Review
Apolipoprotein E structure: insights into function

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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.

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.

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