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New Insights into the Heparan Sulfate Proteoglycan-binding Activity of Apolipoprotein E
Open accessAbstract
Defective binding of apolipoprotein E (apoE) to heparan sulfate proteoglycans (HSPGs) is associated with increased risk of atherosclerosis due to inefficient clearance of lipoprotein remnants by the liver. The interaction of apoE with HSPGs has also been implicated in the pathogenesis of Alzheimer's disease and may play a role in neuronal repair. To identify which residues in the heparin-binding site of apoE and which structural elements of heparan sulfate interact, we used a variety of approaches, including glycosaminoglycan specificity assays, (13)C nuclear magnetic resonance, and heparin affinity chromatography. The formation of the high affinity complex required Arg-142, Lys-143, Arg-145, Lys-146, and Arg-147 from apoE and N- and 6-O-sulfo groups of the glucosamine units from the heparin fragment. As shown by molecular modeling, using a high affinity binding octasaccharide fragment of heparin, these findings are consistent with a binding mode in which five saccharide residues of fully sulfated heparan sulfate lie in a shallow groove of the alpha-helix that contains the HSPG-binding site (helix 4 of the four-helix bundle of the 22-kDa fragment). This groove is lined with residues Arg-136, Ser-139, His-140, Arg-142, Lys-143, Arg-145, Lys-146, and Arg-147. In the model, all of these residues make direct contact with either the 2-O-sulfo groups of the iduronic acid monosaccharides or the N- and 6-O-sulfo groups of the glucosamine sulfate monosaccharides. This model indicates that apoE has an HSPG-binding site highly complementary to heparan sulfate rich in N- and O-sulfo groups such as that found in the liver and the brain.
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“Presumably, the interaction of apoE with syndecan occurs through electrostatic interactions between positively charged helix 4 domains of apoE and negatively charged sulfate groups in syndecan HSPG (Libeu et al., 2001).”
From Apolipoprotein E in Synaptic Plasticity and Alzheimer’s Disease: Potential Cellular and Molecular Mechanisms (2014) · cites this paper as Libeu et al., 2001
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“By contrast, APOE4 has increased binding affinity (up to two-fold) for heparin and HSPG over APOE3 (refs. 32–35).”
From The APOE-R136S mutation protects against APOE4-driven tau pathology, neurodegeneration, and neuroinflammation (2023) · cites this paper as [34]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“However, the receptor-binding sites (AA136-150) for lipoprotein receptors such as the low-density lipoprotein receptor (LDLR), lipoprotein-related receptor 1 (LRP1), and heparan sulfate proteoglycans (HSPGs) are located in a region conserved between species (Fig. 1a) [11–14].”
From APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology (2025) · cites this paper as [14]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“As hepatocyte HS is notably more enriched in sulfate than HS from endothelium and other tissues (27,33,34), binding of these lipoproteins to liver HS may be preferred to binding to HS in other tissues.”
From Liver heparan sulfate proteoglycans mediate clearance of triglyceride-rich lipoproteins independently of LDL receptor family members (2007) · cites this paper as [27]
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In the citing paper
“In general, only 8–12 monosaccharide residues are needed to bind to many proteins, including LPL and apoE (52–55), but the pattern of sulfate groups and uronic acids that mediate TRL binding is unknown.”
From Syndecan-1 is the primary heparan sulfate proteoglycan mediating hepatic clearance of triglyceride-rich lipoproteins in mice (2009) · cites this paper as [54]
In the citing paper
“Liver heparan sulfate is unusual in that it is more highly sulfated than heparan sulfate in other tissues (54, 56, 57).”
From Syndecan-1 is the primary heparan sulfate proteoglycan mediating hepatic clearance of triglyceride-rich lipoproteins in mice (2009) · cites this paper as [54]
In the citing paper
“apoE is known to bind to heparan sulfate proteoglycan (HSPG) through its N-terminal domain (142–147 amino acid domain) (Libeu et al., 2001).”
From Apolipoprotein E in Synaptic Plasticity and Alzheimer’s Disease: Potential Cellular and Molecular Mechanisms (2014) · cites this paper as Libeu et al., 2001
In the citing paper
“and the 22-kDa domain of lipid-bound apoE3[R145C] has 48% reduced HSPG binding capacity compared to apoE3-22kDa [30], [32].”
From Biophysical Analysis of Apolipoprotein E3 Variants Linked with Development of Type III Hyperlipoproteinemia (2011) · cites this paper as [32]
In the citing paper
“the N-terminal domain site is located between residues 136–147, overlapping with the LDLR binding region (25, 26)”
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 [26]
In the citing paper
“In addition, the mutation in lysine 146 which disrupts direct ionic interaction between basic residues on apoE and sulfate groups on the GAG chain (26) greatly reduced the favorable free energy for the first binding step to HS and DS (Fig. 4B).”
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 [26]
In the citing paper
“indicating that the degree of sulfation has a major effect on the electrostatic interaction of GAG with apoE.”
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 [26]
In the citing paper
“quantitative information on the interaction with various GAG molecules is limited (26, 34).”
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 [26]
In the citing paper
“However, the large decreases in the association rate and the favorable free energy of binding in the first step observed for HS and DS compared to heparin (Fig. 3) indicate that the contribution of the initial electrostatic interaction to the overall binding is lower for HS and DS than for heparin (26).”
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 [26]
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Citations
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Metadata
- Authors
- Libeu, C. P., Lund-Katz, S., Phillips, M. C., Wehrli, S., Hernáiz, M. J., Capila, I., Linhardt, R. J., Raffaı̈, R. L., Newhouse, Y. M., Zhou, F., & Weisgraber, K. H.
- Affiliations
- Gladstone Institutes (US)
- Children's Hospital of Philadelphia (US)
- University of Iowa (US)
- Texas A&M University (US)
- Corresponding author
- Weisgraber, Karl H.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2001-10
- Volume
- 276
- Issue
- 42
- Pages
- 39138-39144
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2106771721
- Cited by
- 113
- References
- 61
- Citations by year
- 2026: 5 · 2025: 12 · 2024: 2 · 2023: 8 · 2022: 4 · 2021: 3 · 2020: 3 · 2019: 5 · 2018: 2 · 2017: 3 · 2016: 3 · 2015: 2 · 2014: 5 · 2013: 2 · 2012: 2
- FWCI
- 2.04
- 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-41633, P01HL041633, R01HL056083, HL-56083, HL 52622, R01HL052622)
- National Institute of General Medical Sciences (GM38060, R01GM038060)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Keywords
- apolipoprotein E, heparan sulfate proteoglycans, heparin-binding site, iduronic acid, glucosamine sulfate, atherosclerosis, Alzheimer's disease, lipoprotein clearance, binding site modeling
- MeSH terms
- Animals, Apolipoproteins E, Arginine, Binding Sites, Brain, Cattle, Chromatography, Affinity, Dose-Response Relationship, Drug, Glucosamine, Heparin, Humans, Hydrogen-Ion Concentration, Kinetics, Liver, Lysine, Models, Molecular, Mutation, Magnetic Resonance Spectroscopy, Polysaccharides, Protein Binding, Serine, Time Factors, Streptavidin, Heparan Sulfate Proteoglycans, Biotinylation, Surface Plasmon Resonance
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