Apolipoprotein E isoform-specific binding to the low-density lipoprotein receptor

Yamamoto, Taichi; Choi, Hyungwon; Ryan, Robert O.

doi:10.1016/j.ab.2007.09.005

Cited by 52 publications

(35 citation statements)

References 23 publications

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“…This finding is, however, in accordance with several other studies of untreated patients with FH [31,[39][40][41]. The higher LDL-C levels seen in normal populations carrying an APOE4 is not completely understood, but it may result in part from the higher affinity of APOE4 for the LDLR [42,43]. This higher affinity is believed to promote an increased hepatic uptake of VLDL and IDL remnants, resulting in a downregulation of LDLR activity and, consequently, increased LDL-C levels [44,45].…”

Section: Discussionsupporting

confidence: 92%

Role of rs3846662 and HMGCR alternative splicing in statin efficacy and baseline lipid levels in familial hypercholesterolemia

Leduc

Bourque

Poirier

et al. 2016

Pharmacogenetics and Genomics

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Section: Discussionsupporting

confidence: 92%

Role of rs3846662 and HMGCR alternative splicing in statin efficacy and baseline lipid levels in familial hypercholesterolemia

Leduc

Bourque

Poirier

et al. 2016

Pharmacogenetics and Genomics

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“…While numerous lipoprotein receptors have been shown to interact with apoE in the brain, the LDLR is the only receptor in its class of receptors to show varying binding affinities for the three apoE isoforms (E4 > E3 >> E2) (Innerarity et al, 1983, Yamamoto et al, 2008). Interestingly, the increased CVD risk normally associated with APOE4 genotype disappears in Familial Hypercholesterolemia (FH) patients, who lack functioning LDLR (Vermissen et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein E–low density lipoprotein receptor interaction affects spatial memory retention and brain ApoE levels in an isoform-dependent manner

Johnson

Olsen

Merkens

et al. 2014

Neurobiology of Disease

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Human apolipoprotein E (apoE) exists in three isoforms: apoE2, apoE3 and apoE4. APOE ε4 (E4) is a major genetic risk factor for cardiovascular disease (CVD) and Alzheimer's disease (AD). ApoE mediates cholesterol metabolism by binding various receptors. The low-density lipoprotein receptor (LDLR) has a high affinity for apoE, and is the only member of its receptor family to demonstrate an apoE isoform specific binding affinity (E4>E3>>E2). Evidence suggests that a functional interaction between apoE and LDLR influences the risk of CVD and AD. We hypothesize that the differential cognitive effects of the apoE isoforms are a direct result of their varying interactions with LDLR. To test this hypothesis, we have employed transgenic mice that express human apoE2, apoE3, or apoE4, and either human LDLR (hLDLR) or no LDLR (LDLR−/−). Our results show that plasma and brain apoE levels, cortical cholesterol, and spatial memory are all regulated by isoform-dependent interactions between apoE and LDLR. Conversely, both anxiety-like behavior and cued associative memory are strongly influenced by APOE genotype, but these processes appear to occur via an LDLR-independent mechanism. Both the lack of LDLR and the interaction between E4 and the LDLR were associated with significant impairments in the retention of long term spatial memory. Finally, levels of hippocampal apoE correlate with long term spatial memory retention in mice with human LDLR. In summary, we demonstrate that the apoE-LDLR interaction affects regional brain apoE levels, brain cholesterol, and cognitive function in an apoE isoform-dependent manner.

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“…Based on the structure of apoE3, the arginine side chain projects into the gap between the N-and C-terminal domains. The fact that this residue is at the mouth of the putative lipid-binding site may affect apoE2 binding to lipid and subsequently to the LDL receptor (37)(38)(39), as the gap between the N and C termini may collapse with the smaller cysteine side chain at position 158.…”

Section: Resultsmentioning

confidence: 99%

A mechanism for lipid binding to apoE and the role of intrinsically disordered regions coupled to domain–domain interactions

Frieden

Wang

Ho³

2017

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

101

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Relative to the apolipoprotein E (apoE) E3 allele of the APOE gene, apoE4 strongly increases the risk for the development of late-onset Alzheimer's disease. However, apoE4 differs from apoE3 by only a single amino acid at position 112, which is arginine in apoE4 and cysteine in apoE3. It remains unclear why apoE3 and apoE4 are functionally different. Described here is a proposal for understanding the functional differences between these two isoforms with respect to lipid binding. A mechanism is proposed that is based on the full-length monomeric structure of the protein, on hydrogen-deuterium exchange mass spectrometry data, and on the role of intrinsically disordered regions to control protein motions. It is proposed that lipid binds between the N-terminal and C-terminal domains and that separation of the two domains, along with the presence of intrinsically disordered regions, controls this process. The mechanism explains why apoE3 differs from apoE4 with respect to different lipid-binding specificities, why lipid increases the binding of apoE to its receptor, and why specific residues are conserved.hydrogen-deuterium exchange | domain-domain interaction | conserved residues | protein structure | apolipoprotein E A poE is a 34-kDa protein whose normal function in the brain is to transport lipids and cholesterol to neuronal cells. In humans, there are three common isoforms-apoE2, apoE3, and apoE4-that appear to differ in important functional properties such as the distinct differences between apoE isoforms with respect to lipid transport (1). ApoE4 is the most studied since, relative to apoE3, it is known to be the major risk factor for the development of late-onset Alzheimer's disease (2, 3), whereas apoE2, the less common form, is associated with type III hyperlipoproteinemia (4, 5). A great many papers have discussed possible mechanisms for lipid binding (i.e., refs. 6-11), but there is no proposal for the mechanism of lipid binding that would explain the differences between the isoforms. From studies using FRET, small-angle X-ray diffraction, and electron paramagnetic resonance spectroscopy, it has been shown that apoE undergoes a conformational change on lipid binding, with the protein adopting a hairpin-like structure (7,(11)(12)(13). Here again, however, specific details are lacking.In this paper, we assemble a number of experimental and computational observations to provide a model for the mechanism of lipid binding. This model includes a consideration of the fulllength apoE structure, results from hydrogen-deuterium exchange (HDX) experiments, information on conserved and nonconserved residues, an appreciation of the role of intrinsically disordered regions (IDRs), and molecular dynamics calculations.The proposed model explains why there are differences between apoE isoforms with respect to lipid binding and why lipid enhances apoE binding to receptors such as the low-density lipoprotein receptor (LDLR). As such, it opens the way to develop small molecular weight compounds that could preferentially inf...

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Apolipoprotein E isoform-specific binding to the low-density lipoprotein receptor

Cited by 52 publications

References 23 publications

Role of rs3846662 and HMGCR alternative splicing in statin efficacy and baseline lipid levels in familial hypercholesterolemia

Role of rs3846662 and HMGCR alternative splicing in statin efficacy and baseline lipid levels in familial hypercholesterolemia

Apolipoprotein E–low density lipoprotein receptor interaction affects spatial memory retention and brain ApoE levels in an isoform-dependent manner

A mechanism for lipid binding to apoE and the role of intrinsically disordered regions coupled to domain–domain interactions

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