Dissociation of Apolipoprotein E Oligomers to Monomer Is Required for High-Affinity Binding to Phospholipid Vesicles

Garai, Kanchan; Baban, Berevan; Frieden, Carl

doi:10.1021/bi1020106

Cited by 52 publications

(95 citation statements)

References 59 publications

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“…There is some overlap in specific residues between those involved in the association-dissociation and those that are structurally different, but the overlap is small. The structural differences between apoE3 and apoE4 do not sufficiently overlap with lipid binding regions, in agreement with only small differences in lipid binding between isoforms (22). On the other hand, as noted above, apoE must dissociate before binding lipid.…”

Section: Resultssupporting

confidence: 66%

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Structural differences between apoE3 and apoE4 may be useful in developing therapeutic agents for Alzheimer’s disease

Frieden

Garai

2012

Proc. Natl. Acad. Sci. U.S.A.

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103

110

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Apolipoproteins E3 and E4, proteins with a molecular mass of 34.15 kDa, differ by a single amino acid change. ApoE4 contains an arginine residue at position 112, whereas apoE3 has a cysteine at this position. ApoE4 is the major risk factor for late-onset Alzheimer’s disease, whereas apoE3, the common isoform, is neutral with respect to this disease. Here, using literature data from both hydrogen-deuterium exchange and site-directed mutations, we suggest structural differences between these two isoforms that are distant from the site of the arginine-to-cysteine change. These structural differences involve sequences from both the N- and C-terminal domains, sequentially far apart but structurally close. In addition, these regions are close to regions that bind lipid and to a region involved in association of apoE monomers to higher molecular weight forms. We discuss the possibility that these regions could be targeted preferentially to affect the function of apoE4 relative to apoE3.

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Section: Resultssupporting

confidence: 66%

“…In addition, regions involved in the association to oligomers overlap those of lipid binding. We have discussed elsewhere our results demonstrating that the apoE oligomer, specifically the dimer, must dissociate to monomer in order for lipid to bind to this region (22). Table 1 summarizes those regions discussed here.…”

Section: Resultsmentioning

confidence: 91%

Structural differences between apoE3 and apoE4 may be useful in developing therapeutic agents for Alzheimer’s disease

Frieden

Garai

2012

Proc. Natl. Acad. Sci. U.S.A.

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103

110

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“…6) decreases tetramer stability seems reasonable given that it is well established that truncations of the C-terminal helical region lower the ability of apoE to self-associate (28,36,44). The resultant increase of apoE4 monomer/tetramer ratio compared with apoE3 provides more monomer molecules, which, unlike the tetramers, are functional in lipid binding (15,47). That is, the competition between apo E4 tetramerization and binding to other surfaces is shifted toward the latter.…”

Section: Influence Of Differences In Secondary Structure On Apoe3 Andmentioning

confidence: 95%

“…As summarized in the introductory paragraphs, the physiological functions of the apoE molecule involve various binding events that are mediated by amphipathic α-helices located in the N-and C-terminal domains. After dissociation of apoE tetramers [such as occur in plasma HDL-LpE (35)] to the monomeric state (15,47), the C-terminal helical domain initiates hydrophobic interactions such as binding to lipid and lipoprotein surfaces (7,44), and to amyloid-β (13,48). The present HX results prove that the amphipathic α-helix organization in the C-terminal domains of tetrameric WT apoE3 and apoE4 is different and suggest the following explanation for the molecular basis of the enhanced binding of apoE4 in such situations.…”

Section: Influence Of Differences In Secondary Structure On Apoe3 Andmentioning

confidence: 99%

Helical structure, stability, and dynamics in human apolipoprotein E3 and E4 by hydrogen exchange and mass spectrometry

Chetty

Mayne

Lund‐Katz

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Apolipoprotein E (apoE) plays a critical role in cholesterol transport in both peripheral circulation and brain. Human apoE is a polymorphic 299-residue protein in which the less common E4 isoform differs from the major E3 isoform only by a C112R substitution. ApoE4 interacts with lipoprotein particles and with the amyloid-β peptide, and it is associated with increased incidence of cardiovascular and Alzheimer's disease. To understand the structural basis for the differences between apoE3 and E4 functionality, we used hydrogen−deuterium exchange coupled with a fragment separation method and mass spectrometric analysis to compare their secondary structures at near amino acid resolution. We determined the positions, dynamics, and stabilities of the helical segments in these two proteins, in their normal tetrameric state and in mutation-induced monomeric mutants. Consistent with prior X-ray crystallography and NMR results, the N-terminal domain contains four α-helices, 20 to 30 amino acids long. The C-terminal domain is relatively unstructured in the monomeric state but forms an α-helix ∼70 residues long in the self-associated tetrameric state. Helix stabilities are relatively low, 4 kcal/mol to 5 kcal/mol, consistent with flexibility and facile reversible unfolding. Secondary structure in the tetrameric apoE3 and E4 isoforms is similar except that some helical segments in apoE4 spanning residues 12 to 20 and 204 to 210 are unfolded. These conformational differences result from the C112R substitution in the N-terminal helix bundle and likely relate to a reduced ability of apoE4 to form tetramers, thereby increasing the concentration of functional apoE4 monomers, which gives rise to its higher lipid binding compared with apoE3.apolipoprotein E | hydrogen exchange mass spectrometry | cholesterol | protein secondary structure | amphipathic helix

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“…5 ). In the case of apoE, which exists as oligomers (primarily tetramers) in dilute solution, the rate-limiting step for the solubilization reaction is the dissociation of the apoE tetramers to monomers ( 56,66 ).…”

Section: Interaction Of Apoa-i With Lipidsmentioning

confidence: 99%

New insights into the determination of HDL structure by apolipoproteins

Phillips

2013

Journal of Lipid Research

150

106

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This article is available online at http://www.jlr.orgThe purpose of this review is to summarize current understanding of how apolipoproteins (apoA-I in particular) determine the structures of HDL particles. The focus is on recent advances in the fi eld, so the coverage of the literature on HDL structure is not comprehensive. Knowledge of HDL structure at the molecular level is critical for understanding how this lipoprotein achieves the multiple functions elaborated in other reviews in this thematic series.In human plasma, HDL is a heterogeneous collection of particles ranging 7-12 nm in diameter and 1.063-1.21 g/ml in density ( 1-4 ). The predominant species of HDL are spherical microemulsion particles, in which a core of neutral cholesteryl ester (CE) and triacylglycerol (TG) is encapsulated by a monolayer of phospholipid (PL), unesterifi ed (free) cholesterol (FC), and protein ( 5 ). The protein and PL constituents comprise approximately 50 and 25%, respectively, of the mass of such particles, with the CE, FC, and TG components making up the remainder. Larger, less dense HDL particles have a higher lipidto-protein mass ratio. Approximately 70% of total plasma HDL protein is apoA-I (which is present in normolipidemic human plasma at ‫ف‬ 130 mg/dl), and it is located in essentially every HDL particle. The second most abundant protein is apoA-II, which comprises 15-20% of total plasma HDL protein, but this component is not present in all HDL particles. In human plasma, about 25% of apoA-I is present in HDL particles containing only apoA-I (LpA-I); the remaining HDL particles contain both apoA-I and apoA-II (LpA-I+A-II), typically in a molar ratio of 1-2/1 ( 6 ). ApoA-I and apoA-II are the "scaffold" proteins that primarily determine HDL particle structure. Other members of the exchangeable apolipoprotein gene family that are Abstract Apolipoprotein (apo)A-I is the principal protein component of HDL, and because of its conformational adaptability, it can stabilize all HDL subclasses. The amphipathic ␣ -helix is the structural motif that enables apoA-I to achieve this functionality. In the lipid-free state, the helical segments unfold and refold in seconds and are located in the N-terminal two thirds of the molecule where they are loosely packed as a dynamic, four-helix bundle. The C-terminal third of the protein forms an intrinsically disordered domain that mediates initial binding to phospholipid surfaces, which occurs with coupled ␣ -helix formation. The lipid affi nity of apoA-I confers detergent-like properties; it can solubilize vesicular phospholipids to create discoidal HDL particles with diameters of approximately 10 nm. Such particles contain a segment of phospholipid bilayer and are stabilized by two apoA-I molecules that are arranged in an anti-parallel, double-belt conformation around the edge of the disc, shielding the hydrophobic phospholipid acyl chains from exposure to water. The apoA-I molecules are in a highly dynamic state, and they stabilize discoidal particles of different sizes by certain s...

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Dissociation of Apolipoprotein E Oligomers to Monomer Is Required for High-Affinity Binding to Phospholipid Vesicles

Cited by 52 publications

References 59 publications

Structural differences between apoE3 and apoE4 may be useful in developing therapeutic agents for Alzheimer’s disease

Structural differences between apoE3 and apoE4 may be useful in developing therapeutic agents for Alzheimer’s disease

Helical structure, stability, and dynamics in human apolipoprotein E3 and E4 by hydrogen exchange and mass spectrometry

New insights into the determination of HDL structure by apolipoproteins

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