P02649 · APOE_HUMAN
- ProteinApolipoprotein E
- GeneAPOE
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids317 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
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:14754908, PubMed:1911868, PubMed:6860692).
APOE is a core component of plasma lipoproteins and is involved in their production, conversion and clearance (PubMed:14754908, PubMed:1911868, PubMed:1917954, PubMed:23620513, PubMed:2762297, PubMed:6860692, PubMed:9395455).
Apolipoproteins are amphipathic molecules that interact both with lipids of the lipoprotein particle core and the aqueous environment of the plasma (PubMed:2762297, PubMed:6860692, 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:1911868, PubMed:6860692).
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:12950167, PubMed:1530612, PubMed:1917954, PubMed:20030366, PubMed:20303980, PubMed:2063194, PubMed:2762297, PubMed:7635945, PubMed:7768901, PubMed:8756331, PubMed:8939961).
Finally, APOE has also a heparin-binding activity and binds heparan-sulfate proteoglycans on the surface of cells, a property that supports the capture and the receptor-mediated uptake of APOE-containing lipoproteins by cells (PubMed:23676495, PubMed:7635945, PubMed:9395455, PubMed:9488694).
A main function of APOE is to mediate lipoprotein clearance through the uptake of chylomicrons, VLDLs, and HDLs by hepatocytes (PubMed:1911868, PubMed:1917954, PubMed:23676495, PubMed:29516132, PubMed:9395455).
APOE is also involved in the biosynthesis by the liver of VLDLs as well as their uptake by peripheral tissues ensuring the delivery of triglycerides and energy storage in muscle, heart and adipose tissues (PubMed:2762297, PubMed:29516132).
By participating in the lipoprotein-mediated distribution of lipids among tissues, APOE plays a critical role in plasma and tissues lipid homeostasis (PubMed:1917954, PubMed:2762297, PubMed:29516132).
APOE is also involved in two steps of reverse cholesterol transport, the HDLs-mediated transport of cholesterol from peripheral tissues to the liver, and thereby plays an important role in cholesterol homeostasis (PubMed:14754908, PubMed:23620513, PubMed:9395455).
First, it is functionally associated with ABCA1 in the biogenesis of HDLs in tissues (PubMed:14754908, PubMed:23620513).
Second, it is enriched in circulating HDLs and mediates their uptake by hepatocytes (PubMed:9395455).
APOE also plays an important role in lipid transport in the central nervous system, regulating neuron survival and sprouting (PubMed:25173806, PubMed:8939961).
APOE is also involved in innate and adaptive immune responses, controlling for instance the survival of myeloid-derived suppressor cells (By similarity).
Binds to the immune cell receptor LILRB4 (PubMed:30333625).
APOE may also play a role in transcription regulation through a receptor-dependent and cholesterol-independent mechanism, that activates MAP3K12 and a non-canonical MAPK signal transduction pathway that results in enhanced AP-1-mediated transcription of APP (PubMed:28111074).
APOE is a core component of plasma lipoproteins and is involved in their production, conversion and clearance (PubMed:14754908, PubMed:1911868, PubMed:1917954, PubMed:23620513, PubMed:2762297, PubMed:6860692, PubMed:9395455).
Apolipoproteins are amphipathic molecules that interact both with lipids of the lipoprotein particle core and the aqueous environment of the plasma (PubMed:2762297, PubMed:6860692, 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:1911868, PubMed:6860692).
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:12950167, PubMed:1530612, PubMed:1917954, PubMed:20030366, PubMed:20303980, PubMed:2063194, PubMed:2762297, PubMed:7635945, PubMed:7768901, PubMed:8756331, PubMed:8939961).
Finally, APOE has also a heparin-binding activity and binds heparan-sulfate proteoglycans on the surface of cells, a property that supports the capture and the receptor-mediated uptake of APOE-containing lipoproteins by cells (PubMed:23676495, PubMed:7635945, PubMed:9395455, PubMed:9488694).
A main function of APOE is to mediate lipoprotein clearance through the uptake of chylomicrons, VLDLs, and HDLs by hepatocytes (PubMed:1911868, PubMed:1917954, PubMed:23676495, PubMed:29516132, PubMed:9395455).
APOE is also involved in the biosynthesis by the liver of VLDLs as well as their uptake by peripheral tissues ensuring the delivery of triglycerides and energy storage in muscle, heart and adipose tissues (PubMed:2762297, PubMed:29516132).
By participating in the lipoprotein-mediated distribution of lipids among tissues, APOE plays a critical role in plasma and tissues lipid homeostasis (PubMed:1917954, PubMed:2762297, PubMed:29516132).
APOE is also involved in two steps of reverse cholesterol transport, the HDLs-mediated transport of cholesterol from peripheral tissues to the liver, and thereby plays an important role in cholesterol homeostasis (PubMed:14754908, PubMed:23620513, PubMed:9395455).
First, it is functionally associated with ABCA1 in the biogenesis of HDLs in tissues (PubMed:14754908, PubMed:23620513).
Second, it is enriched in circulating HDLs and mediates their uptake by hepatocytes (PubMed:9395455).
APOE also plays an important role in lipid transport in the central nervous system, regulating neuron survival and sprouting (PubMed:25173806, PubMed:8939961).
APOE is also involved in innate and adaptive immune responses, controlling for instance the survival of myeloid-derived suppressor cells (By similarity).
Binds to the immune cell receptor LILRB4 (PubMed:30333625).
APOE may also play a role in transcription regulation through a receptor-dependent and cholesterol-independent mechanism, that activates MAP3K12 and a non-canonical MAPK signal transduction pathway that results in enhanced AP-1-mediated transcription of APP (PubMed:28111074).
(Microbial infection) Through its interaction with HCV envelope glycoprotein E2, participates in the attachment of HCV to HSPGs and other receptors (LDLr, VLDLr, and SR-B1) on the cell surface and to the assembly, maturation and infectivity of HCV viral particles (PubMed:25122793, PubMed:29695434).
This interaction is probably promoted via the up-regulation of cellular autophagy by the virus (PubMed:29695434).
This interaction is probably promoted via the up-regulation of cellular autophagy by the virus (PubMed:29695434).
Miscellaneous
Binds to and activates LILRB4 on acute myeloid leukemia (AML) cells which leads to suppression of T cell proliferation and promotion of AML cell migration and infiltration.
Features
Showing features for binding site.
GO annotations
Keywords
- Molecular function
- Biological process
- Ligand
Enzyme and pathway databases
Protein family/group databases
Names & Taxonomy
Protein names
- Recommended nameApolipoprotein E
- Short namesApo-E
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionP02649
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
UniProt Annotation
GO Annotation
Note: In the plasma, APOE is associated with chylomicrons, chylomicrons remnants, VLDL, LDL and HDL lipoproteins (PubMed:1911868, PubMed:8340399).
Lipid poor oligomeric APOE is associated with the extracellular matrix in a calcium- and heparan-sulfate proteoglycans-dependent manner (PubMed:9488694).
Lipidation induces the release from the extracellular matrix (PubMed:9488694).
Colocalizes with CD63 and PMEL at exosomes and in intraluminal vesicles within multivesicular endosomes
Lipid poor oligomeric APOE is associated with the extracellular matrix in a calcium- and heparan-sulfate proteoglycans-dependent manner (PubMed:9488694).
Lipidation induces the release from the extracellular matrix (PubMed:9488694).
Colocalizes with CD63 and PMEL at exosomes and in intraluminal vesicles within multivesicular endosomes
Keywords
- Cellular component
Disease & Variants
Involvement in disease
Hyperlipoproteinemia 3 (HLPP3)
- Note
- DescriptionA disorder characterized by the accumulation of intermediate-density lipoprotein particles (IDL or broad-beta-lipoprotein) rich in cholesterol. Clinical features include xanthomas, yellowish lipid deposits in the palmar crease, or less specific on tendons and on elbows. The disorder rarely manifests before the third decade in men. In women, it is usually expressed only after the menopause.
- See alsoMIM:617347
Natural variants in HLPP3
Variant ID | Position(s) | Change | Description | |
---|---|---|---|---|
VAR_000646 | 31 | E>K | in HLPP3; ApoE4 Philadelphia, ApoE5 French-Canadian and ApoE5-type; only ApoE4 Philadelphia is associated with HLPP3; dbSNP:rs201672011 | |
VAR_000652 | 130 | C>R | in HLPP3 and AD2; ApoE4, ApoE3 Leiden, ApoE3**, ApoE5-Frankfurt and ApoE5-type; ApoE3 Leiden and ApoE3** are associated with HLPP3; ApoE4 is associated with AD2; changed protein structure; no effect on binding to LDL receptor; decreased association with HDL and enrichment in VLDL and IDL; may prevent the interaction with MAP2 and MAPT; changed interaction with APP/A4 amyloid-beta peptide; increased ability to induce APP transcription; increased C-terminal proteolytic processing in neurons; decreased function in neurite outgrowth; ApoE4 is associated with higher susceptibility to SARS-CoV-2 infection in neurons and astrocytes; dbSNP:rs429358 | |
VAR_000654 | 145 | G>GEVQAMLG | in HLPP3; ApoE3 Leiden; no effect on glycosylation | |
VAR_000657 | 154 | R>C | in HLPP3; ApoE2-type; dbSNP:rs121918393 | |
VAR_000656 | 154 | R>S | in HLPP3; ApoE2 Christchurch; decreased binding to LDL receptor; dbSNP:rs121918393 | |
VAR_000658 | 160 | R>C | in HLPP3; ApoE3**; dbSNP:rs387906567 | |
VAR_000659 | 163 | R>C | in HLPP3; also found in a patient with hypercholesterolemia; ApoE4 Philadelphia and ApoE2-type; dbSNP:rs769455 | |
VAR_000660 | 163 | R>H | in HLPP3; uncertain significance; ApoEKochi; dbSNP:rs121918397 | |
VAR_000662 | 164 | K>E | in HLPP3; ApoE1 Harrisburg; decreased binding to LDL receptor; probable dominant negative effect; decreased in vitro binding to heparin; dbSNP:rs121918394 | |
VAR_000661 | 164 | K>Q | in HLPP3; ApoE2**; dbSNP:rs121918394 | |
VAR_000664 | 176 | R>C | in HLPP3; ApoE2, ApoE2 Fukuoka, ApoE1 Weisgraber and ApoE3**; ApoE3** is associated with HLPP3; changed protein structure; decreased binding to LDLR and other lipoprotein receptors; decreased in vitro binding to heparin; no effect on distribution among plasma lipoproteins; dbSNP:rs7412 | |
VAR_081136 | 228-317 | missing | in HLPP3; ApoE3 Washington | |
VAR_000668 | 262-263 | EE>KK | in HLPP3; ApoE7 Suita |
Alzheimer disease 2 (AD2)
- Note
- DescriptionA late-onset form of Alzheimer disease. Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituents of these plaques are neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42, that are produced by the proteolysis of the transmembrane APP protein. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products, such as C31, are also implicated in neuronal death.
- See alsoMIM:104310
Natural variants in AD2
Variant ID | Position(s) | Change | Description | |
---|---|---|---|---|
VAR_000652 | 130 | C>R | in HLPP3 and AD2; ApoE4, ApoE3 Leiden, ApoE3**, ApoE5-Frankfurt and ApoE5-type; ApoE3 Leiden and ApoE3** are associated with HLPP3; ApoE4 is associated with AD2; changed protein structure; no effect on binding to LDL receptor; decreased association with HDL and enrichment in VLDL and IDL; may prevent the interaction with MAP2 and MAPT; changed interaction with APP/A4 amyloid-beta peptide; increased ability to induce APP transcription; increased C-terminal proteolytic processing in neurons; decreased function in neurite outgrowth; ApoE4 is associated with higher susceptibility to SARS-CoV-2 infection in neurons and astrocytes; dbSNP:rs429358 |
Sea-blue histiocyte disease (SBHD)
- Note
- DescriptionCharacterized by splenomegaly, mild thrombocytopenia and, in the bone marrow, numerous histiocytes containing cytoplasmic granules which stain bright blue with the usual hematologic stains. The syndrome is the consequence of an inherited metabolic defect analogous to Gaucher disease and other sphingolipidoses.
- See alsoMIM:269600
Natural variants in SBHD
Variant ID | Position(s) | Change | Description | |
---|---|---|---|---|
VAR_035015 | 167 | missing | in SBHD; also found in patients with a diagnosis of familial combined hyperlipidemia |
Lipoprotein glomerulopathy (LPG)
- Note
- DescriptionUncommon kidney disease characterized by proteinuria, progressive kidney failure, and distinctive lipoprotein thrombi in glomerular capillaries.
- See alsoMIM:611771
Natural variants in LPG
Variant ID | Position(s) | Change | Description | |
---|---|---|---|---|
VAR_042734 | 43 | R>C | in LPG; ApoE2 Kyoto; dbSNP:rs121918399 | |
VAR_042735 | 163 | R>P | in LPG; ApoE2 Sendai; decreased binding to LDL receptor; induces intraglomerular deposition of ApoE-containing lipoproteins; dbSNP:rs121918397 |
Features
Showing features for natural variant, mutagenesis.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Natural variant | VAR_000645 | 21 | in ApoE5; associated with hyperlipoproteinemia and atherosclerosis; increased binding to LDL receptor; dbSNP:rs121918392 | |||
Sequence: E → K | ||||||
Natural variant | VAR_000646 | 31 | in HLPP3; ApoE4 Philadelphia, ApoE5 French-Canadian and ApoE5-type; only ApoE4 Philadelphia is associated with HLPP3; dbSNP:rs201672011 | |||
Sequence: E → K | ||||||
Natural variant | VAR_042734 | 43 | in LPG; ApoE2 Kyoto; dbSNP:rs121918399 | |||
Sequence: R → C | ||||||
Natural variant | VAR_000647 | 46 | found in a patient with hypercholesterolemia; uncertain significance; ApoE4 Freiburg; dbSNP:rs769452 | |||
Sequence: L → P | ||||||
Natural variant | VAR_000648 | 60 | in ApoE3 Freiburg; dbSNP:rs28931576 | |||
Sequence: T → A | ||||||
Natural variant | VAR_014114 | 64 | confirmed at protein level; dbSNP:rs370594287 | |||
Sequence: Q → H | ||||||
Mutagenesis | 79 | Changes the plasma lipoprotein distribution of ApoE4 to the HDL. | ||||
Sequence: R → T | ||||||
Natural variant | VAR_000649 | 99 | in ApoE5 Frankfurt; dbSNP:rs1180612218 | |||
Sequence: Q → K | ||||||
Natural variant | VAR_000650 | 102 | in ApoE5-type; no hyperlipidemia; dbSNP:rs11083750 | |||
Sequence: P → R | ||||||
Natural variant | VAR_000651 | 117 | in ApoE3*; dbSNP:rs28931577 | |||
Sequence: A → T | ||||||
Natural variant | VAR_016789 | 124 | in ApoE3 Basel; dbSNP:rs937063425 | |||
Sequence: A → V | ||||||
Mutagenesis | 127 | No effect on plasma lipoprotein distribution. | ||||
Sequence: E → A | ||||||
Natural variant | VAR_000652 | 130 | in HLPP3 and AD2; ApoE4, ApoE3 Leiden, ApoE3**, ApoE5-Frankfurt and ApoE5-type; ApoE3 Leiden and ApoE3** are associated with HLPP3; ApoE4 is associated with AD2; changed protein structure; no effect on binding to LDL receptor; decreased association with HDL and enrichment in VLDL and IDL; may prevent the interaction with MAP2 and MAPT; changed interaction with APP/A4 amyloid-beta peptide; increased ability to induce APP transcription; increased C-terminal proteolytic processing in neurons; decreased function in neurite outgrowth; ApoE4 is associated with higher susceptibility to SARS-CoV-2 infection in neurons and astrocytes; dbSNP:rs429358 | |||
Sequence: C → R | ||||||
Natural variant | VAR_000653 | 145 | found in a patient with hypercholesterolemia; uncertain significance; ApoE1 Weisgraber; dbSNP:rs267606664 | |||
Sequence: G → D | ||||||
Natural variant | VAR_000654 | 145 | in HLPP3; ApoE3 Leiden; no effect on glycosylation | |||
Sequence: G → GEVQAMLG | ||||||
Natural variant | VAR_000655 | 152 | in ApoE2-type; no hyperlipidemia; dbSNP:rs28931578 | |||
Sequence: R → Q | ||||||
Natural variant | VAR_000657 | 154 | in HLPP3; ApoE2-type; dbSNP:rs121918393 | |||
Sequence: R → C | ||||||
Natural variant | VAR_000656 | 154 | in HLPP3; ApoE2 Christchurch; decreased binding to LDL receptor; dbSNP:rs121918393 | |||
Sequence: R → S | ||||||
Mutagenesis | 157 | Increased binding to LDL receptor; when associated with A-167. | ||||
Sequence: S → R | ||||||
Mutagenesis | 158 | Decreased binding to LDL receptor. | ||||
Sequence: H → A | ||||||
Natural variant | VAR_000658 | 160 | in HLPP3; ApoE3**; dbSNP:rs387906567 | |||
Sequence: R → C | ||||||
Mutagenesis | 161 | Decreased binding to LDL receptor. | ||||
Sequence: K → A | ||||||
Mutagenesis | 162 | Decreased binding to LDL receptor. | ||||
Sequence: L → P | ||||||
Natural variant | VAR_000659 | 163 | in HLPP3; also found in a patient with hypercholesterolemia; ApoE4 Philadelphia and ApoE2-type; dbSNP:rs769455 | |||
Sequence: R → C | ||||||
Natural variant | VAR_000660 | 163 | in HLPP3; uncertain significance; ApoEKochi; dbSNP:rs121918397 | |||
Sequence: R → H | ||||||
Natural variant | VAR_042735 | 163 | in LPG; ApoE2 Sendai; decreased binding to LDL receptor; induces intraglomerular deposition of ApoE-containing lipoproteins; dbSNP:rs121918397 | |||
Sequence: R → P | ||||||
Natural variant | VAR_000662 | 164 | in HLPP3; ApoE1 Harrisburg; decreased binding to LDL receptor; probable dominant negative effect; decreased in vitro binding to heparin; dbSNP:rs121918394 | |||
Sequence: K → E | ||||||
Natural variant | VAR_000661 | 164 | in HLPP3; ApoE2**; dbSNP:rs121918394 | |||
Sequence: K → Q | ||||||
Natural variant | VAR_035015 | 167 | in SBHD; also found in patients with a diagnosis of familial combined hyperlipidemia | |||
Sequence: Missing | ||||||
Mutagenesis | 167 | Increased binding to LDL receptor; when associated with R-157. | ||||
Sequence: L → A | ||||||
Mutagenesis | 168 | Decreased binding to LDL receptor. | ||||
Sequence: R → A | ||||||
Natural variant | VAR_000663 | 170 | in ApoE3*; decreased binding to LDL receptor; dbSNP:rs267606662 | |||
Sequence: A → P | ||||||
Mutagenesis | 172 | Restores the LDL receptor binding activity of ApoE2. | ||||
Sequence: D → A | ||||||
Natural variant | VAR_000664 | 176 | in HLPP3; ApoE2, ApoE2 Fukuoka, ApoE1 Weisgraber and ApoE3**; ApoE3** is associated with HLPP3; changed protein structure; decreased binding to LDLR and other lipoprotein receptors; decreased in vitro binding to heparin; no effect on distribution among plasma lipoproteins; dbSNP:rs7412 | |||
Sequence: R → C | ||||||
Mutagenesis | 212 | Loss of O-glycosylation. | ||||
Sequence: T → A | ||||||
Natural variant | VAR_081136 | 228-317 | in HLPP3; ApoE3 Washington | |||
Sequence: Missing | ||||||
Natural variant | VAR_000665 | 242 | in ApoE2 Fukuoka; dbSNP:rs267606663 | |||
Sequence: R → Q | ||||||
Natural variant | VAR_000666 | 246 | in ApoE2 Dunedin; dbSNP:rs121918395 | |||
Sequence: R → C | ||||||
Natural variant | VAR_000667 | 254 | in ApoE2 WG; dbSNP:rs199768005 | |||
Sequence: V → E | ||||||
Natural variant | VAR_000668 | 262-263 | in HLPP3; ApoE7 Suita | |||
Sequence: EE → KK | ||||||
Natural variant | VAR_000669 | 269 | in ApoE3 HB; dbSNP:rs267606661 | |||
Sequence: R → G | ||||||
Natural variant | VAR_000670 | 270 | in ApoE1 HE; requires 2 nucleotide substitutions | |||
Sequence: L → E | ||||||
Natural variant | VAR_000671 | 292 | in ApoE4 PD; dbSNP:rs121918398 | |||
Sequence: R → H | ||||||
Natural variant | VAR_000672 | 314 | in ApoE4 HG; dbSNP:rs28931579 | |||
Sequence: S → R |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 502 variants from UniProt as well as other sources including ClinVar and dbSNP.
Keywords
- Disease
Organism-specific databases
Miscellaneous
Chemistry
Genetic variation databases
PTM/Processing
Features
Showing features for signal, chain, glycosylation, modified residue, modified residue (large scale data).
Type | ID | Position(s) | Source | Description | |||
---|---|---|---|---|---|---|---|
Signal | 1-18 | UniProt | |||||
Sequence: MKVLWAALLVTFLAGCQA | |||||||
Chain | PRO_0000001987 | 19-317 | UniProt | Apolipoprotein E | |||
Sequence: KVEQAVETEPEPELRQQTEWQSGQRWELALGRFWDYLRWVQTLSEQVQEELLSSQVTQELRALMDETMKELKAYKSELEEQLTPVAEETRARLSKELQAAQARLGADMEDVCGRLVQYRGEVQAMLGQSTEELRVRLASHLRKLRKRLLRDADDLQKRLAVYQAGAREGAERGLSAIRERLGPLVEQGRVRAATVGSLAGQPLQERAQAWGERLRARMEEMGSRTRDRLDEVKEQVAEVRAKLEEQAQQIRLQAEAFQARLKSWFEPLVEDMQRQWAGLVEKVQAAVGTSAAPVPSDNH | |||||||
Glycosylation | 26 | UniProt | O-linked (GalNAc...) threonine | ||||
Sequence: T | |||||||
Glycosylation | 36 | UniProt | O-linked (GalNAc...) threonine | ||||
Sequence: T | |||||||
Glycosylation | 93 | UniProt | N-linked (Glc) (glycation) lysine | ||||
Sequence: K | |||||||
Modified residue | 143 | UniProt | Methionine sulfoxide | ||||
Sequence: M | |||||||
Modified residue | 147 | UniProt | Phosphoserine; by FAM20C | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 147 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 148 | PRIDE | Phosphothreonine | ||||
Sequence: T | |||||||
Glycosylation | 212 | UniProt | O-linked (GalNAc...) threonine | ||||
Sequence: T | |||||||
Glycosylation | 307 | UniProt | O-linked (GalNAc...) threonine | ||||
Sequence: T | |||||||
Glycosylation | 308 | UniProt | O-linked (GalNAc...) serine | ||||
Sequence: S | |||||||
Glycosylation | 314 | UniProt | O-linked (GalNAc...) serine | ||||
Sequence: S |
Post-translational modification
APOE exists as multiple glycosylated and sialylated glycoforms within cells and in plasma (PubMed:29516132).
The extent of glycosylation and sialylation are tissue and context specific (PubMed:29516132).
Plasma APOE undergoes desialylation and is less glycosylated and sialylated than the cellular form (PubMed:19838169, PubMed:20511397, PubMed:23234360, PubMed:2498325).
Glycosylation is not required for proper expression and secretion (PubMed:2498325).
O-glycosylated with core 1 or possibly core 8 glycans. Thr-307 and Ser-314 are minor glycosylation sites compared to Ser-308 (PubMed:19838169, PubMed:23234360).
The extent of glycosylation and sialylation are tissue and context specific (PubMed:29516132).
Plasma APOE undergoes desialylation and is less glycosylated and sialylated than the cellular form (PubMed:19838169, PubMed:20511397, PubMed:23234360, PubMed:2498325).
Glycosylation is not required for proper expression and secretion (PubMed:2498325).
O-glycosylated with core 1 or possibly core 8 glycans. Thr-307 and Ser-314 are minor glycosylation sites compared to Ser-308 (PubMed:19838169, PubMed:23234360).
Glycated in plasma VLDL of normal subjects, and of hyperglycemic diabetic patients at a higher level (2-3 fold).
Phosphorylated by FAM20C in the extracellular medium.
Undergoes C-terminal proteolytic processing in neurons. C-terminally truncated APOE has a tendency to form neurotoxic intracellular neurofibrillary tangle-like inclusions in neurons.
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Tissue specificity
Produced by several tissues and cell types and mainly found associated with lipid particles in the plasma, the interstitial fluid and lymph (PubMed:25173806).
Mainly synthesized by liver hepatocytes (PubMed:25173806).
Significant quantities are also produced in brain, mainly by astrocytes and glial cells in the cerebral cortex, but also by neurons in frontal cortex and hippocampus (PubMed:10027417, PubMed:3115992).
It is also expressed by cells of the peripheral nervous system (PubMed:10027417, PubMed:25173806).
Also expressed by adrenal gland, testis, ovary, skin, kidney, spleen and adipose tissue and macrophages in various tissues (PubMed:25173806).
Mainly synthesized by liver hepatocytes (PubMed:25173806).
Significant quantities are also produced in brain, mainly by astrocytes and glial cells in the cerebral cortex, but also by neurons in frontal cortex and hippocampus (PubMed:10027417, PubMed:3115992).
It is also expressed by cells of the peripheral nervous system (PubMed:10027417, PubMed:25173806).
Also expressed by adrenal gland, testis, ovary, skin, kidney, spleen and adipose tissue and macrophages in various tissues (PubMed:25173806).
Gene expression databases
Organism-specific databases
Interaction
Subunit
Homotetramer (PubMed:8340399).
May interact with ABCA1; functionally associated with ABCA1 in the biogenesis of HDLs (PubMed:14754908).
May interact with APP/A4 amyloid-beta peptide; the interaction is extremely stable in vitro but its physiological significance is unclear (PubMed:23620513, PubMed:8367470).
May interact with MAPT (PubMed:7972031).
May interact with MAP2 (PubMed:7891887).
In the cerebrospinal fluid, interacts with secreted SORL1 (PubMed:30448281).
Interacts with PMEL; this allows the loading of PMEL luminal fragment on ILVs to induce fibril nucleation
May interact with ABCA1; functionally associated with ABCA1 in the biogenesis of HDLs (PubMed:14754908).
May interact with APP/A4 amyloid-beta peptide; the interaction is extremely stable in vitro but its physiological significance is unclear (PubMed:23620513, PubMed:8367470).
May interact with MAPT (PubMed:7972031).
May interact with MAP2 (PubMed:7891887).
In the cerebrospinal fluid, interacts with secreted SORL1 (PubMed:30448281).
Interacts with PMEL; this allows the loading of PMEL luminal fragment on ILVs to induce fibril nucleation
(Microbial infection) Interacts with hepatitis C virus (HCV) envelope glycoprotein E2; this interaction is required for HCV infectivity and production.
Binary interactions
Protein-protein interaction databases
Miscellaneous
Structure
Family & Domains
Features
Showing features for repeat, region.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Repeat | 80-101 | 1 | ||||
Sequence: ALMDETMKELKAYKSELEEQLT | ||||||
Region | 80-255 | 8 X 22 AA approximate tandem repeats | ||||
Sequence: ALMDETMKELKAYKSELEEQLTPVAEETRARLSKELQAAQARLGADMEDVCGRLVQYRGEVQAMLGQSTEELRVRLASHLRKLRKRLLRDADDLQKRLAVYQAGAREGAERGLSAIRERLGPLVEQGRVRAATVGSLAGQPLQERAQAWGERLRARMEEMGSRTRDRLDEVKEQVA | ||||||
Repeat | 102-123 | 2 | ||||
Sequence: PVAEETRARLSKELQAAQARLG | ||||||
Repeat | 124-145 | 3 | ||||
Sequence: ADMEDVCGRLVQYRGEVQAMLG | ||||||
Repeat | 146-167 | 4 | ||||
Sequence: QSTEELRVRLASHLRKLRKRLL | ||||||
Region | 158-168 | LDL and other lipoprotein receptors binding | ||||
Sequence: HLRKLRKRLLR | ||||||
Repeat | 168-189 | 5 | ||||
Sequence: RDADDLQKRLAVYQAGAREGAE | ||||||
Repeat | 190-211 | 6 | ||||
Sequence: RGLSAIRERLGPLVEQGRVRAA | ||||||
Region | 210-290 | Lipid-binding and lipoprotein association | ||||
Sequence: AATVGSLAGQPLQERAQAWGERLRARMEEMGSRTRDRLDEVKEQVAEVRAKLEEQAQQIRLQAEAFQARLKSWFEPLVEDM | ||||||
Repeat | 212-233 | 7 | ||||
Sequence: TVGSLAGQPLQERAQAWGERLR | ||||||
Repeat | 234-255 | 8 | ||||
Sequence: ARMEEMGSRTRDRLDEVKEQVA | ||||||
Region | 266-317 | Homooligomerization | ||||
Sequence: QQIRLQAEAFQARLKSWFEPLVEDMQRQWAGLVEKVQAAVGTSAAPVPSDNH | ||||||
Region | 278-290 | Specificity for association with VLDL | ||||
Sequence: RLKSWFEPLVEDM |
Sequence similarities
Belongs to the apolipoprotein A1/A4/E family.
Keywords
- Domain
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Sequence processingThe displayed sequence is further processed into a mature form.
- Length317
- Mass (Da)36,154
- Last updated1986-07-21 v1
- Checksum91AFC04210A30689
Computationally mapped potential isoform sequences
There are 3 potential isoforms mapped to this entry
Polymorphism
There are three common APOE alleles identified: APOE*2/APOE-epsilon2/E2, APOE*3/APOE-epsilon3/E3, and APOE*4/APOE-epsilon4/E4. The corresponding ApoE2, ApoE3 and ApoE4 isoforms differentially present Cys and Arg residues at positions 130 and 176. The most common allele in the human population is APOE*3 which sequence is the one displayed in that entry with a Cys at position 130 and an Arg at position 176. Common APOE variants influence lipoprotein metabolism in healthy individuals. Additional variants have been described and are described relative to the three common alleles. Allele APOE*4 is strongly associated with risk for severe COVID-19, increases susceptibility to SARS-CoV-2 infection in neurons and astrocytes (PubMed:33450186).
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
M12529 EMBL· GenBank· DDBJ | AAB59518.1 EMBL· GenBank· DDBJ | mRNA | ||
K00396 EMBL· GenBank· DDBJ | AAB59546.1 EMBL· GenBank· DDBJ | mRNA | ||
M10065 EMBL· GenBank· DDBJ | AAB59397.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AF050154 EMBL· GenBank· DDBJ | AAD02505.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AF261279 EMBL· GenBank· DDBJ | AAG27089.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AK314898 EMBL· GenBank· DDBJ | BAG37412.1 EMBL· GenBank· DDBJ | mRNA | ||
FJ525876 EMBL· GenBank· DDBJ | ACN81314.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
BC003557 EMBL· GenBank· DDBJ | AAH03557.1 EMBL· GenBank· DDBJ | mRNA | ||
AB035149 EMBL· GenBank· DDBJ | BAA96080.1 EMBL· GenBank· DDBJ | Genomic DNA |