Abnormal lipoprotein receptor‐binding activity of the human E apoprotein due to cysteine‐arginine interchange at a single site
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APOE2 exhibits a lower LDLR binding capacity than APOE4.
“Biochemical studies have also identified isoform‐specific differences in LDLR binding, with APOE2 exhibiting a lower binding capacity than APOE4 does.”
From Deletion of neuronal <i>Idol</i> ameliorates Alzheimer's disease–related pathologies via APOE receptors (2025) · cites this paper as [69]
Previous reports have revealed differential activation of APOE receptors by APOE variants.
“Previous reports have revealed differential activation of APOE receptors by APOE variants, potentially explaining the differential biological impact of these variants7–9.”
From Common germline variants of the human APOE gene modulate melanoma progression and survival (2020) · cites this paper as [7]
APOE2 has been shown to exhibit reduced binding to APOE receptors.
“APOE2 has been shown to exhibit reduced binding to APOE receptors7,8.”
From Common germline variants of the human APOE gene modulate melanoma progression and survival (2020) · cites this paper as [7]
The amino acid substitution R158C, which distinguishes ApoE2 from ApoE3 and ApoE4, disrupts LDLR interaction in the lipidated state.
“The amino acid substitution R158C, which distinguishes ApoE2 from ApoE3 and ApoE4, disrupts LDLR interaction in the lipidated state19,21.”
From Decreased lipidated ApoE‐receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes (2025) · cites this paper as [19]
Lipidated ApoE2 exhibits reduced binding to LDLR compared to ApoE3/E4.
“One of the most striking ApoE isoform-specific biochemical features is that ApoE2 exhibits defective binding to low density lipoprotein receptor (LDLR), based on ligand competition assays19,20.”
From Decreased lipidated ApoE‐receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes (2025) · cites this paper as [19]
ApoE2, which is associated with a recessive form of type III HLP, binds to the LDL receptor 50-fold weaker than apoE3.
“For example, apoE2, which is associated with a recessive form of type III HLP, binds to the LDL receptor 50-fold weaker than apoE3 [22], [75].”
From Biophysical Analysis of Apolipoprotein E3 Variants Linked with Development of Type III Hyperlipoproteinemia (2011) · cites this paper as [75]
In many cases, the studied molecular properties of apoE variants associated with disease do not correlate well with disease penetrance or severity, indicating that other factors may also contribute to the pathogenesis of the disease.
“In many cases the studied molecular properties of apoE variants associated with the disease do not correlate well with disease penetrance or severity indicating that other factors may also contribute to the pathogenesis of the disease.”
From Biophysical Analysis of Apolipoprotein E3 Variants Linked with Development of Type III Hyperlipoproteinemia (2011) · cites this paper as [75]
Apo E3 and apo E4 bind with similarly high affinity to the LDL receptor, whereas apo E2 binding is 50- to 100-times weaker.
“Whereas apo E3 and apo E4 bind with similarly high affinity to the LDL receptor, the binding of apo E2 is 50- to 100- times weaker (Weisgraber KH et al. 1982).”
From Description of a Large Family with Autosomal Dominant Hypercholesterolemia Associated with the<i>APOE</i>p.Leu167del Mutation (2013) · cites this paper as Weisgraber KH et al. 1982
ApoE2 exhibits a lower affinity to the LDL receptor compared with apoE3, with ~1% of the binding activity of apoE3 and apoE4.
“ApoE2 exhibits a lower affinity to the LDL receptor compared to apoE3: ~1% of the binding activity of apoE3 and apoE4 [28,36].”
From Plasma levels of apolipoprotein E, APOE genotype and risk of dementia and ischemic heart disease: A review (2016) · cites this paper as [36]
ApoE3 and apoE4 have normal binding activity to the LDL receptor, while apoE2 is defective in such binding (<2% of the normal activity) due to the presence of Arg158Cys near the LDL receptor binding site.
“ApoE3 and apoE4 have normal binding activity to the LDL receptor, while apoE2 is defective in such binding (＜2% of the normal activity.) due to the presence of Arg158Cys near the LDL receptor binding site16).”
From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [16]
The most common apoE variant associated with type III hyperlipoproteinemia is apoE2(158 Arg→Cys), which exhibits only about 1% of the in vitro receptor binding activity of normal apoE3.
“The most common apoE variant associated with this disorder is apoE2(158 Arg→Cys) (4), which exhibits only ~1% of the in vitro receptor binding activity of normal apoE3 (7).”
From Apolipoprotein E3-Leiden contains a seven-amino acid insertion that is a tandem repeat of residues 121–127 (1989) · cites this paper as [7]
After cysteine residues were modified with cysteamine, only a small portion of apoE3-Leiden shifted to the E4 position.
“After cysteine residues were modified with cysteamine (7), only a small portion shifted to the E4 position (Fig. 2).”
From Apolipoprotein E3-Leiden contains a seven-amino acid insertion that is a tandem repeat of residues 121–127 (1989) · cites this paper as [7]
The receptor binding activity of apoE2(158 Arg→Cys)·DMPC is only 1% of normal apoE3·DMPC.
“The receptor binding activity of apoE2(158 Arg→Cys)·DMPC is only 1% of normal apoE3.DMPC (7).”
From Apolipoprotein E3-Leiden contains a seven-amino acid insertion that is a tandem repeat of residues 121–127 (1989) · cites this paper as [7]
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“19,21 While this feature may relate to type III hyperlipoproteinemia observed in 1%–10% of APOE2 homozygotes, 22 it has been underappreciated as a potential (legend continued on next page) protective mechanism for LOAD, despite the fact LDLR is a key receptor for lipidated ApoE (lipApoE) in the…”
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“In addition, APOE4 is linked to hypercholesterolemia and increased risk of cardiovascular disorders (CVD) [7, 41], although the specific underlying mechanism remains unclear [39, 42].”
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“65,66 69 A recent study explored how these binding differences may affect lipid metabolism and tau pathology.”
- Authors
- Weisgraber, K. H., Innerarity, T. L., & Mahley, R. W.
- ORCID
- Mahley, R W
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1982-03
- Volume
- 257
- Issue
- 5
- Pages
- 2518-2521
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1577502861
- Cited by
- 673
- References
- 1
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 15 · 2023: 9 · 2022: 7 · 2021: 9 · 2020: 13 · 2019: 11 · 2018: 9 · 2017: 12 · 2016: 16 · 2015: 10 · 2014: 16 · 2013: 14 · 2012: 11
- FWCI
- 46.27
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Keywords
- apolipoprotein E, point mutations, receptor binding activity, amino acid substitutions
- MeSH terms
- Apolipoproteins, Apolipoproteins E, Arginine, Cysteamine, Cysteine, Homozygote, Humans, Hyperlipoproteinemia Type III, Kinetics, Lipoproteins, LDL, Receptors, Cell Surface, Receptors, LDL
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