Trends in Biochemical Sciences
ReviewApolipoprotein E structure: insights into function
Introduction
ApoE is a principal genetic determinant of Alzheimer's disease and several other neurological conditions, such as recovery from injury and stroke [1]. Of the three common allelic isoforms, apoE4 confers the greatest risk of developing Alzheimer's disease, apoE2 confers the least and apoE3 confers an intermediate risk [2]. Intensive research over the past two decades into how the isoforms differentially mediate this risk has resulted in numerous potential mechanisms, including the fragmentation of apoE into toxic products, apoE-mediated binding to amyloid β-peptide and plaque formation, apoE-induced membrane disruption, apoE-mediated lipid transport, apoE-stimulated neuronal sensitivity to injury and recovery, and apoE acting as an antioxidant 3, 4, 5, 6, 7, 8, 9, 10, 11, 12.
In this review, we focus on the intrinsic biophysical and structural features of apoE, which provide insight into how the three isoforms behave differently from each other in vivo. Knowledge of these differences aids our understanding of the mechanisms underlying the neurological disorders associated with apoE and provides potential for structure-guided therapies aimed at combating these diseases. We start by describing how amino acid polymorphisms affect apoE function. We then discuss current knowledge of apoE conformation and lipid binding and conclude by outlining the questions remaining for future studies.
Section snippets
Basic structural arrangement of lipid-free apoE
ApoE contains 299 residues (relative molecular mass = 34 000) and was originally identified as a main component of lipoproteins in plasma. Similar to other soluble apolipoproteins, apoE contains amphipathic α-helical lipid-binding domains that enable it to switch reversibly between a lipoprotein-bound and a lipid-free state. ApoE binds with micromolar affinity to synthetic emulsions containing a triglyceride core with a phospholipid monolayer surface that resemble very-low-density lipoproteins
ApoE polymorphism and its effect on disease
ApoE is polymorphic, which influences its functional and structural properties. The three common allelic isoforms, apoE2, apoE3 and apoE4, differ at positions 112 and 158. ApoE3, the most common isoform, contains cysteine and arginine, respectively, whereas apoE2 has two cysteines and apoE4 has two arginines at these positions [23] (Figure 1a and Table 1). ApoE3 and apoE4 bind to LDL receptors with similarly high affinity, but the binding of apoE2 is 50- to 100- times weaker [24]. As a result,
Effect of stability differences on lipid binding
Various studies indicate that partially folded or molten-globule-like conformations give proteins flexibility and adaptability for the substantial conformational changes that accompany ligand binding 39, 40, 41. For apoE, the differences in conformational stability and folding behavior of the N-terminal domain could be important in lipid binding. In particular, variation in the stability of the N-terminal domains of the three isoforms might contribute to their differences in lipoprotein-binding
Conformational heterogeneity of lipoprotein-bound apoE
Much evidence suggests that apoE adopts different conformations in complex with lipoproteins of varying size and shape. This variation was first inferred from early studies showing that binding affinity for the LDL receptor is low for lipid-free apoE and high for lipid-bound apoE [53]. Subsequent studies have shown that the receptor-binding activity of apoE-containing lipoproteins also depends on their size [54] and lipid composition [55] and on the presence of other apolipoproteins in the
Structure of lipid-bound apoE
Because the composition of plasma lipoproteins is complex, simple synthetic models of lipoproteins have been used to study the conformation of lipid-bound apoE. The most commonly used model, apoE bound to phospholipids, results in discrete particles that resemble HDLs in size and density [53].
On binding to phospholipids, apoE undergoes a considerable conformational change (Figure 4). Recent studies using EPR, FRET and X-ray diffraction suggest that phospholipid-bound apoE folds into a α-helical
Future perspectives
Studies of lipid-free apoE have revealed much about the relationship between the structure and function of apoE. A remaining challenge is to examine the structure–function relationships of apoE bound to lipid in its multiple conformations. The difficulty of this challenge lies in the inherent conformational flexibility of apoE, which is influenced by lipoprotein particle size and composition.
Another challenge is to define better how the structural differences in the isoforms relate to phenotype
Acknowledgements
We thank Stephen Ordway and Gary Howard for editorial assistance, John Carroll, Jack Hull, Steven Gonzales and Chris Goodfellow for graphics assistance, and Karina Fantillo for manuscript preparation. This work was supported, in part, by grants from the NIH P01 AG022074, R01 AG020235 and a postdoctoral fellowship to D.M.H. from the John Douglas French Alzheimer's Foundation.
References (86)
Apolipoprotein E4 potentiates amyloid β peptide-induced lysosomal leakage and apoptosis in neuronal cells
J. Biol. Chem.
(2002)Behavior of human apolipoprotein E in aqueous solutions and at interfaces
J. Biol. Chem.
(1985)Cell surface receptor binding of phospholipid–protein complexes containing different ratios of receptor-active and -inactive E apoprotein
J. Biol. Chem.
(1980)The amphipathic helix in the exchangeable apolipoproteins: a review of secondary structure and function
J. Lipid Res.
(1992)Human apolipoprotein E3 in aqueous solution. I. Evidence for two structural domains
J. Biol. Chem.
(1988)Apolipoprotein E: Structure–function relationships
Adv. Protein Chem.
(1994)Effect of arginine 172 on the binding of apolipoprotein E to the low density lipoprotein receptor
J. Biol. Chem.
(2000)Human apolipoprotein E. Role of arginine 61 in mediating the lipoprotein preferences of the E3 and E4 isoforms
J. Biol. Chem.
(1994)Human E apoprotein heterogeneity. Cysteine–arginine interchanges in the amino acid sequence of the apo-E isoforms
J. Biol. Chem.
(1981)Abnormal lipoprotein receptor-binding activity of the human E apoprotein due to cysteine–arginine interchange at a single site
J. Biol. Chem.
(1982)
Human apolipoprotein E4 domain interaction. Arginine 61 and glutamic acid 255 interact to direct the preference for very low density lipoproteins
J. Biol. Chem.
Apolipoprotein E distribution among human plasma lipoproteins: role of the cysteine–arginine interchange at residue 112
J. Lipid Res.
Modulation of apolipoprotein E structure by domain interaction. Differences in lipid-bound and lipid-free forms
J. Biol. Chem.
Apolipoprotein E4 domain interaction occurs in living neuronal cells as determined by fluorescence resonance energy transfer
J. Biol. Chem.
Comparison of the stabilities and unfolding pathways of human apolipoprotein E isoforms by differential scanning calorimetry and circular dichroism
Biochim. Biophys. Acta
Apolipoprotein E4 forms a molten globule: a potential basis for its association with disease
J. Biol. Chem.
Intrinsically unstructured proteins: re-assessing the protein structure-function paradigm
J. Mol. Biol.
Molten globule and protein folding
Adv. Protein Chem.
Engineering conformational destabilization into mouse apolipoprotein E. A model for a unique property of human apolipoprotein E4
J. Biol. Chem.
Conformational, thermodynamic, and stability properties of Manduca sexta apolipophorin III
J. Biol. Chem.
Reactivity of apolipoprotein E4 and amyloid β peptide: lysosomal stability and neurodegeneration
J. Biol. Chem.
Is Alzheimer's disease an apolipoprotein E amyloidosis?
Lancet
Binding of arginine-rich (E) apoprotein after recombination with phospholipid vesicles to the low density lipoprotein receptors of fibroblasts
J. Biol. Chem.
Apolipoprotein E mediates uptake of Sf 100–400 hypertriglyceridemic very low density lipoproteins by the low density lipoprotein receptor pathway in normal human fibroblasts
J. Biol. Chem.
A change in apolipoprotein B expression is required for the binding of apolipoprotein E to very low density lipoprotein
J. Biol. Chem.
Opposing effects of apolipoproteins E and C on lipoprotein binding to low density lipoprotein receptor-related protein
J. Biol. Chem.
Apolipoprotein C-I modulates the interaction of apolipoprotein E with β-migrating very low density lipoproteins (β-VLDL) and inhibits binding of β-VLDL to low density lipoprotein receptor-related protein
J. Biol. Chem.
Heterogeneity of apolipoprotein E epitope expression on human lipoproteins: importance for apolipoprotein E function
J. Lipid Res.
Molecular basis of exchangeable apolipoprotein function
Biochim. Biophys. Acta
Lipid binding-induced conformational change in human apolipoprotein E. Evidence for two lipid-bound states on spherical particles
J. Biol. Chem.
Cell surface receptor binding of phospholipid–protein complexes containing different ratios of receptor-active and -inactive E apoprotein
J. Biol. Chem.
The receptor-binding domain of human apolipoprotein E. Binding of apolipoprotein E fragments
J. Biol. Chem.
Helix orientation of the functional domains in apolipoprotein E in discoidal high density lipoprotein particles
J. Biol. Chem.
Model of biologically active apolipoprotein E bound to dipalmitoylphosphatidylcholine
J. Biol. Chem.
Examination of lipid-bound conformation of apolipoprotein E4 by pyrene excimer fluorescence
J. Biol. Chem.
Lipid binding-induced conformational changes in the N-terminal domain of human apolipoprotein E
J. Lipid Res.
Conformational reorganization of the four-helix bundle of human apolipoprotein E in binding to phospholipid
J. Biol. Chem.
The low density lipoprotein receptor active conformation of apolipoprotein E. Helix organization in N-terminal domain-phospholipid disc particles
J. Biol. Chem.
The lipid-associated conformation of the low density lipoprotein receptor binding domain of human apolipoprotein E
J. Biol. Chem.
Detailed molecular model of apolipoprotein A-I on the surface of high-density lipoproteins and its functional implications
Trends Cardiovasc. Med.
Obligatory role of cholesterol and apolipoprotein E in the formation of large cholesterol-enriched and receptor-active high density lipoproteins
J. Biol. Chem.
The plasma lecithin:cholesterol acyltransferase reaction
J. Lipid Res.
Increased 3-nitrotyrosine in brains of ApoE-deficient mice
Brain Res.
Cited by (458)
Apolipoprotein E O-glycosylation is associated with amyloid plaques and APOE genotype
2023, Analytical BiochemistryCell type-specific functions of Alzheimer’s disease endocytic risk genes
2024, Philosophical Transactions of the Royal Society B: Biological SciencesThe association between APO-E genotype and inflammation and the risk of premature CHD in smokers versus non-smokers
2024, Journal of Applied Pharmaceutical ScienceBiomaterials Comprising Implantable and Dermal Drug Delivery Targeting Brain in Management of Alzheimer’s Disease: A Review
2024, Regenerative Engineering and Translational Medicine