Apolipoprotein E (APOE)
The protein contains 317 amino acids for an estimated molecular weight of 36154 Da.
APOE is an apolipoprotein, a protein associating with lipid particles, that mainly functions in lipoprotein-mediated lipid transport between organs via the plasma and interstitial fluids (PubMed:6860692, PubMed:1911868, PubMed:14754908). APOE is a core component of plasma lipoproteins and is involved in their production, conversion and clearance (PubMed:6860692, PubMed:2762297, PubMed:1911868, PubMed:1917954, PubMed:9395455, PubMed:14754908, PubMed:23620513). Apoliproteins are amphipathic molecules that interact both with lipids of the lipoprotein particle core and the aqueous environment of the plasma (PubMed:6860692, PubMed:2762297, PubMed:9395455). As such, APOE associates with chylomicrons, chylomicron remnants, very low density lipoproteins (VLDL) and intermediate density lipoproteins (IDL) but shows a preferential binding to high-density lipoproteins (HDL) (PubMed:6860692, PubMed:1911868). It also binds a wide range of cellular receptors including the LDL receptor/LDLR, the LDL receptor-related proteins LRP1, LRP2 and LRP8 and the very low-density lipoprotein receptor/VLDLR that mediate the cellular uptake of the APOE-containing lipoprotein particles (PubMed:2762297, PubMed:1917954, PubMed:7768901, PubMed:8939961, PubMed:12950167, PubMed:20030366, PubMed:2063194, PubMed:8756331, PubMed:20303980, PubMed:1530612, PubMed:7635945). Finally, APOE has also a heparin-binding activity and binds heparan-sulfate proteoglycans on the surface of cells, a property that supports the (updated: Dec. 5, 2018)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
This protein is annotated as membranous in Gene Ontology.
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Biological Process
Aging
AMPA glutamate receptor clustering
Amyloid precursor protein metabolic process
Artery morphogenesis
Cellular calcium ion homeostasis
Cellular protein metabolic process
Cellular response to cholesterol
Cellular response to growth factor stimulus
Cellular response to interleukin-1
CGMP-mediated signaling
Cholesterol biosynthetic process
Cholesterol catabolic process
Cholesterol efflux
Cholesterol homeostasis
Cholesterol metabolic process
Chylomicron assembly
Chylomicron remnant clearance
Chylomicron remodeling
Cytoskeleton organization
Fatty acid homeostasis
G protein-coupled receptor signaling pathway
Gene expression
High-density lipoprotein particle assembly
High-density lipoprotein particle clearance
High-density lipoprotein particle remodeling
Intermediate-density lipoprotein particle clearance
Intracellular receptor signaling pathway
Intracellular transport
Lipid transport involved in lipid storage
Lipoprotein biosynthetic process
Lipoprotein catabolic process
Lipoprotein metabolic process
Locomotory exploration behavior
Long-chain fatty acid transport
Long-term memory
Low-density lipoprotein particle remodeling
Maintenance of location in cell
Negative regulation of amyloid fibril formation
Negative regulation of amyloid-beta formation
Negative regulation of blood coagulation
Negative regulation of blood vessel endothelial cell migration
Negative regulation of canonical Wnt signaling pathway
Negative regulation of cellular protein metabolic process
Negative regulation of cholesterol biosynthetic process
Negative regulation of cholesterol efflux
Negative regulation of dendritic spine development
Negative regulation of dendritic spine maintenance
Negative regulation of endothelial cell migration
Negative regulation of endothelial cell proliferation
Negative regulation of gene expression
Negative regulation of inflammatory response
Negative regulation of lipid biosynthetic process
Negative regulation of lipid transport across blood-brain barrier
Negative regulation of long-term synaptic potentiation
Negative regulation of MAP kinase activity
Negative regulation of neuron apoptotic process
Negative regulation of neuron death
Negative regulation of neuron projection development
Negative regulation of phospholipid efflux
Negative regulation of platelet activation
Negative regulation of postsynaptic membrane organization
Negative regulation of presynaptic membrane organization
Negative regulation of protein secretion
Negative regulation of triglyceride metabolic process
Neuron projection development
Neuron projection regeneration
Nitric oxide mediated signal transduction
NMDA glutamate receptor clustering
Obsolete positive regulation of cGMP biosynthetic process
Oligodendrocyte differentiation
Peripheral nervous system axon regeneration
Phospholipid efflux
Phototransduction, visible light
Positive regulation by host of viral process
Positive regulation of amyloid fibril formation
Positive regulation of amyloid-beta clearance
Positive regulation of amyloid-beta formation
Positive regulation of axon extension
Positive regulation of cholesterol efflux
Positive regulation of cholesterol esterification
Positive regulation of dendritic spine development
Positive regulation of dendritic spine maintenance
Positive regulation of endocytosis
Positive regulation of ERK1 and ERK2 cascade
Positive regulation of heparan sulfate binding
Positive regulation of heparan sulfate proteoglycan binding
Positive regulation of lipid biosynthetic process
Positive regulation of lipid transport across blood-brain barrier
Positive regulation of low-density lipoprotein particle receptor catabolic process
Positive regulation of membrane protein ectodomain proteolysis
Positive regulation of neurofibrillary tangle assembly
Positive regulation of neuron death
Positive regulation of neuron projection development
Positive regulation of nitric-oxide synthase activity
Positive regulation of phospholipid efflux
Positive regulation of postsynaptic membrane organization
Positive regulation of presynaptic membrane organization
Positive regulation of transcription, DNA-templated
Post-translational protein modification
Protein import
Receptor-mediated endocytosis
Regulation of amyloid fibril formation
Regulation of amyloid precursor protein catabolic process
Regulation of amyloid-beta clearance
Regulation of axon extension
Regulation of behavioral fear response
Regulation of Cdc42 protein signal transduction
Regulation of cellular response to very-low-density lipoprotein particle stimulus
Regulation of cholesterol metabolic process
Regulation of cholesterol transport
Regulation of gene expression
Regulation of innate immune response
Regulation of neuron death
Regulation of neuronal synaptic plasticity
Regulation of proteasomal protein catabolic process
Regulation of protein homooligomerization
Regulation of protein metabolic process
Regulation of protein-containing complex assembly
Regulation of tau-protein kinase activity
Regulation of transcription by RNA polymerase II
Response to caloric restriction
Response to dietary excess
Response to ethanol
Response to insulin
Response to reactive oxygen species
Response to retinoic acid
Retinoid metabolic process
Reverse cholesterol transport
Small molecule metabolic process
Synaptic transmission, cholinergic
Triglyceride catabolic process
Triglyceride homeostasis
Triglyceride metabolic process
Triglyceride-rich lipoprotein particle clearance
Vasodilation
Very-low-density lipoprotein particle clearance
Very-low-density lipoprotein particle remodeling
Virion assembly
Cellular Component
Blood microparticle
Chylomicron
Clathrin-coated endocytic vesicle membrane
Collagen-containing extracellular matrix
Cytoplasm
Dendrite
Discoidal high-density lipoprotein particle
Early endosome
Endocytic vesicle lumen
Endoplasmic reticulum
Endoplasmic reticulum lumen
Extracellular exosome
Extracellular matrix
Extracellular region
Extracellular space
Extracellular vesicle
Extrinsic component of external side of plasma membrane
Glutamatergic synapse
Golgi apparatus
High-density lipoprotein particle
Intermediate-density lipoprotein particle
Late endosome
Lipoprotein particle
Low-density lipoprotein particle
Lysosome
Membrane
Microtubule
Neuronal cell body
Nuclear envelope
Nucleus
Obsolete cell
Plasma membrane
Synaptic cleft
Very-low-density lipoprotein particle
Vesicle
Molecular Function
Amyloid-beta binding
Antioxidant activity
Cholesterol binding
Cholesterol transfer activity
Cholesterol transporter activity
Heparan sulfate proteoglycan binding
Heparin binding
Hydroxyapatite binding
Identical protein binding
Lipid binding
Lipid transporter activity
Lipoprotein particle binding
Low-density lipoprotein particle receptor binding
Metal chelating activity
Phosphatidylcholine-sterol O-acyltransferase activator activity
Phospholipid binding
Protein dimerization activity
Protein homodimerization activity
Protein-containing complex binding
Signaling receptor binding
Structural molecule activity
Tau protein binding
Very-low-density lipoprotein particle receptor binding
The reference OMIM entry for this protein is 104310
Alzheimer disease 2
Ad2
Alzheimer disease 2, late-onset
Alzheimer disease associated with apoe4
A number sign (#) is used with this entry because of the association of the apolipoprotein E (107741) E4 allele with Alzheimer disease (AD). For a general phenotypic description and a discussion of genetic heterogeneity of Alzheimer disease, see 104300.
CLINICAL FEATURES
Using positron emission tomography (PET), Reiman et al. (1996) found that 11 cognitively normal subjects aged 50 to 65 years who were homozygous for the APOE4 allele had reduced glucose metabolism in the same regions of the brain as patients with probable Alzheimer disease. The affected areas included temporal, parietal, posterior cingulate, and prefrontal regions. These findings provided preclinical evidence that the presence of the APOE4 allele is a risk factor for Alzheimer disease. Reiman et al. (1996) suggested that PET may offer a relatively rapid way of testing treatments to prevent Alzheimer disease in the future. Reiman et al. (2001) found that 10 cognitively normal apoE4 heterozygotes aged 50 to 63 years also had abnormally low measurements of the cerebral metabolic rate for glucose in the same regions as AD patients. Over a period of 2 years, the E4 heterozygotes had declines in several regions, including temporal, posterior cingulate, prefrontal cortex, basal forebrain, parahippocampal gyrus, and thalamus. These declines were significantly greater than those of 15 non-E4 carriers. Using PET scans, Reiman et al. (2004) found that 12 young adult volunteers, ranging in age from 20 to 39 years, who were heterozygous for the apoE4 allele had abnormally low rates of glucose metabolism bilaterally in the posterior cingulate, parietal, temporal, and prefrontal cortex. Reiman et al. (2004) concluded that carriers of the E4 allele have brain abnormalities in young adulthood, several decades before the possible onset of dementia. Rippon et al. (2006) examined potential modifying risk factors for familial AD in a Latino population comprising 778 AD patients from 350 families. The population was primarily from the Dominican Republic and Puerto Rico and had been previously studied by Romas et al. (2002). The APOE E4 allele was associated with a nearly 2-fold increased risk of AD, a history of stroke (601367) was associated with a 4-fold increase, and a statistical interaction between APOE E4 and stroke was observed. Women with the E4 allele who were on estrogen replacement therapy did not have an increased risk of AD, but in women with a history of stroke, estrogen therapy was a deleterious effect modifier. Among risk factors, diabetes mellitus, myocardial infarction, head injury, hypertension, and smoking were not associated with AD. Among 100 patients with AD, van der Flier et al. (2006) found an association between presence of the E4 allele and the typical amnestic phenotype, characterized by initial presentation of forgetfulness and difficulties with memory. Those with the memory phenotype were 3 times more likely to carry an E4 allele compared to AD patients who displayed a nonmemory phenotype, with initial complaints including problems with calculation, agnosia, and apraxia. The memory phenotype was almost exclusively observed in homozygous E4 carriers. Borroni et al. (2007) also reported an association between the memory phenotype of AD and presence of the E4 allele. Among 319 late-onset AD patients, 77.6% of E4 allele carriers presented with the memory phenotype compared to 64.6% of noncarriers. Wolk et al. (2010) compared the phenotypes of 67 AD patien ... More on the omim web site
Dec. 9, 2018: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated
June 20, 2017: Protein entry updated
Automatic update: comparative model was added.
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 104310 was added.
Jan. 27, 2016: Protein entry updated
Automatic update: model status changed
Jan. 24, 2016: Protein entry updated
Automatic update: model status changed