Human apolipoprotein E3 in aqueous solution. II. Properties of the amino- and carboxyl-terminal domains.
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Hydrodynamic, chromatographic, and spectroscopic techniques were used to study the aqueous solution properties of the two structural domains of human apolipoprotein (apo) E3. An amino-terminal thrombolytic fragment of apoE (22 kDa, residues 1-191) and a carboxyl-terminal thrombolytic fragment of apoE (10 kDa, residues 216-299) were used as models for the two domains. Sedimentation equilibrium ultracentrifugation showed that apoE and the 10-kDa model domain self-associated predominantly as tetramers. The 22-kDa model domain was primarily monomeric. Molecular weights calculated from the weight average sedimentation and diffusion coefficients or from the sedimentation coefficients and Stokes radii were in agreement with the sedimentation equilibrium results. Derived frictional coefficients suggest larger axial ratios and/or more extensive hydration for the apoE and the 10-kDa domain tetramers as compared with the 22-kDa domain. Proteolysis of apoE followed by high performance liquid chromatography showed rapid production of free 22-kDa domain, whereas the free 10-kDa domain appeared as a tetramer late in the course of the hydrolysis. Assessment by circular dichroism demonstrated that both model domains and apoE had over 54% alpha-helical content, which changed little in a detergent (octyl-beta-D-glucopyranoside) or lipid (dimyristoylphosphatidylcholine) environment. In contrast to the circular dichroism results, apoE and the 10-kDa domain showed a marked blue shift in the fluorescence maximum in a lipid environment. The results suggest that the self-association of apoE in solution as a tetramer is mediated by the carboxyl-terminal domain and that the amino- and carboxyl-terminal domains do not associate with one another. The amino-terminal domain is most likely compact and globular, whereas the carboxyl-terminal domain is probably elongated. The isolated model domains appear to have structures that are similar to those of the domains in the intact protein.
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ApoE is prone to aggregation and forms oligomeric structures in solution.
“Furthermore, apoE has been shown to be prone to aggregation and to form oligomeric structures in solution (21,22).”
From Thermodynamic destabilization and aggregation propensity as the mechanism behind the association of apoE3 mutants and lipoprotein glomerulopathy (2018) · cites this paper as [37]
Lipid-free apoE is folded into two seemingly independent structural domains that can be separated after digestion with thrombin, generating an N-terminal, 22-kDa fragment (residues 1-191) and a C-terminal, 10-kDa fragment (residues 216-299).
“Lipid-free apoE is folded into two seemingly independent structural domains that can be separated after digestion with thrombin, generating an N-terminal, 22-kDa fragment (residues 1-191) and a C-terminal, 10-kDa fragment (residues 216 -299) (21,22).”
From Molecular Basis for Increased Risk for Late-onset Alzheimer Disease Due to the Naturally Occurring L28P Mutation in Apolipoprotein E4 (2014) · cites this paper as [22]
The amino- and carboxyl-terminal structural domains of apoE appear to be independently folded.
“Even though the amino- and carboxyl-terminal structural domains of apoE appear to be independently folded (12, 29), evidence suggests that the carboxyl-terminal domain can modulate the receptor binding function of the amino-terminal domain (25).”
From Apolipoprotein E3-Leiden contains a seven-amino acid insertion that is a tandem repeat of residues 121–127 (1989) · cites this paper as [29]
ApoE contains N-terminal and C-terminal domains that unfold independently.
“ApoE contains N-terminal and C-terminal domains that unfold independently ( 42,43 ).”
From Molecular etiology of a dominant form of type III hyperlipoproteinemia caused by R142C substitution in apoE4 (2011) · cites this paper as [43]
ApoE self-associates through the C-terminal domain, and the C-terminal α-helical regions are responsible for the self-association.
“ApoE is known to self-associate through the C-terminal domain in solution and the C-terminal α-helical regions are responsible for the self-association (21, 45–47).”
From Role of the N- and C-Terminal Domains in Binding of Apolipoprotein E Isoforms to Heparan Sulfate and Dermatan Sulfate: A Surface Plasmon Resonance Study (2008) · cites this paper as [45]
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- Authors
- Aggerbeck, L. P., Wetterau, J. R., Weisgraber, K. H., Wu, C. S., & Lindgren, F. T.
- Affiliations
- University of California, San Francisco (US)
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1988-05
- Volume
- 263
- Issue
- 13
- Pages
- 6249-6258
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1490077018
- Cited by
- 229
- References
- 54
- Citations by year
- 2025: 4 · 2024: 2 · 2022: 2 · 2021: 1 · 2020: 3 · 2019: 5 · 2018: 4 · 2017: 3 · 2016: 3 · 2015: 1 · 2014: 2 · 2013: 3 · 2012: 4
- FWCI
- 2.24
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL 18577-11)
- National Institute of General Medical Sciences (GM-10880)
- Topics
- 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
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- apolipoprotein E3, protein self-association, tetramer formation, N-terminal domain, C-terminal domain, protein conformation, alpha-helical content, octyl glucoside, dimyristoylphosphatidylcholine, hydrodynamic radius, friction coefficient, protein hydration, proteolysis, fluorescence blue shift
- MeSH terms
- Algorithms, Apolipoproteins E, Chromatography, High Pressure Liquid, Circular Dichroism, Diffusion, Humans, Molecular Weight, Protein Conformation, Spectrometry, Fluorescence, Apolipoprotein E3
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