically less rigid compared to ApoE3. Consistent with an experimental report of the molten globule state of ApoE4, simulations identify multiple partially folded intermediates for ApoE4, which are implicated in the stronger aggregation propensity of ApoE4.
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The local electrostatic environment around residues 96 and 114 differs meaningfully between ApoE3 and ApoE4, likely as a consequence of the ApoE4-specific domain interaction driven by Arg112.
“In contrast the isoform-specific response suggests that the local electrostatic environment around residues 96 and 114 differ meaningfully between the two isoforms, likely as a consequence of the ApoE4-specific domain interaction driven by Arg112 57 .”
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 [57]
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Jackson, R. J., Dierksmeier, S., Nishtar, M., Meltzer, J., Balduin, F., Beaumont, B., Fan, Z., Sergienko, E., Olson, S., Jackson, M. R., et al. (2026) · doi:10.64898/2026.06.09.730809
- Authors
- Ray, A., Ahalawat, N., & Mondal, J.
- Affiliations
- Tata Institute of Fundamental Research (IN)
- Corresponding author
- Mondal, Jagannath
- Venue
- Biophysical Journal
- Publisher
- Elsevier BV
- Published
- 2017-12
- Volume
- 113
- Issue
- 12
- Pages
- 2682-2694
- ISSN
- 0006-3495 (ISSN-L)
- PMC
- PMC5770556
- OpenAlex
- W2780241272
- Cited by
- 23
- References
- 14
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 2 · 2023: 5 · 2022: 2 · 2021: 2 · 2020: 4 · 2019: 2 · 2018: 1
- FWCI
- 1.42
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Biophysical Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Tata Institute of Fundamental Research Hyderabad (CIS/TIFR-H)
- Department of Science and Technology (DST) Science and Engineering Research Board (ECR/2016/000672)
- Science and Engineering Research Board (SERB) (PDF/2016/002712)
- Tata Institute of Fundamental Research
- 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, Alzheimer's disease risk, protein structure, protein stability, molten globule, folding intermediates, protein aggregation, monomeric protein, atomistic simulation
- MeSH terms
- Protein Domains, Hydrogen Bonding, Markov Chains, Mutation, Temperature, Protein Structure, Secondary, Nuclear Magnetic Resonance, Biomolecular, Protein Isoforms, Apolipoprotein E3, Apolipoprotein E4, Protein Stability, Molecular Dynamics Simulation
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