P02649 (APOE_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Apolipoprotein E
Short name=Apo-E

Gene names

Name:

APOE

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	317 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Mediates the binding, internalization, and catabolism of lipoprotein particles. It can serve as a ligand for the LDL (apo B/E) receptor and for the specific apo-E receptor (chylomicron remnant) of hepatic tissues.
Subcellular location	Secreted.
Tissue specificity	Occurs in all lipoprotein fractions in plasma. It constitutes 10-20% of very low density lipoproteins (VLDL) and 1-2% of high density lipoproteins (HDL). APOE is produced in most organs. Significant quantities are produced in liver, brain, spleen, lung, adrenal, ovary, kidney and muscle.
Post-translational modification	Synthesized with the sialic acid attached by O-glycosidic linkage and is subsequently desialylated in plasma. O-glycosylated with core 1 or possibly core 8 glycans. Thr-307 and Thr-314 are minor glycosylation siteS compared to Ser-308. Ref.20 Glycated in plasma VLDL of normal subjects, and of hyperglycemic diabetic patients at a higher level (2-3 fold). Phosphorylation sites are present in the extracellular medium.
Polymorphism	Three common APOE alleles have been identified: APOE*2, APOE*3, and APOE*4. The corresponding three major isoforms, E2, E3, and E4, are recognized according to their relative position after isoelectric focusing. Different mutations causing the same migration pattern after isoelectric focusing define different isoform subtypes. The most common isoform is E3 and is present in 40-90% of the population. Common APOE variants influence lipoprotein metabolism in healthy individuals.
Involvement in disease	Hyperlipoproteinemia 3 (HLPP3) [MIM:107741]: A 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. Note: The disease is caused by mutations affecting the gene represented in this entry. The vast majority of the patients are homozygous for APOE*2 alleles. More severe cases of HLPP3 have also been observed in individuals heterozygous for rare APOE variants. The influence of APOE on lipid levels is often suggested to have major implications for the risk of coronary artery disease (CAD). Individuals carrying the common APOE*4 variant are at higher risk of CAD. Ref.16 Ref.26 Ref.27 Ref.29 Ref.39 Alzheimer disease 2 (AD2) [MIM:104310]: A late-onset 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 constituent of these plaques is the neurotoxic amyloid-beta-APP 40-42 peptide (s), derived proteolytically from the transmembrane precursor protein APP by sequential secretase processing. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products such as C31 derived from APP, are also implicated in neuronal death. Note: Disease susceptibility is associated with variations affecting the gene represented in this entry. The APOE*4 allele is genetically associated with the common late onset familial and sporadic forms of Alzheimer disease. Risk for AD increased from 20% to 90% and mean age at onset decreased from 84 to 68 years with increasing number of APOE*4 alleles in 42 families with late onset AD. Thus APOE*4 gene dose is a major risk factor for late onset AD and, in these families, homozygosity for APOE*4 was virtually sufficient to cause AD by age 80. The mechanism by which APOE*4 participates in pathogenesis is not known. Ref.16 Sea-blue histiocyte disease (SBHD) [MIM:269600]: Characterized 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. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.16 Ref.33 Ref.36 Lipoprotein glomerulopathy (LPG) [MIM:611771]: Uncommon kidney disease characterized by proteinuria, progressive kidney failure, and distinctive lipoprotein thrombi in glomerular capillaries. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.16 Ref.30 Ref.32 Ref.37 Familial hypercholesterolemia (FH) [MIM:143890]: Common autosomal semi-dominant disease that affects about 1 in 500 individuals. The receptor defect impairs the catabolism of LDL, and the resultant elevation in plasma LDL-cholesterol promotes deposition of cholesterol in the skin (xanthelasma), tendons (xanthomas), and coronary arteries (atherosclerosis). Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.16 Ref.40
Sequence similarities	Belongs to the apolipoprotein A1/A4/E family.

Ontologies

Keywords
Biological process	Cholesterol metabolism Lipid metabolism Lipid transport Steroid metabolism Sterol metabolism Transport
Cellular component	Chylomicron HDL Secreted VLDL
Coding sequence diversity	Polymorphism
Disease	Alzheimer disease Amyloidosis Disease mutation Hyperlipidemia Neurodegeneration
Domain	Repeat Signal
Ligand	Heparin-binding
PTM	Glycation Glycoprotein Phosphoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	G-protein coupled receptor signaling pathway Inferred from direct assay PubMed 16443932. Source: BHF-UCL aging Inferred from electronic annotation. Source: Compara artery morphogenesis Inferred from electronic annotation. Source: Compara cGMP-mediated signaling Inferred from direct assay PubMed 8995232. Source: BHF-UCL cell death Inferred from electronic annotation. Source: UniProtKB-KW cellular calcium ion homeostasis Inferred from electronic annotation. Source: Compara cellular response to cholesterol Inferred from electronic annotation. Source: Compara cellular response to growth factor stimulus Inferred from electronic annotation. Source: Compara cellular response to interleukin-1 Inferred from electronic annotation. Source: Compara cholesterol catabolic process Inferred from electronic annotation. Source: Compara cholesterol efflux Inferred from direct assay PubMed 11162594PubMed 16443932. Source: BHF-UCL cholesterol homeostasis Inferred from direct assay PubMed 9649566. Source: BHF-UCL cholesterol metabolic process Inferred from direct assay PubMed 9649566. Source: BHF-UCL chylomicron remnant clearance Inferred from mutant phenotype PubMed 7175379. Source: BHF-UCL cytoskeleton organization Traceable author statement PubMed 9622609. Source: UniProtKB high-density lipoprotein particle assembly Inferred from direct assay PubMed 17305370. Source: BHF-UCL high-density lipoprotein particle clearance Inferred from direct assay PubMed 210175. Source: BHF-UCL high-density lipoprotein particle remodeling Inferred from genetic interaction PubMed 12401887. Source: BHF-UCL induction of apoptosis Inferred from direct assay PubMed 12753088. Source: UniProtKB intracellular transport Traceable author statement PubMed 9622609. Source: UniProtKB lipoprotein biosynthetic process Inferred from electronic annotation. Source: Compara lipoprotein catabolic process Inferred from electronic annotation. Source: Compara lipoprotein metabolic process Traceable author statement. Source: Reactome low-density lipoprotein particle remodeling Inferred from electronic annotation. Source: Compara maintenance of location in cell Inferred from electronic annotation. Source: Compara negative regulation of MAP kinase activity Inferred from direct assay PubMed 9685360. Source: BHF-UCL negative regulation of apoptotic process Inferred from direct assay PubMed 9685360. Source: BHF-UCL negative regulation of blood vessel endothelial cell migration Inferred from direct assay PubMed 9685360. Source: BHF-UCL negative regulation of cholesterol biosynthetic process Inferred from direct assay PubMed 1917954. Source: BHF-UCL negative regulation of endothelial cell proliferation Inferred from direct assay PubMed 9685360. Source: BHF-UCL negative regulation of inflammatory response Inferred by curator PubMed 8995232. Source: BHF-UCL negative regulation of neuron apoptotic process Inferred from electronic annotation. Source: Compara negative regulation of platelet activation Inferred from direct assay PubMed 8995232. Source: BHF-UCL nitric oxide mediated signal transduction Inferred from direct assay PubMed 8995232. Source: BHF-UCL oligodendrocyte differentiation Inferred from electronic annotation. Source: Compara peripheral nervous system axon regeneration Inferred from electronic annotation. Source: Compara phospholipid efflux Inferred from direct assay PubMed 11162594. Source: BHF-UCL positive regulation of axon extension Inferred from electronic annotation. Source: Compara positive regulation of cGMP biosynthetic process Inferred from direct assay PubMed 8995232. Source: BHF-UCL positive regulation of cholesterol efflux Inferred from direct assay PubMed 14754908. Source: BHF-UCL positive regulation of cholesterol esterification Inferred from direct assay PubMed 15654758. Source: BHF-UCL positive regulation of low-density lipoprotein particle receptor catabolic process Inferred from direct assay PubMed 15950758. Source: BHF-UCL positive regulation of membrane protein ectodomain proteolysis Inferred from direct assay PubMed 15950758. Source: BHF-UCL positive regulation of nitric-oxide synthase activity Inferred from direct assay PubMed 8995232. Source: BHF-UCL receptor-mediated endocytosis Inferred from direct assay PubMed 1917954. Source: BHF-UCL regulation of Cdc42 protein signal transduction Inferred from direct assay PubMed 16443932. Source: BHF-UCL regulation of axon extension Traceable author statement PubMed 9622609. Source: UniProtKB regulation of gene expression Inferred from electronic annotation. Source: Compara regulation of neuronal synaptic plasticity Traceable author statement PubMed 9622609. Source: UniProtKB response to dietary excess Inferred from electronic annotation. Source: Compara response to ethanol Inferred from electronic annotation. Source: Compara response to insulin stimulus Inferred from electronic annotation. Source: Compara response to reactive oxygen species Non-traceable author statement PubMed 11743999. Source: UniProtKB response to retinoic acid Inferred from electronic annotation. Source: Compara reverse cholesterol transport Inferred from direct assay PubMed 8127890. Source: BHF-UCL synaptic transmission, cholinergic Traceable author statement PubMed 9622609. Source: UniProtKB triglyceride metabolic process Inferred from direct assay PubMed 9649566. Source: BHF-UCL vasodilation Inferred from electronic annotation. Source: Compara very-low-density lipoprotein particle clearance Inferred from direct assay PubMed 1917954. Source: BHF-UCL very-low-density lipoprotein particle remodeling Inferred from direct assay PubMed 15654758. Source: BHF-UCL
Cellular_component	Golgi apparatus Inferred from electronic annotation. Source: Compara chylomicron Inferred from direct assay PubMed 16935699PubMed 8245722. Source: BHF-UCL cytoplasm Traceable author statement PubMed 9622609. Source: UniProtKB dendrite Non-traceable author statement PubMed 8083695. Source: BHF-UCL extrinsic to external side of plasma membrane Inferred from electronic annotation. Source: Compara high-density lipoprotein particle Inferred from direct assay PubMed 210174. Source: BHF-UCL intermediate-density lipoprotein particle Inferred from direct assay PubMed 17336988. Source: BHF-UCL late endosome Inferred from electronic annotation. Source: Compara low-density lipoprotein particle Inferred from direct assay PubMed 8245722. Source: BHF-UCL neuronal cell body Non-traceable author statement PubMed 8083695. Source: BHF-UCL plasma membrane Traceable author statement. Source: Reactome very-low-density lipoprotein particle Inferred from direct assay PubMed 17154273PubMed 8245722. Source: BHF-UCL
Molecular_function	antioxidant activity Inferred from direct assay PubMed 9685360. Source: BHF-UCL beta-amyloid binding Inferred from direct assay PubMed 11305869. Source: UniProtKB cholesterol transporter activity Inferred from electronic annotation. Source: Compara heparin binding Inferred from direct assay PubMed 2745454. Source: BHF-UCL hydroxyapatite binding Inferred from electronic annotation. Source: Compara lipid transporter activity Inferred from direct assay PubMed 17305370. Source: BHF-UCL lipoprotein particle binding Inferred from electronic annotation. Source: Compara low-density lipoprotein particle receptor binding Inferred from direct assay PubMed 210175. Source: BHF-UCL metal chelating activity Inferred from direct assay PubMed 9685360. Source: BHF-UCL phosphatidylcholine-sterol O-acyltransferase activator activity Inferred from direct assay PubMed 15654758. Source: BHF-UCL phospholipid binding Inferred from direct assay PubMed 4066713. Source: BHF-UCL protein homodimerization activity Inferred from direct assay PubMed 8245722. Source: BHF-UCL very-low-density lipoprotein particle receptor binding Inferred from direct assay PubMed 1384047. Source: BHF-UCL
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
CDC37	Q16543	3	EBI-1222467,EBI-295634
ECSIT	Q9BQ95	4	EBI-1222467,EBI-712452
PDCD4	Q53EL6	3	EBI-1222467,EBI-935824
ST13	P50502	3	EBI-1222467,EBI-357285
TMCC2	O75069	5	EBI-1222467,EBI-726731

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 18

18

Ref.13

Chain

19 – 317

299

Apolipoprotein E

PRO_0000001987

Regions

Repeat

80 – 101

22

1

Repeat

102 – 123

22

2

Repeat

124 – 145

22

3

Repeat

146 – 167

22

4

Repeat

168 – 189

22

5

Repeat

190 – 211

22

6

Repeat

212 – 233

22

7

Repeat

234 – 255

22

8

Region

80 – 255

176

8 X 22 AA approximate tandem repeats

Region

158 – 168

11

LDL receptor binding Potential

Region

162 – 165

4

Heparin-binding

Region

229 – 236

8

Heparin-binding

Amino acid modifications

Glycosylation

26

1

O-linked (GalNAc...) Ref.20

Glycosylation

36

1

O-linked (GalNAc...) Ref.20

Glycosylation

93

1

N-linked (Glc) (glycation) Ref.17

Glycosylation

212

1

O-linked (GalNAc...) Ref.18

Glycosylation

307

1

O-linked (GalNAc...) Ref.18

Glycosylation

308

1

O-linked (GalNAc...) Ref.18

Glycosylation

314

1

O-linked (GalNAc...) Ref.20

Natural variations

Natural variant

21

1

E → K in isoform E5; associated with hyperlipoproteinemia and atherosclerosis. Ref.25

VAR_000645

Natural variant

31

1

E → K in HLPP3; isoforms E4 Philadelphia and isoform E5-type; only isoform E4 Philadelphia is disease-linked. Ref.27

VAR_000646

Natural variant

43

1

R → C in LPG; isoform E2 Kyoto. Ref.32 Ref.37

VAR_042734

Natural variant

46

1

L → P in isoform E4 Freiburg. Ref.6
Corresponds to variant rs769452 [ dbSNP | Ensembl ].

VAR_000647

Natural variant

60

1

T → A in isoform E3 Freiburg.
Corresponds to variant rs28931576 [ dbSNP | Ensembl ].

VAR_000648

Natural variant

64

1

Q → H Polymorphism confirmed at protein level. Ref.10 Ref.38

VAR_014114

Natural variant

99

1

Q → K in isoform E5 Frankfurt.

VAR_000649

Natural variant

102

1

P → R in isoform E5-type; no hyperlipidemia.
Corresponds to variant rs28931578 [ dbSNP | Ensembl ].

VAR_000650

Natural variant

117

1

A → T in isoform E3*.
Corresponds to variant rs28931577 [ dbSNP | Ensembl ].

VAR_000651

Natural variant

124

1

A → V in isoform E3 Basel. Ref.34

VAR_016789

Natural variant

130

1

C → R in HLPP3; isoform E3**, isoform E4, isoform E4/3 and some isoforms E5-type; only isoform E3** is disease-linked. Ref.6 Ref.29 Ref.31 Ref.35
Corresponds to variant rs429358 [ dbSNP | Ensembl ].

VAR_000652

Natural variant

145

1

G → D in isoform E1 Weisgraber. Ref.29

VAR_000653

Natural variant

145

1

G → GEVQAMLG in HLPP3; isoform E3 Leiden.

VAR_000654

Natural variant

152

1

R → Q in isoform E2-type; no hyperlipidemia.
Corresponds to variant rs28931578 [ dbSNP | Ensembl ].

VAR_000655

Natural variant

154

1

R → C in HLPP3; isoform E2-type.

VAR_000657

Natural variant

154

1

R → S in HLPP3; isoform E2 Christchurch. Ref.29 Ref.39

VAR_000656

Natural variant

160

1

R → C in HLPP3; isoform E3**. Ref.29

VAR_000658

Natural variant

163

1

R → C in HLPP3; isoform E4 Philadelphia and isoform E2-type; only isoform E4 Philadelphia is disease-linked. Ref.6 Ref.27
Corresponds to variant rs769455 [ dbSNP | Ensembl ].

VAR_000659

Natural variant

163

1

R → H in E3 Kochi.

VAR_000660

Natural variant

163

1

R → P in LPG; isoform E2 Sendai. Ref.30

VAR_042735

Natural variant

164

1

K → E in HLPP3; isoform E1 Harrisburg.

VAR_000662

Natural variant

164

1

K → Q in HLPP3; isoform E2**.

VAR_000661

Natural variant

167

1

Missing in SBHD and FH; also found in patients with a diagnosis of familial combined hyperlipidemia. Ref.33 Ref.36 Ref.39 Ref.40

VAR_035015

Natural variant

170

1

A → P in isoform E3*.

VAR_000663

Natural variant

176

1

R → C in HLPP3; isoforms E1 Weisgraber, isoform E2 and isoform E3**. Ref.6 Ref.29 Ref.35
Corresponds to variant rs7412 [ dbSNP | Ensembl ].

VAR_000664

Natural variant

242

1

R → Q in isoform E2 Fukuoka.

VAR_000665

Natural variant

246

1

R → C in isoform E2 Dunedin.

VAR_000666

Natural variant

254

1

V → E in isoform E2 W.G.. Ref.28

VAR_000667

Natural variant

262 – 263

2

EE → KK in HLPP3; isoform E7 Suita.

VAR_000668

Natural variant

269

1

R → G in isoform E3 H.B. and isoform E4/3. Ref.28 Ref.31

VAR_000669

Natural variant

270

1

L → E in isoform E1 H.E.; requires 2 nucleotide substitutions. Ref.28

VAR_000670

Natural variant

292

1

R → H in isoform E4 P.D.. Ref.28

VAR_000671

Natural variant

314

1

S → R in isoform E4 H.G.. Ref.28
Corresponds to variant rs28931579 [ dbSNP | Ensembl ].

VAR_000672

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

317

Helix Strand Turn

Details...

Beta strand

22 – 24

3

Helix

31 – 39

9

Turn

40 – 42

3

Helix

43 – 60

18

Helix

63 – 70

8

Helix

73 – 96

24

Turn

97 – 99

3

Helix

106 – 141

36

Turn

143 – 145

3

Helix

149 – 179

31

Turn

180 – 182

3

Turn

187 – 190

4

Helix

193 – 198

6

Beta strand

200 – 202

3

Helix

209 – 217

9

Helix

228 – 241

14

Helix

257 – 283

27

Helix

286 – 303

18

Beta strand

307 – 309

3

Sequences

	Sequence		Length	Mass (Da)
	P02649 [UniParc]. Last modified July 21, 1986. Version 1. Checksum: 91AFC04210A30689	FASTA	317	36,154
	10 20 30 40 50 60 MKVLWAALLV TFLAGCQAKV EQAVETEPEP ELRQQTEWQS GQRWELALGR FWDYLRWVQT 70 80 90 100 110 120 LSEQVQEELL SSQVTQELRA LMDETMKELK AYKSELEEQL TPVAEETRAR LSKELQAAQA 130 140 150 160 170 180 RLGADMEDVC GRLVQYRGEV QAMLGQSTEE LRVRLASHLR KLRKRLLRDA DDLQKRLAVY 190 200 210 220 230 240 QAGAREGAER GLSAIRERLG PLVEQGRVRA ATVGSLAGQP LQERAQAWGE RLRARMEEMG 250 260 270 280 290 300 SRTRDRLDEV KEQVAEVRAK LEEQAQQIRL QAEAFQARLK SWFEPLVEDM QRQWAGLVEK 310 VQAAVGTSAA PVPSDNH

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Synthesis, intracellular processing, and signal peptide of human apolipoprotein E." Zannis V.I., McPherson J., Goldberger G., Karathanasis S.K., Breslow J.L. J. Biol. Chem. 259:5495-5499(1984) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (VARIANT E3).
[2]	"Human apolipoprotein E mRNA. cDNA cloning and nucleotide sequencing of a new variant." McLean J.W., Elshourbagy N.A., Chang D.J., Mahley R.W., Taylor J.M. J. Biol. Chem. 259:6498-6504(1984) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (VARIANT E3).
[3]	"Nucleotide sequence and structure of the human apolipoprotein E gene." Paik Y.-K., Chang D.J., Reardon C.A., Davies G.E., Mahley R.W., Taylor J.M. Proc. Natl. Acad. Sci. U.S.A. 82:3445-3449(1985) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] (VARIANT E4).
[4]	"Genotyping and sequence analysis of apolipoprotein E isoforms." Emi M., Wu L.L., Robertson M.A., Myers R.L., Hegele R.A., Williams R.R., White R., Lalouel J.-M. Genomics 3:373-379(1988) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] (VARIANT E2).
[5]	"Sequencing of 42kb of the APO E-C2 gene cluster reveals a new gene: PEREC1." Freitas E.M., Zhang W.J., Lalonde J.P., Tay G.K., Gaudieri S., Ashworth L.K., Van Bockxmeer F.M., Dawkins R.L. DNA Seq. 9:89-100(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[6]	"Sequence diversity and large-scale typing of SNPs in the human apolipoprotein E gene." Nickerson D.A., Taylor S.L., Fullerton S.M., Weiss K.M., Clark A.G., Stengard J.H., Salomaa V., Boerwinkle E., Sing C.F. Genome Res. 10:1532-1545(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS PRO-46; ARG-130; CYS-163 AND CYS-176.
[7]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Cerebellum.
[8]	NHLBI resequencing and genotyping service (RS&G) Submitted (DEC-2008) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[9]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Eye.
[10]	"A new apolipoprotein E variant (Gln46-->His)." Imura T., Kimura H., Kawasaki M. Submitted (NOV-1999) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 16-78, VARIANT HIS-64. Tissue: Blood.
[11]	"Identification and DNA sequence of a human apolipoprotein E cDNA clone." Breslow J.L., McPherson J., Nussbaum A.L., Williams H.W., Lofquist-Kahl F., Karathanasis S.K., Zannis V.I. J. Biol. Chem. 257:14639-14641(1982) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 99-317 (VARIANT E3).
[12]	Erratum Breslow J.L., McPherson J., Nussbaum A.L., Williams H.W., Lofquist-Kahl F., Karathanasis S.K., Zannis V.I. J. Biol. Chem. 258:11422-11422(1983)
[13]	"Human apolipoprotein E. The complete amino acid sequence." Rall S.C. Jr., Weisgraber K.H., Mahley R.W. J. Biol. Chem. 257:4171-4178(1982) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 19-317 (VARIANT E2).
[14]	"Apolipoprotein E: cholesterol transport protein with expanding role in cell biology." Mahley R.W. Science 240:622-630(1988) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW.
[15]	"Binding of a high reactive heparin to human apolipoprotein E: identification of two heparin-binding domains." Cardin A.D., Hirose N., Blankenship D.T., Jackson R.L., Harmony J.A.K., Sparrow D.A., Sparrow J.T. Biochem. Biophys. Res. Commun. 134:783-789(1986) [PubMed] [Europe PMC] [Abstract] Cited for: HEPARIN-BINDING SITES.
[16]	"Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families." Corder E.H., Saunders A.M., Strittmatter W.J., Schmechel D.E., Gaskell P.C., Small G.W., Roses A.D., Haines J.L., Pericak-Vance M.A. Science 261:921-923(1993) [PubMed] [Europe PMC] [Abstract] Cited for: ASSOCIATION OF APOE*4 WITH ALZHEIMER DISEASE.
[17]	"Glycation of apolipoprotein E impairs its binding to heparin: identification of the major glycation site." Shuvaev V.V., Fujii J., Kawasaki Y., Itoh H., Hamaoka R., Barbier A., Ziegler O., Siest G., Taniguchi N. Biochim. Biophys. Acta 1454:296-308(1999) [PubMed] [Europe PMC] [Abstract] Cited for: GLYCATION AT LYS-93, MASS SPECTROMETRY.
[18]	"Enrichment of glycopeptides for glycan structure and attachment site identification." Nilsson J., Rueetschi U., Halim A., Hesse C., Carlsohn E., Brinkmalm G., Larson G. Nat. Methods 6:809-811(2009) [PubMed] [Europe PMC] [Abstract] Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT THR-212; THR-307 AND SER-308, STRUCTURE OF CARBOHYDRATES, MASS SPECTROMETRY. Tissue: Cerebrospinal fluid.
[19]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[20]	"LC-MS/MS characterization of O-glycosylation sites and glycan structures of human cerebrospinal fluid glycoproteins." Halim A., Ruetschi U., Larson G., Nilsson J. J. Proteome Res. 12:573-584(2013) [PubMed] [Europe PMC] [Abstract] Cited for: GLYCOSYLATION AT THR-26; THR-36 AND SER-314, MASS SPECTROMETRY.
[21]	"Three-dimensional structure of the LDL receptor-binding domain of human apolipoprotein E." Wilson C., Wardell M.R., Weisgraber K.H., Mahley R.W., Agard D.A. Science 252:1817-1822(1991) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.25 ANGSTROMS) OF 41-184.
[22]	"Novel mechanism for defective receptor binding of apolipoprotein E2 in type III hyperlipoproteinemia." Dong L.-M., Parkin S., Trakhanov S.D., Rupp B., Simmons T., Arnold K.S., Newhouse Y.M., Innerarity T.L., Weisgraber K.H. Nat. Struct. Biol. 3:718-722(1996) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 41-181.
[23]	"Conformational flexibility in the apolipoprotein E amino-terminal domain structure determined from three new crystal forms: implications for lipid binding." Segelke B.W., Forstner M., Knapp M., Trakhanov S.D., Parkin S., Newhouse Y.M., Bellamy H.D., Weisgraber K.H., Rupp B. Protein Sci. 9:886-897(2000) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF 22-165.
[24]	"Genetic heterogeneity of apolipoprotein E and its influence on plasma lipid and lipoprotein levels." de Knijff P., van den Maagdenberg A.M.J.M., Frants R.R., Havekes L.M. Hum. Mutat. 4:178-194(1994) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON VARIANTS.
[25]	"Molecular cloning of a human apolipoprotein E variant: E5 (Glu-3-->Lys)." Maeda H., Nakamura H., Kobori S., Okada M., Niki H., Ogura T., Hiraga S. J. Biochem. 105:491-493(1989) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT E5 LYS-21.
[26]	"Apolipoprotein E3-Leiden contains a seven-amino acid insertion that is a tandem repeat of residues 121-127." Wardell M.R., Weisgraber K.H., Havekes L.M., Rall S.C. Jr. J. Biol. Chem. 264:21205-21210(1989) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT HLPP3 E3 LEIDEN GLU-VAL-GLN-ALA-MET-LEU-GLY-145 INS.
[27]	"Apolipoprotein E-4 Philadelphia (Glu-13-->Lys,Arg-145-->Cys). Homozygosity for two rare point mutations in the apolipoprotein E gene combined with severe type III hyperlipoproteinemia." Lohse P., Mann W.A., Stein E.A., Brewer H.B. Jr. J. Biol. Chem. 266:10479-10484(1991) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS HLPP3 E4 PHILADELPHIA LYS-31 AND CYS-163.
[28]	"Characterization of five new mutants in the carboxyl-terminal domain of human apolipoprotein E: no cosegregation with severe hyperlipidemia." van den Maagdenberg A.M.J.M., Weng W., de Bruijn I.H., de Knijff P., Funke H., Smelt A.H.M., Leuven J.A.G., van 't Hooft F.M., Assmann G., Hofker M.H., Havekes L.M., Frants R.R. Am. J. Hum. Genet. 52:937-946(1993) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS GLU-254; GLY-269; GLU-270; HIS-292 AND ARG-314.
[29]	"Common and rare genotypes of human apolipoprotein E determined by specific restriction profiles of polymerase chain reaction-amplified DNA." Richard P., Thomas G., de Zulueta M.P., de Gennes J.-L., Thomas M., Cassaigne A., Bereziat G., Iron A. Clin. Chem. 40:24-29(1994) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS HLPP3 ARG-130; ASP-145; SER-154; CYS-160 AND CYS-176.
[30]	"Apolipoprotein E Sendai (arginine 145-->proline): a new variant associated with lipoprotein glomerulopathy." Oikawa S., Matsunaga A., Saito T., Sato H., Seki T., Hoshi K., Hayasaka K., Kotake H., Midorikawa H., Sekikawa A., Hara S., Abe K., Toyota T., Jingami H., Nakamura H., Sasaki J. J. Am. Soc. Nephrol. 8:820-823(1997) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT LPG PRO-163.
[31]	"Apolipoprotein E R112; R251G: a carboxy-terminal variant found in patients with hyperlipidemia and coronary heart disease." Kang A.K., Jenkins D.J.A., Wolever T.M.S., Huff M.W., Maguire G.F., Connelly P.W., Hegele R.A. Mutat. Res. 382:57-65(1997) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS E4/3 ARG-130 AND GLY-269.
[32]	"A novel apolipoprotein E mutation, E2 (Arg25Cys), in lipoprotein glomerulopathy." Matsunaga A., Sasaki J., Komatsu T., Kanatsu K., Tsuji E., Moriyama K., Koga T., Arakawa K., Oikawa S., Saito T., Kita T., Doi T. Kidney Int. 56:421-427(1999) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT LPG CYS-43.
[33]	"Familial splenomegaly: macrophage hypercatabolism of lipoproteins associated with apolipoprotein E mutation [apolipoprotein E (delta149 Leu)]." Nguyen T.T., Kruckeberg K.E., O'Brien J.F., Ji Z.-S., Karnes P.S., Crotty T.B., Hay I.D., Mahley R.W., O'Brien T. J. Clin. Endocrinol. Metab. 85:4354-4358(2000) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT SBHD LEU-167 DEL.
[34]	"Apolipoprotein E3Basel: new insights into a highly conserved protein region." Miserez A.R., Scharnagl H., Muller P.Y., Mirsaidi R., Stahelin H.B., Monsch A., Marz W., Hoffmann M.M. Eur. J. Clin. Invest. 33:677-685(2003) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT E3 BASEL VAL-124.
[35]	"Association of extreme blood lipid profile phenotypic variation with 11 reverse cholesterol transport genes and 10 non-genetic cardiovascular disease risk factors." Morabia A., Cayanis E., Costanza M.C., Ross B.M., Flaherty M.S., Alvin G.B., Das K., Gilliam T.C. Hum. Mol. Genet. 12:2733-2743(2003) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS ARG-130 AND CYS-176.
[36]	"Variable expressivity of the clinical and biochemical phenotype associated with the apolipoprotein E p.Leu149del mutation." Faivre L., Saugier-Veber P., Pais de Barros J.-P., Verges B., Couret B., Lorcerie B., Thauvin C., Charbonnier F., Huet F., Gambert P., Frebourg T., Duvillard L. Eur. J. Hum. Genet. 13:1186-1191(2005) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT SBHD LEU-167 DEL.
[37]	"APOE Kyoto mutation in European Americans with lipoprotein glomerulopathy." Rovin B.H., Roncone D., McKinley A., Nadasdy T., Korbet S.M., Schwartz M.M. N. Engl. J. Med. 357:2522-2524(2007) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT LPG CYS-43.
[38]	"Quantitative detection of single amino acid polymorphisms by targeted proteomics." Su Z.D., Sun L., Yu D.X., Li R.X., Li H.X., Yu Z.J., Sheng Q.H., Lin X., Zeng R., Wu J.R. J. Mol. Cell Biol. 3:309-315(2011) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT HIS-64, MASS SPECTROMETRY.
[39]	"Apolipoprotein E gene mutations in subjects with mixed hyperlipidemia and a clinical diagnosis of familial combined hyperlipidemia." Solanas-Barca M., de Castro-Oros I., Mateo-Gallego R., Cofan M., Plana N., Puzo J., Burillo E., Martin-Fuentes P., Ros E., Masana L., Pocovi M., Civeira F., Cenarro A. Atherosclerosis 222:449-455(2012) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT HLPP3 SER-154, VARIANT LEU-167 DEL.
[40]	"Description of a large family with autosomal dominant hypercholesterolemia associated with the APOE p.Leu167del mutation." Marduel M., Ouguerram K., Serre V., Bonnefont-Rousselot D., Marques-Pinheiro A., Erik Berge K., Devillers M., Luc G., Lecerf J.M., Tosolini L., Erlich D., Peloso G.M., Stitziel N., Nitchke P., Jais J.P., Abifadel M., Kathiresan S., Leren T.P. , Rabes J.P., Boileau C., Varret M. Hum. Mutat. 34:83-87(2013) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT FH LEU-167 DEL.
+	Additional computationally mapped references.

Web resources

GeneReviews

SHMPD

The Singapore human mutation and polymorphism database

Wikipedia

Apolipoprotein E entry

Protein Spotlight

Tangled - Issue 83 of June 2007

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

M12529 mRNA. Translation: AAB59518.1.
K00396 mRNA. Translation: AAB59546.1.
M10065 Genomic DNA. Translation: AAB59397.1.
AF050154 Genomic DNA. Translation: AAD02505.1.
AF261279 Genomic DNA. Translation: AAG27089.1.
AK314898 mRNA. Translation: BAG37412.1.
FJ525876 Genomic DNA. Translation: ACN81314.1.
BC003557 mRNA. Translation: AAH03557.1.
AB035149 Genomic DNA. Translation: BAA96080.1.

IPI

IPI00021842.

PIR

LPHUE. A92478.

RefSeq

NP_000032.1. NM_000041.2.

UniGene

Hs.654439.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1B68	X-ray	2.00	A	19-209	[»]
1BZ4	X-ray	1.85	A	40-183	[»]
1EA8	X-ray	1.95	A	19-209	[»]
1GS9	X-ray	1.70	A	19-183	[»]
1H7I	X-ray	1.90	A	19-209	[»]
1LE2	X-ray	3.00	A	41-184	[»]
1LE4	X-ray	2.50	A	41-184	[»]
1LPE	X-ray	2.25	A	41-184	[»]
1NFN	X-ray	1.80	A	19-209	[»]
1NFO	X-ray	2.00	A	19-209	[»]
1OEF	NMR	-	A	281-304	[»]
1OEG	NMR	-	A	285-307	[»]
1OR2	X-ray	2.50	A	19-183	[»]
1OR3	X-ray	1.73	A	19-183	[»]
2KC3	NMR	-	A	19-201	[»]
2KNY	NMR	-	A	147-167	[»]
2L7B	NMR	-	A	19-317	[»]

DisProt

DP00355.

ProteinModelPortal

P02649.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-1120N.

IntAct

P02649. 17 interactions.

MINT

MINT-4999641.

STRING

9606.ENSP00000252486.

PTM databases

PhosphoSite

P02649.

Polymorphism databases

DMDM

114039.

2D gel databases

DOSAC-COBS-2DPAGE

P02649.

SWISS-2DPAGE

P02649.

Proteomic databases

PaxDb

P02649.

PeptideAtlas

P02649.

PRIDE

P02649.

Protocols and materials databases

DNASU

348.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000252486; ENSP00000252486; ENSG00000130203.

GeneID

348.

KEGG

hsa:348.

UCSC

uc002pab.3. human.

Organism-specific databases

CTD

348.

GeneCards

GC19P045408.

HGNC

HGNC:613. APOE.

HPA

CAB008363.

MIM

104310. phenotype.
107741. gene+phenotype.
143890. phenotype.
269600. phenotype.
611771. phenotype.

neXtProt

NX_P02649.

Orphanet

238616. Alzheimer disease.
412. Hyperlipidemia type 3.
158029. Sea-blue histiocytosis.

PharmGKB

PA55.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG44867.

HOGENOM

HOG000034006.

HOVERGEN

HBG010582.

InParanoid

P02649.

KO

K04524.

OMA

EMGSRTR.

OrthoDB

EOG4GB76S.

PhylomeDB

P02649.

Enzyme and pathway databases

Reactome

REACT_111217. Metabolism.

Gene expression databases

ArrayExpress

P02649.

Bgee

P02649.

CleanEx

HS_APOE.

Genevestigator

P02649.

GermOnline

ENSG00000130203. Homo sapiens.

Family and domain databases

InterPro

IPR013326. ApoA.
IPR000074. ApoA1_A4_E.
[Graphical view]

Pfam

PF01442. Apolipoprotein. 1 hit.
[Graphical view]

SUPFAM

SSF47162. SSF47162. 1 hit.

ProtoNet

Search...

Other

ChiTaRS

APOE. human.

DrugBank

DB00062. Human Serum Albumin.
DB00064. Serum albumin iodonated.

EvolutionaryTrace

P02649.

GenomeRNAi

348.

NextBio

1435.

PMAP-CutDB

P02649.

SOURCE

Search...

Entry information

Entry name

APOE_HUMAN

Accession

Primary (citable) accession number: P02649
Secondary accession number(s): B2RC15, C0JYY5, Q9P2S4

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 21, 1986
Last sequence update:	July 21, 1986
Last modified:	May 1, 2013
This is version 177 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.