ArticleBiochemistry2010
Molecular basis for the differences in lipid and lipoprotein binding properties of human apolipoproteins E3 and E4.
Article in Biochemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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Who cites it
52 citing papers in PubMed, 85 citations in OpenAlex.
- Cholesterol at the Center of Alzheimer's Disease: A Unifying Hypothesis on the Pathogenic Mechanism.Molecules (Basel, Switzerland) · 2026Review
- HDL-mimetic peptide treatment reverses APOE4-induced transcriptomic and lipidomic alterations in the brain of humanized APOE mice.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Effect of High-Salt Diet on Memory and Behavior in Mice Expressing Human Apolipoprotein Epsilon-4 (APOE4) Allele.NeuroSci · 2026Article
- Correlation between ApoE gene polymorphisms and the prognosis of coronary artery disease in patients undergoing percutaneous coronary intervention.BMC cardiovascular disorders · 2025Article
- Increased cerebrospinal fluid and plasma apoE glycosylation is associated with reduced levels of Alzheimer's disease biomarkers.Alzheimer's research & therapy · 2025Article
- Conformational features of guinea pig apolipoprotein E offer insights into functioning of human apolipoprotein E.Archives of biochemistry and biophysics · 2025Article
- Normolipidemic lipoprotein glomerulopathy with IgA nephropathy - ApoE Kyoto mutation: a case report.Diagnostic pathology · 2025Article
- Effects of APOE isoforms in diabetic nephropathy patients of South India.Acta diabetologica · 2025Article
- Multifaceted roles of APOE in Alzheimer disease.Nature reviews. Neurology · 2024Review
- Influence of apolipoprotein E gene polymorphisms on coronary artery disease in patients undergoing coronary angiography.Heliyon · 2024Article
- Human apolipoprotein E glycosylation and sialylation: from structure to function.Frontiers in molecular neuroscience · 2024Review
- Investigation of the Relationship between Apolipoprotein E Alleles and Serum Lipids in Alzheimer's Disease: A Meta-Analysis.Brain sciences · 2023Review
- Apolipoprotein E in lipid metabolism and neurodegenerative disease.Trends in endocrinology and metabolism: TEM · 2023Review
- Isoform-specific modification of apolipoprotein E by 4-hydroxynonenal: protective role of apolipoprotein E3 against oxidative species.The FEBS journal · 2023Article
- An association of CSF apolipoprotein E glycosylation and amyloid-beta 42 in individuals who carry the APOE4 allele.Alzheimer's research & therapy · 2023Article
- Plasma and cerebrospinal fluid cholesterol esterification is hampered in Alzheimer's disease.Alzheimer's research & therapy · 2023Article
- Neuronal ApoE4 in Alzheimer's disease and potential therapeutic targets.Frontiers in aging neuroscience · 2023Review
- APOE in the bullseye of neurodegenerative diseases: impact of the APOE genotype in Alzheimer's disease pathology and brain diseases.Molecular neurodegeneration · 2022Review
- Dysfunction of the Blood-brain Barrier in Cerebral Microbleeds: from Bedside to Bench.Aging and disease · 2021Review
- Isoform-Specific Effects of Apolipoprotein E on Hydrogen Peroxide-Induced Apoptosis in Human Induced Pluripotent Stem Cell (iPSC)-Derived Cortical Neurons.International journal of molecular sciences · 2021Article
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
Human apolipoprotein (apo) E4 binds preferentially to very low-density lipoproteins (VLDLs), whereas apoE3 binds preferentially to high-density lipoproteins (HDLs), resulting in different plasma cholesterol levels for the two isoforms. To understand the molecular basis for this effect, we engineered the isolated apoE N-terminal domain (residues 1-191) and C-terminal domain (residues 192-299) together with a series of variants containing deletions in the C-terminal domain and assessed their lipid and lipoprotein binding properties. Both isoforms can bind to a phospholipid (PL)-stabilized triolein emulsion, and residues 261-299 are primarily responsible for this activity. ApoE4 exhibits better lipid binding ability than apoE3 as a consequence of a rearrangement involving the segment spanning residues 261-272 in the C-terminal domain. The strong lipid binding ability of apoE4 coupled with the VLDL particle surface being ∼60% PL-covered is the basis for its preference for binding VLDL rather than HDL. ApoE4 binds much more strongly than apoE3 to VLDL but less strongly than apoE3 to HDL(3), consistent with apoE-lipid interactions being relatively unimportant for binding to HDL. The preference of apoE3 for binding to HDL(3) arises because binding is mediated primarily by interaction of the N-terminal helix bundle domain with the resident apolipoproteins that cover ∼80% of the HDL(3) particle surface. Thus, the selectivity in the binding of apoE3 and apoE4 to HDL(3) and VLDL is dependent upon two factors: (1) the stronger lipid binding ability of apoE4 relative to that of apoE3 and (2) the differences in the nature of the surfaces of VLDL and HDL(3) particles, with the former being largely covered with PL and the latter with protein.
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