Inter-molecular Coiled-coil Formation in Human Apolipoprotein E C-terminal Domain
Abstract
Human apolipoprotein E (apoE) is composed of an N-terminal (NT) domain (residues 1-191) that bears low-density lipoprotein receptor-binding sites, and a C-terminal (CT) domain (residues 210-299), which houses lipoprotein binding and apoE self-association sites. The NT domain is comprised of a four-helix bundle, while the structural organization of the CT domain is not known. Secondary structural algorithms predict that the apoE CT domain adopts an amphipathic alpha-helical conformation. On the basis of further sequence predictions, we identified a segment (residues 218-266) in the apoE CT domain that bears a high propensity to form a coiled-coil helix, which coincides with the putative lipoprotein-binding surface. An apoE construct bearing residues 201-299 that encompasses the entire CT domain was designed, expressed in Escherichia coli and purified by affinity chromatography. Circular dichroism (CD) spectroscopy of the apoE CT domain reveals spectra characteristic of coiled-coil helices, with the ratio of molar ellipticities at 222 nm and 208 nm ([theta](222)/[theta](208)) of 1.03. Trifluoroethanol (TFE) stabilized the secondary structure of the apoE CT domain and disrupted coiled-coil helix formation as determined by CD and tryptophan fluorescence analysis. Analytical ultracentrifugation and lysine-specific cross-linking analysis of the apoE CT domain revealed predominant formation of dimeric and tetrameric species in aqueous buffers, and monomeric forms in 50% TFE. Guanidi…
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Lipid-free apoE tends to self-aggregate in aqueous solution due to hydrophobic interaction between amphipathic α-helices in the C-terminal domain.
“Lipid-free apoE tends to self-aggregate in aqueous solution due to the hydrophobic interaction between amphipathic α-helices in the C-terminal domain (17, 18).”
From <i>APOE3</i> -Jacksonville (V236E) variant reduces self-aggregation and risk of dementia (2021) · cites this paper as [18]
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 [10]
Val236 is located in the C-terminal amphipathic helix that forms the core of the intermolecular coiled-coil interface.
“Val236 is located in the C-terminal amphipathic helix that forms the core of the intermolecular coiled-coil interface (10,12), and the introduction of a charged glutamate residue at this position likely disrupts hydrophobic packing.”
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 [10]
The introduction of a charged glutamate residue at position 236 likely disrupts hydrophobic packing.
“Val236 is located in the C-terminal amphipathic helix that forms the core of the intermolecular coiled-coil interface (10,12), and the introduction of a charged glutamate residue at this position likely disrupts hydrophobic packing.”
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 [10]
Cites
Apolipoprotein E: Structure-Function Relationships
Weisgraber, K. H. (1994) · Advances in Protein Chemistry · doi:10.1016/s0065-3233(08)60642-7 · Cited by 830 · see citing works
Three-Dimensional Structure of the LDL Receptor-Binding Domain of Human Apolipoprotein E
Wilson, C., Wardell, M. R., Weisgraber, K. H., Mahley, R. W., & Agard, D. A. (1991) · Science · doi:10.1126/science.2063194 · Cited by 678 · see citing works
Aggerbeck, L. P., Wetterau, J. R., Weisgraber, K. H., Wu, C. S., & Lindgren, F. T. (1988) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)68779-4 · Cited by 229 · see citing works
Westerlund, J. A., & Weisgraber, K. H. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)82318-3 · Cited by 164 · see citing works
Characterization of the Heparin Binding Sites in Human Apolipoprotein E
Saito, H., Dhanasekaran, P., Nguyen, D., Baldwin, F., Weisgraber, K. H., Wehrli, S., Phillips, M. C., & Lund-Katz, S. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m213207200 · Cited by 90 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Amino-terminal domain stability mediates apolipoprotein E aggregation into neurotoxic fibrils
Hatters, D. M., Zhong, N., Rutenber, E., & Weisgraber, K. H. (2006) · Journal of Molecular Biology · doi:10.1016/j.jmb.2006.06.080 · Cited by 105 · see citing works
<i>APOE3</i> -Jacksonville (V236E) variant reduces self-aggregation and risk of dementia
Liu, C.-C., Murray, M. E., Li, X., Zhao, N., Wang, N., Heckman, M. G., Shue, F., Martens, Y., Li, Y., Raulin, A.-C., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abc9375 · Cited by 108 · see citing works
Association of Rare <i>APOE</i> Missense Variants V236E and R251G With Risk of Alzheimer Disease
Le Guen, Y., Belloy, M. E., Grenier-Boley, B., de Rojas, I., Castillo-Morales, A., Jansen, I., Nicolas, A., Bellenguez, C., Dalmasso, C., Küçükali, F., et al. (2022) · JAMA Neurology · doi:10.1001/jamaneurol.2022.1166 · Cited by 93 · see citing works
Sakamoto, T., Tanaka, M., Vedhachalam, C., Nickel, M., Nguyen, D., Dhanasekaran, P., Phillips, M. C., Lund-Katz, S., & Saito, H. (2008) · Biochemistry · doi:10.1021/bi701923h · Cited by 54 · see citing works
Effect of Carboxyl-Terminal Truncation on Structure and Lipid Interaction of Human Apolipoprotein E4
Tanaka, M., Vedhachalam, C., Sakamoto, T., Dhanasekaran, P., Phillips, M. C., Lund-Katz, S., & Saito, H. (2006) · Biochemistry · doi:10.1021/bi060023b · Cited by 43 · see citing works
Clément-Collin, V., Barbier, A., Dergunov, A. D., Visvikis, A., Siest, G., Desmadril, M., Takahashi, M., & Aggerbeck, L. P. (2006) · Biophysical Chemistry · doi:10.1016/j.bpc.2005.07.009 · Cited by 32 · see citing works
Andrieieva, D., Falltrick, I., Chiang, C.-Y., Beaumont, B., Guen, Y. L., Liu, C., Pergolesi, S., Ma, C.-T., Jackson, M. R., Hyman, B. T., et al. (2026) · doi:10.64898/2026.05.09.26352797 · Cited by 2 · see citing works
- Authors
- Choy, N., Raussens, V., & Narayanaswami, V.
- Affiliations
- Université Libre de Bruxelles (BE)
- Corresponding author
- Narayanaswami, Vasanthy
- Venue
- Journal of Molecular Biology
- Publisher
- Elsevier BV
- Published
- 2003-11
- Volume
- 334
- Issue
- 3
- Pages
- 527-539
- ISSN
- 0022-2836 (ISSN-L)
- OpenAlex
- W2062344966
- Cited by
- 131
- References
- 5
- Citations by year
- 2026: 7 · 2025: 4 · 2024: 3 · 2023: 5 · 2022: 12 · 2021: 4 · 2020: 3 · 2019: 5 · 2018: 3 · 2017: 5 · 2016: 7 · 2015: 9 · 2014: 7 · 2013: 3 · 2012: 6
- FWCI
- 1.96
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion)
- Funders
- American Heart Association
- 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, C-terminal domain, lipoprotein binding, salt bridges, oligomeric state, guanidine hydrochloride denaturation, tryptophan fluorescence, circular dichroism
- MeSH terms
- Amino Acid Sequence, Apolipoproteins E, Circular Dichroism, Humans, Hydrogen-Ion Concentration, Kinetics, Models, Molecular, Molecular Sequence Data, Protein Conformation, Protein Denaturation, Recombinant Proteins, Spectrometry, Fluorescence, Thermodynamics, Trifluoroethanol, Protein Structure, Tertiary, Guanidine
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
