Structural Analysis of Lipoprotein E Particles
Abstract
Apolipoprotein E (apoE) is a key regulator of cholesterol homeostasis. Human apoE has three common isoforms, each with different risk implications for cardiovascular and neurodegenerative disease. Neither the structure of lipoprotein E particles nor the structural consequences of the isoform differences are known. In this investigation, synthetic lipoprotein particles were prepared by complexing phospholipids with full-length apoE isoforms, or with truncated N-terminal and C-terminal domains of apoE. These particles were examined with calorimetry, electron microscopy, circular dichroism spectroscopy, and internal reflection infrared spectroscopy. Results indicate that particles made with the three full-length apoE isoforms are discoidal in shape, and structurally indistinguishable. Thus, differences in their pathological consequences are not due to gross differences in particle structure. Although apoE is predominantly helical, and the axes of the helices are parallel to the flat surfaces of the particles, the orientational order of lipid acyl chains is low and inconsistent with the belt model of lipoprotein A-I structure. Instead, the data suggest that there are at least two different types of apoE-lipid interactions within lipoprotein E particles. One type occurs between apoE helices and the edge of the lipid bilayer as in the belt model, while a second type involves apoE helices that situate in the plane of the membrane and disturb acyl chain order. These interactions allow LpE particles to form with different protein/lipid ratios, and they account for the structure of LpE particles made with only the truncated domains.
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It is unlikely that the higher binding ability of apoE4 to GAG is due to cooperative effects of the heparin binding sites.
“Since apoE4 has a lesser propensity to self-associate than apoE3 in solution (47) and the number of apoE molecules on DMPC discs is similar among apoE isoforms (52), it is unlikely that the higher ability of binding of apoE4 to GAG is due to the cooperative effects of the heparin binding sites.”
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 [52]
The similar electrostatic interaction in GAG binding of full-length apoE3 in the lipid-free state and in a discoidal complex may result from apoE being a tetramer in the lipid-free state and about four apoE molecules being bound to DMPC discs.
“In this regard, the similar electrostatic interaction in GAG binding of full-length apoE3 in the lipid-free state and in a discoidal complex (Fig. 7) may result from the fact that apoE is a tetramer in the lipid-free state and that there are about four apoE molecules bound to DMPC discs (52).”
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 [52]
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- Authors
- Schneeweis, L. A., Koppaka, V., Lund-Katz, S., Phillips, M. C., & Axelsen, P. H.
- Affiliations
- Children's Hospital of Philadelphia (US)
- University of Pennsylvania, Philadelphia, Pennsylvania 19104, and Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104
- Venue
- Biochemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2005-08-23
- Volume
- 44
- Issue
- 37
- Pages
- 12525-12534
- ISSN
- 0006-2960 (ISSN-L)
- 1520-4995
- OpenAlex
- W2018624063
- Cited by
- 39
- References
- 28
- Citations by year
- 2025: 1 · 2023: 1 · 2021: 1 · 2020: 1 · 2018: 2 · 2017: 1 · 2015: 1 · 2014: 6 · 2013: 1 · 2012: 3
- FWCI
- 3.18
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (AG20238)
- National Heart, Lung, and Blood Institute (HL68186, R01HL068186, R01HL056083, HL-56083)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Keywords
- apolipoprotein E, APOE isoforms, cholesterol homeostasis, lipid/protein ratio, cardiovascular risk, neurodegenerative disease risk
- MeSH terms
- Apolipoproteins E, Microscopy, Electron, Scanning, Models, Molecular, Peptide Fragments, Phospholipids, Protein Conformation, Protein Structure, Secondary, Crystallography, X-Ray
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