Helical structure, stability, and dynamics in human apolipoprotein E3 and E4 by hydrogen exchange and mass spectrometry
Open accessAbstract
Significance: Apoliprotein E (apoE) serves as a cholesterol transport protein in both the peripheral circulation and the brain. In humans, the less common apoE4 isoform, which differs from the most abundant parent apoE3 by a single C112R substitution, is associated with increased incidence of cardiovascular disease and Alzheimer’s disease. To understand the structural basis for the altered functionality, we used hydrogen exchange mass spectrometry to compare the structure, stability, and molecular dynamics of these isoforms. The C112R substitution in apoE4 leads to unfolding of certain helical segments that reduces self-association and is expected to enhance the binding of apoE4 to triglyceride-rich lipoprotein particles in plasma and to amyloid-β deposits in the brain.
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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 [16]
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 [16]
ApoE4 exhibits reduced thermodynamic stability compared to ApoE3 in prior studies using purified recombinant protein.
“ApoE4 exhibits reduced thermodynamic stability compared to ApoE3, but prior characterisation has relied on purified recombinant protein”
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 [33]
Thermal stability may be a particularly sensitive indicator of structural perturbation in the helical bundle and domain-domain interaction regions.
“suggests that thermal stability may be a particularly sensitive indicator of structural perturbation in these regions 22,24,33,41,51 .”
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 [33]
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Katsarou, M., Stratikos, E., & Chroni, A. (2018) · Journal of Lipid Research · doi:10.1194/jlr.m088732 · Cited by 22 · see citing works
Georgiadou, D., & Chroni, A. (2026) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2025.149644 · Cited by 2 · see citing works
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
- Chetty, P. S., Mayne, L., Lund-Katz, S., Englander, S. W., & Phillips, M. C.
- Affiliations
- University of Pennsylvania (US)
- Division of Translational Medicine and Human Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104-5158;
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2017-01-17
- Volume
- 114
- Issue
- 5
- Pages
- 968-973
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC5293021
- OpenAlex
- W2574219503
- Cited by
- 58
- References
- 7
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 4 · 2023: 9 · 2022: 3 · 2021: 4 · 2020: 10 · 2019: 2 · 2018: 7 · 2017: 6
- FWCI
- 2.79
- Type
- journal article
- Language
- en
- 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 Institutes if Health (GM031847)
- National Science Foundation (MCB1020649)
- The Mathers Charitable Foundation (none)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Physical Sciences › Chemistry › Spectroscopy › Mass Spectrometry Techniques and Applications
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- apolipoprotein E, APOE3, APOE ε4, helical conformation, secondary structure, helix stability, protein dynamics, tetramerization, C-terminal domain, lipid binding, Alzheimer's disease, hydrogen-deuterium exchange
- MeSH terms
- Protein Domains, Circular Dichroism, Hydrogen, Lipoproteins, Protein Binding, Recombinant Fusion Proteins, Mass Spectrometry, Point Mutation, Protein Structure, Secondary, Protein Folding, Amino Acid Substitution, Genetic Predisposition to Disease, Protein Isoforms, Mutation, Missense, Apolipoprotein E3, Apolipoprotein E4, Protein Multimerization, Hydrophobic and Hydrophilic Interactions
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