The structure of human apolipoprotein E2, E3 and E4 in solution. 2. Multidomain organization correlates with the stability of apoE structure

Clément-Collin, Vanessa; Barbier, Anne; Dergunov, Alexander D.; Visvikis, Athanase; Siest, Gérard; Desmadril, Michel; Takahashi, Miwako; Aggerbeck, Lawrence P.

doi:10.1016/j.bpc.2005.07.009

Cited by 28 publications

(35 citation statements)

References 53 publications

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“…Conformational changes within the N-terminal domain (where the R145P, R147P, and R158P mutations reside) and between the N-terminal and C-terminal domains have been proposed to be part of the monomer-to-oligomer transition ( 50,51 ). Furthermore, all three mutated positions studied here participate in specifi c intra-and inter-domain interactions, as seen in the recently solved structure of a monomeric variant of apoE3 ( 28 ).…”

Section: Mutations Cause Aggregation Of Apoe3 and Structurally Defectmentioning

confidence: 64%

“…ApoE is known to be prone to self-association and to form oligomeric structures at higher concentrations ( 30,50,51 ). To examine whether the introduction of the mutations affects the aggregation kinetics of apoE3, we utilized DLS to record the hydrodynamic diameter of our protein preparations immediately after refolding or after incubation at 37°C for 4 or 24 h ( Fig.…”

Section: Aggregation Statementioning

confidence: 99%

“…Although apoE2 is a common allele in the human population, it is a major risk factor for type III hyperlipoproteinemia ( 15,62 ). Structural differences between apoE3 and apoE2 have been demonstrated and suggested to revolve around changes in intramolecular bonds and, more specifi cally, disruptions in salt bridges within the N-terminal domain ( 28,33,51 ). The fact that both mutations at the same location can be pathogenic in humans highlights the importance of this position for apoE function.…”

Section: Apoe3 R158p Variant and Apoe2mentioning

confidence: 99%

“…Lipid-free apoE is prone to oligomerization and forms poorly characterized dimeric, tetrameric, or octameric structures ( 30,50,51 ). Conformational changes within the N-terminal domain (where the R145P, R147P, and R158P mutations reside) and between the N-terminal and C-terminal domains have been proposed to be part of the monomer-to-oligomer transition ( 50,51 ).…”

Section: Mutations Cause Aggregation Of Apoe3 and Structurally Defectmentioning

confidence: 99%

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Thermodynamic and structural destabilization of apoE3 by hereditary mutations associated with the development of lipoprotein glomerulopathy

Georgiadou

Stamatakis

Efthimiadou

et al. 2013

Journal of Lipid Research

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Section: Mutations Cause Aggregation Of Apoe3 and Structurally Defectmentioning

confidence: 64%

Section: Aggregation Statementioning

confidence: 99%

Section: Apoe3 R158p Variant and Apoe2mentioning

confidence: 99%

Section: Mutations Cause Aggregation Of Apoe3 and Structurally Defectmentioning

confidence: 99%

See 2 more Smart Citations

Thermodynamic and structural destabilization of apoE3 by hereditary mutations associated with the development of lipoprotein glomerulopathy

Georgiadou

Stamatakis

Efthimiadou

et al. 2013

Journal of Lipid Research

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“…However, many differences between apoE3 and apoE4 structure and function have been reported that are potentially relevant to AD. These include: reduced lipid-binding capacity of apoE4 due to isoform-specific domain interactions [21], lipidated apoE4 has a lower affinity for Aβ [22,23], apoE4 is less efficient at stabilizing microtubules [14], apoE4 exhibits weaker antioxidant activity [13] and apoE4 is structurally less stable [24,25] when compared to apoE3. It is also clear that the proteolytic fragmentation of apoE in the human brain is isoform-dependent [26-29].…”

Section: Introductionmentioning

confidence: 99%

Apolipoprotein-E forms dimers in human frontal cortex and hippocampus

2010

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BackgroundApolipoprotein-E (apoE) plays important roles in neurobiology and the apoE4 isoform increases risk for Alzheimer's disease (AD). ApoE3 and apoE2 are known to form disulphide-linked dimers in plasma and cerebrospinal fluid whereas apoE4 cannot form these dimers as it lacks a cysteine residue. Previous in vitro research indicates dimerisation of apoE3 has a significant impact on its functions related to cholesterol homeostasis and amyloid-beta peptide degradation. The possible occurrence of apoE dimers in cortical tissues has not been examined and was therefore assessed. Human frontal cortex and hippocampus from control and AD post-mortem samples were homogenised and analysed for apoE by western blotting under both reducing and non-reducing conditions.ResultsIn apoE3 homozygous samples, ~12% of apoE was present as a homodimer and ~2% was detected as a 43 kDa heterodimer. The level of dimerisation was not significantly different when control and AD samples were compared. As expected, these dimerised forms of apoE were not detected in apoE4 homozygous samples but were detected in apoE3/4 heterozygotes at a level approximately 60% lower than seen in the apoE3 homozygous samples. Similar apoE3 dimers were also detected in lysates of SK-N-SH neuroblastoma cells and in freshly prepared rabbit brain homogenates. The addition of the thiol trapping agent, iodoacetamide, to block reactive thiols during both human and rabbit brain sample homogenisation and processing did not reduce the amount of apoE homodimer recovered. These data indicate that the apoE dimers we detected in the human brain are not likely to be post-mortem artefacts.ConclusionThe identification of disulphide-linked apoE dimers in human cortical and hippocampal tissues represents a distinct structural difference between the apoE3 and apoE4 isoforms that may have functional consequences.

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Functional diversity of apolipoprotein E: from subcellular localization to mitochondrial function

Rueter¹,

Rimbach²,

Huebbe³

2022

Cell. Mol. Life Sci.

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Human apolipoprotein E (APOE), originally known for its role in lipid metabolism, is polymorphic with three major allele forms, namely, APOEε2, APOEε3, and APOEε4, leading to three different human APOE isoforms. The ε4 allele is a genetic risk factor for Alzheimer’s disease (AD); therefore, the vast majority of APOE research focuses on its role in AD pathology. However, there is increasing evidence for other functions of APOE through the involvement in other biological processes such as transcriptional regulation, mitochondrial metabolism, immune response, and responsiveness to dietary factors. Therefore, the aim of this review is to provide an overview of the potential novel functions of APOE and their characterization. The detection of APOE in various cell organelles points to previously unrecognized roles in mitochondria and others, although it is actually considered a secretory protein. Furthermore, numerous interactions of APOE with other proteins have been detected, providing indications for new metabolic pathways involving APOE. The present review summarizes the current evidence on APOE beyond its original role in lipid metabolism, to change the perspective and encourage novel approaches to future research on APOE and its isoform-dependent role in the cellular metabolism.

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The structure of human apolipoprotein E2, E3 and E4 in solution. 2. Multidomain organization correlates with the stability of apoE structure

Cited by 28 publications

References 53 publications

Thermodynamic and structural destabilization of apoE3 by hereditary mutations associated with the development of lipoprotein glomerulopathy

Thermodynamic and structural destabilization of apoE3 by hereditary mutations associated with the development of lipoprotein glomerulopathy

Apolipoprotein-E forms dimers in human frontal cortex and hippocampus

Functional diversity of apolipoprotein E: from subcellular localization to mitochondrial function

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