Effect of Carboxyl-Terminal Truncation on Structure and Lipid Interaction of Human Apolipoprotein E4
Abstract
Apolipoprotein (apo) E4 has been identified as a major risk factor for Alzheimer's disease. Recently, apoE4 was found to undergo proteolytic cleavage in Alzheimer's disease brains, resulting in neurotoxic C-terminal-truncated fragments. In this study, we examined the effect of progressive truncation of the C-terminal domain in apoE4 on its lipid-free structure and lipid binding properties. Circular dichroism measurements demonstrated that deletion of residues 273-299 or 261-299 significantly decreased the number of helical residues, suggesting that the C-terminal residues 261-299 have alpha-helical structure. Although the progressive deletions in the C-terminal domain appear to somewhat increase thermal stability, apoE4 (delta273-299) and apoE4 (delta261-299) showed stability similar to that of the apoE4 22-kDa fragment (residues 1-191) when denatured with guanidine-HCl, indicating that residues 192-272 have a negligible effect on the stability of the C-terminal-truncated apoE4. Comparison of Trp-264 fluorescence in single Trp mutants of full-length and C-terminal-truncated apoE4 (delta273-299) indicated that the C-terminal domain structure in the latter is both less organized and cooperative. In addition, comparison of the binding of the C-terminal-truncated mutants to a hydrophobic fluorescent dye and to lipid emulsions revealed that residues 261-272 create a hydrophobic site which is critical for lipid binding. These results suggest that removal of a hydrophobic C-terminal alpha-helical segment (residues 273-299) to create C-terminal-truncated apoE4 forms found in brain leads to less organized C-terminal structure while still retaining a second alpha-helical lipid-binding region (residues 261-272) that is available for interaction with cell membranes and other proteins such as amyloid beta peptide.
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Structural and biophysical properties of apoE can dictate the function of the protein.
“Several studies have suggested that the structural and biophysical properties of apoE can dictate the function of the protein and have provided insight into the mechanisms by which apoE is involved in cardiovascular and neurological diseases [42], [43], [44], [45], [46], [47], [48], [49].”
From Biophysical Analysis of Apolipoprotein E3 Variants Linked with Development of Type III Hyperlipoproteinemia (2011) · cites this paper as [42]
C-terminal helical residues 261-299 or 272-299 modulate the tetramerization of apoE in solution.
“Using C-terminally truncated mutants of apoE, we showed previously that the C-terminal helical residues, 261–299 or 272–299 modulate the tetramerization of apoE in solution (37, 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 [37]
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- Authors
- Tanaka, M., Vedhachalam, C., Sakamoto, T., Dhanasekaran, P., Phillips, M. C., Lund-Katz, S., & Saito, H.
- Affiliations
- Children's Hospital of Philadelphia (US)
- Department of Biophysical Chemistry, Kobe Pharmaceutical University, Kobe 658-8558, Japan, and Lipid Research Group, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-4318
- Venue
- Biochemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2006-03-10
- Volume
- 45
- Issue
- 13
- Pages
- 4240-4247
- ISSN
- 0006-2960 (ISSN-L)
- 1520-4995
- OpenAlex
- W2062913572
- Cited by
- 43
- References
- 57
- Citations by year
- 2025: 2 · 2022: 1 · 2021: 1 · 2019: 4 · 2018: 1 · 2017: 2 · 2016: 1 · 2015: 1 · 2014: 5 · 2013: 1 · 2012: 4
- FWCI
- 2.65
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL056083, HL-56083)
- 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
- APOE ε4, C-terminal truncation, Alzheimer's disease, proteolytic cleavage, alpha-helical structure, thermal stability, lipid binding, amyloid-beta
- MeSH terms
- Amino Acid Sequence, Anilino Naphthalenesulfonates, Apolipoproteins E, Chromatography, Gel, Emulsions, Humans, Protein Denaturation, Spectrometry, Fluorescence, Tryptophan, Protein Structure, Tertiary, Protein Folding, Guanidine, Apolipoprotein E4
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