Apolipoprotein E structure: insights into function

Hatters, Danny M.; Peters-Libeu, Clare A.; Weisgraber, Karl H.

doi:10.1016/j.tibs.2006.06.008

Cited by 583Alzheimer's disease research and treatmentsLipoproteins and Cardiovascular HealthCholesterol and Lipid Metabolism

Apolipoprotein E structure: insights into function

Hatters, Danny M., Peters-Libeu, Clare A., Weisgraber, Karl H.·2006·Trends in Biochemical Sciences

DOI 10.1016/j.tibs.2006.06.008

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Abstract

Human apolipoprotein E (apoE) is a member of the family of soluble apolipoproteins. Through its interaction with members of the low-density lipoprotein receptor family, apoE has a key role in lipid transport both in the plasma and in the central nervous system. Its three common structural isoforms differentially affect the risk of developing atherosclerosis and neurodegenerative disorders, including Alzheimer's disease. Because the function of apoE is dictated by its structure, understanding the structural properties of apoE and its isoforms is required both to determine its role in disease and for the development of therapeutic strategies.

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Allelic differences and single point mutations affect apoE conformation and hinder physiological function.
“Several biophysical studies have shown that apoE displays low thermodynamic stability and significant conformational plasticity, and allelic differences as well as single point mutations have been shown to affect protein conformation and to hinder physiological function”
From Thermodynamic destabilization and aggregation propensity as the mechanism behind the association of apoE3 mutants and lipoprotein glomerulopathy (2018) · cites this paper as [13]
ApoE displays low thermodynamic stability and significant conformational plasticity.
“Several biophysical studies have shown that apoE displays low thermodynamic stability and significant conformational plasticity, and allelic differences as well as single point mutations have been shown to affect protein conformation and to hinder physiological function”
From Thermodynamic destabilization and aggregation propensity as the mechanism behind the association of apoE3 mutants and lipoprotein glomerulopathy (2018) · cites this paper as [13]
Inter-domain interactions within apoE have been hypothesized to underlie key conformational changes related to apoE function.
“Inter-domain interactions within apoE have been hypothesized to underlie key conformational changes related to apoE function [44], [45].”
From Biophysical Analysis of Apolipoprotein E3 Variants Linked with Development of Type III Hyperlipoproteinemia (2011) · cites this paper as [44]
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 [44]
The second unfolding transition of apoE3 variant corresponds to the unfolding of the N-terminal domain where the K146E mutation is located.
“of the second unfolding transition of apoE3 variant (Table 3) that corresponds to the unfolding of the N-terminal domain where the K146E mutation is located [13], [44], [65].”
From Biophysical Analysis of Apolipoprotein E3 Variants Linked with Development of Type III Hyperlipoproteinemia (2011) · cites this paper as [44]

Apo E4 isoform is associated with elevated total and LDL-cholesterol levels, due to the higher affinity of apo E4 for VLDL and LDL.
“Apo E4 isoform is associated with elevated total and LDL-cholesterol levels, due to the higher affinity of apo E4 for VLDL and LDL”
From Description of a Large Family with Autosomal Dominant Hypercholesterolemia Associated with theAPOEp.Leu167del Mutation (2013) · cites this paper as Hatters DM et al. 2006
Mutated ApoE2 (Arg158Cys) exhibits only 2% affinity to LDL receptor compared to wild type ApoE3 isoform.
“Mutated ApoE2 (Arg158Cys) exhibits only 2% affinity to LDL receptor compared to the wide type ApoE3 isoform [13]”
From A case report of youth-onset lipoprotein glomerulopathy with APOE Chicago mutation (2024) · cites this paper as [13]
Unfolding of the N-terminal domain constitutes a necessary conformational change for lipid binding and apoE function.
“Biophysical and computational analyses suggest that unfolding of the N-terminal domain constitutes a necessary conformational change for lipid binding and apoE function (19).”
From Molecular Basis for Increased Risk for Late-onset Alzheimer Disease Due to the Naturally Occurring L28P Mutation in Apolipoprotein E4 (2014) · cites this paper as [19]
ApoE variants with lower thermodynamic stability and changes in conformational plasticity have been shown to have altered interdomain interactions and defective physiological functions.
“ApoE variants with lower thermodynamic stability and changes in conformational plasticity have been shown to have altered interdomain interactions and defective physiological functions (19, 24 -28).”
From Molecular Basis for Increased Risk for Late-onset Alzheimer Disease Due to the Naturally Occurring L28P Mutation in Apolipoprotein E4 (2014) · cites this paper as [19]
ApoE4 preferentially forms a molten globule state that reduces its in vitro stability relative to the other isoforms.
“First, apoE4 preferentially forms a “molten globule state” that ultimately reduces the in vitro stability of apoE4 relative to the other isoforms.”
From Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels (2008) · cites this paper as Hatters et al., 2006
ApoE4 forms a unique salt bridge interaction between Arg-61 in the N terminal and Glu-255 in the carboxy-terminal domain.
“Second, apoE4 forms a unique salt bridge interaction between Arg-61 in the N terminal and Glu-255 in the carboxy-terminal domain.”
From Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels (2008) · cites this paper as Hatters et al., 2006
ApoE contains two independently folded functional domains: a 22-kDa N-terminal domain (residues 1-191) and a 10-kDa C-terminal domain (residues 216-299) linked by a hinge region.
“ApoE contains two independently folded functional domains; these are a 22-kDa N-terminal domain (residues 1–191) and a 10-kDa C-terminal domain (residues 216–299) linked by a hinge region (18, 19).”
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 [19]
The apoE4 domain interaction mediated by a salt bridge between Arg-61 and Glu-255 is unique to apoE4.
“This domain interaction mediated by a salt bridge formation between Arg-61 and Glu-255 is unique to apoE4 (Fig. 1) [15].”
From Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease (2019) · cites this paper as [15]

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Neuronal ROS-Induced Glial Lipid Droplet Formation is Altered by Loss of Alzheimer's Disease-Associated Genes
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Direct Transcriptional Effects of Apolipoprotein E
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Oxidative Stress and Metabolic Syndrome: Cause or Consequence of Alzheimer's Disease?
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Phospholipids of APOE lipoproteins activate microglia in an isoform-specific manner in preclinical models of Alzheimer’s disease
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The C-Terminal α-Helix Domain of Apolipoprotein E Is Required for Interaction with Nonstructural Protein 5A and Assembly of Hepatitis C Virus
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Blood protein coating of gold nanoparticles as potential tool for organ targeting
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TLR4 Targeting as a Promising Therapeutic Strategy for Alzheimer Disease Treatment
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Authors: Hatters, D. M., Peters-Libeu, C. A., & Weisgraber, K. H.
Affiliations: Gladstone Institutes (US)
Corresponding author: Weisgraber, Karl H.
ORCID: Hatters, Danny M.
Venue: Trends in Biochemical Sciences
Publisher: Elsevier BV
Published: 2006-08
Volume: 31
Issue: 8
Pages: 445-454
ISSN: 0968-0004 (ISSN-L)
DOI: 10.1016/j.tibs.2006.06.008
OpenAlex: W2051394059
Cited by: 583
References: 88
Citations by year: 2026: 25 · 2025: 32 · 2024: 26 · 2023: 32 · 2022: 34 · 2021: 37 · 2020: 22 · 2019: 21 · 2018: 24 · 2017: 25 · 2016: 32 · 2015: 32 · 2014: 42 · 2013: 24 · 2012: 42
FWCI: 2.88
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
doi.org/10.15223/policy-017 (stm-asf)
doi.org/10.15223/policy-037 (stm-asf)
doi.org/10.15223/policy-012 (stm-asf)
doi.org/10.15223/policy-029 (stm-asf)
doi.org/10.15223/policy-004 (stm-asf)
Locations: Trends in Biochemical Sciences (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute on Aging (R01AG020235, P01AG022074)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Keywords: apolipoprotein E, protein structure, APOE isoforms, low-density lipoprotein receptor family, lipid transport, atherosclerosis, Alzheimer's disease, neurodegenerative diseases, central nervous system, treatment options
MeSH terms: Animals, Apolipoproteins E, Humans, Models, Molecular, Protein Binding, Protein Folding, Neurodegenerative Diseases, Protein Isoforms, Atherosclerosis

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