Reviewed, UniProtKB/Swiss-Prot P02649 (APOE_HUMAN)

Names and origin

Protein names

Recommended name:
    Apolipoprotein E
      Short name=Apo-E

Gene names

Name:

APOE

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › 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. Glycated in plasma VLDL of normal subjects, and of hyperglycemic diabetic patients at a higher level (2-3 fold).
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	Defects in APOE are a cause of hyperlipoproteinemia type III [MIM:107741]; also known as familial dysbetalipoproteinemia. Individuals with hyperlipoproteinemia type III, are clinically characterized by 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. The vast majority of the patients are homozygous for APOE*2 alleles. More severe cases of hyperlipoproteinemia type III 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.15 Ref.30 Ref.33 The APOE*4 allele is associated with late onset Alzheimer disease 2 (AD2) [MIM:104310]. The APOE*4 allele is genetically associated with the common late onset familial and sporadic forms of Alzheimer disease (AD). 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.15 Ref.30 Ref.33 Defects in APOE are a cause of sea-blue histiocyte disease [MIM:269600]; also called sea-blue histiocytosis. This disorder is 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. Ref.15 Ref.30 Ref.33 Defects in APOE are a cause of lipoprotein glomerulopathy (LPG) [MIM:611771]. LPG is an uncommon kidney disease characterized by proteinuria, progressive kidney failure, and distinctive lipoprotein thrombi in glomerular capillaries. It mainly affects people of Japanese and Chinese origin. The disorder has rarely been described in Caucasians. Ref.15 Ref.30 Ref.33 Ref.27 Ref.29 Ref.34
Sequence similarities	Belongs to the apolipoprotein A1/A4/E family.

Ontologies

Keywords
Biological process	Lipid transport Transport
Cellular component	Chylomicron HDL Secreted VLDL
Coding sequence diversity	Polymorphism
Disease	Alzheimer disease Disease mutation Hyperlipidemia
Domain	Repeat Signal
Ligand	Heparin-binding
PTM	Glycation Glycoprotein
Technical term	3D-structure Direct protein sequencing
Gene Ontology (GO)
Biological process	Cdc42 protein signal transduction Inferred from direct assay. Source: UniProtKB G-protein coupled receptor protein signaling pathway Inferred from direct assay. Source: UniProtKB anti-apoptosis Inferred from direct assay. Source: UniProtKB cGMP-mediated signaling Inferred from direct assay. Source: UniProtKB cholesterol efflux Inferred from direct assay. Source: UniProtKB cholesterol homeostasis Inferred from direct assay. Source: UniProtKB chylomicron remnant clearance Inferred from mutant phenotype. Source: UniProtKB cytoskeleton organization Traceable author statement. Source: UniProtKB high-density lipoprotein particle assembly Inferred from direct assay. Source: UniProtKB high-density lipoprotein particle clearance Inferred from direct assay. Source: UniProtKB high-density lipoprotein particle remodeling Inferred from genetic interaction. Source: UniProtKB induction of apoptosis Inferred from direct assay. Source: UniProtKB intracellular transport Traceable author statement. Source: UniProtKB negative regulation of MAP kinase activity Inferred from direct assay. Source: UniProtKB negative regulation of blood vessel endothelial cell migration Inferred from direct assay. Source: UniProtKB negative regulation of cholesterol biosynthetic process Inferred from direct assay. Source: UniProtKB negative regulation of endothelial cell proliferation Inferred from direct assay. Source: UniProtKB negative regulation of inflammatory response Inferred by curator. Source: UniProtKB negative regulation of platelet activation Inferred from direct assay. Source: UniProtKB nitric oxide mediated signal transduction Inferred from direct assay. Source: UniProtKB phospholipid efflux Inferred from direct assay. Source: UniProtKB positive regulation of cGMP biosynthetic process Inferred from direct assay. Source: UniProtKB positive regulation of cholesterol efflux Inferred from direct assay. Source: UniProtKB positive regulation of low-density lipoprotein receptor catabolic process Inferred from direct assay. Source: UniProtKB positive regulation of membrane protein ectodomain proteolysis Inferred from direct assay. Source: UniProtKB positive regulation of nitric-oxide synthase activity Inferred from direct assay. Source: UniProtKB receptor-mediated endocytosis Inferred from direct assay. Source: UniProtKB regulation of axon extension Traceable author statement. Source: UniProtKB regulation of neuronal synaptic plasticity Traceable author statement. Source: UniProtKB response to reactive oxygen species Non-traceable author statement. Source: UniProtKB reverse cholesterol transport Inferred from direct assay. Source: UniProtKB synaptic transmission, cholinergic Traceable author statement. Source: UniProtKB triglyceride metabolic process Inferred from direct assay. Source: UniProtKB very-low-density lipoprotein particle clearance Inferred from direct assay. Source: UniProtKB very-low-density lipoprotein particle remodeling Inferred from genetic interaction. Source: UniProtKB
Cellular component	cell soma Non-traceable author statement. Source: UniProtKB chylomicron Inferred from direct assay. Source: UniProtKB dendrite Non-traceable author statement. Source: UniProtKB high-density lipoprotein particle Inferred from direct assay. Source: UniProtKB intermediate-density lipoprotein particle Inferred from direct assay. Source: UniProtKB low-density lipoprotein particle Inferred from direct assay. Source: UniProtKB very-low-density lipoprotein particle Inferred from direct assay. Source: UniProtKB
Molecular function	antioxidant activity Inferred from direct assay. Source: UniProtKB beta-amyloid binding Inferred from direct assay. Source: UniProtKB heparin binding Inferred from direct assay. Source: UniProtKB low-density lipoprotein receptor binding Inferred from direct assay. Source: UniProtKB metal chelating activity Inferred from direct assay. Source: UniProtKB phospholipid binding Inferred from direct assay. Source: UniProtKB protein heterodimerization activity Inferred from physical interaction. Source: UniProtKB protein homodimerization activity Inferred from direct assay. Source: UniProtKB tau protein binding Inferred from physical interaction. Source: UniProtKB very-low-density lipoprotein receptor binding Inferred from direct assay. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 18

18

Ref.12

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

93

1

N-linked (Glc) (glycation)

Glycosylation

212

1

O-linked (GalNAc...)

Natural variations

Natural variant

21

1

E → K in isoform E5; associated with hyperlipoproteinemia and atherosclerosis. Ref.22

VAR_000645

Natural variant

31

1

E → K in hyperlipoproteinemia type III; isoforms E4 Philadelphia and isoform E5-type; only isoform E4 Philadelphia is disease-linked. Ref.24

VAR_000646

Natural variant

43

1

R → C in LPG; isoform E2 Kyoto. Ref.29 Ref.34

VAR_042734

Natural variant

46

1

L → P in isoform E4 Freiburg. dbSNP rs769452. Ref.6

VAR_000647

Natural variant

60

1

T → A in isoform E3 Freiburg. dbSNP rs28931576.

VAR_000648

Natural variant

64

1

Q → H Ref.9

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. dbSNP rs28931578.

VAR_000650

Natural variant

117

1

A → T in isoform E3*. dbSNP rs28931577.

VAR_000651

Natural variant

124

1

A → V in isoform E3 Basel. Ref.31

VAR_016789

Natural variant

130

1

C → R in hyperlipoproteinemia type III; isoform E3**, isoform E4, isoform E4/3 and some isoforms E5-type; only isoform E3** is disease-linked. dbSNP rs429358. Ref.6 Ref.26 Ref.28 Ref.32

VAR_000652

Natural variant

145

1

G → D in isoform E1 Weisgraber. Ref.26

VAR_000653

Natural variant

145

1

G → GEVQAMLG in hyperlipoproteinemia type III; isoform E3 Leiden. Ref.26

VAR_000654

Natural variant

152

1

R → Q in isoform E2-type; no hyperlipidemia.

VAR_000655

Natural variant

154

1

R → C in hyperlipoproteinemia type III; isoform E2-type. Ref.26

VAR_000657

Natural variant

154

1

R → S in hyperlipoproteinemia type III; isoform E2 Christchurch. Ref.26

VAR_000656

Natural variant

160

1

R → C in hyperlipoproteinemia type III; isoform E3**. Ref.26

VAR_000658

Natural variant

163

1

R → C in hyperlipoproteinemia type III; isoform E4 Philadelphia and isoform E2-type; only isoform E4 Philadelphia is disease-linked. dbSNP rs769455. Ref.27 Ref.24 Ref.6

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.27

VAR_042735

Natural variant

164

1

K → E in hyperlipoproteinemia type III; isoform E1 Harrisburg.

VAR_000662

Natural variant

164

1

K → Q in hyperlipoproteinemia type III; isoform E2**.

VAR_000661

Natural variant

167

1

Missing in sea-blue histiocyte disease. Ref.30 Ref.33

VAR_035015

Natural variant

170

1

A → P in isoform E3*.

VAR_000663

Natural variant

176

1

R → C in hyperlipoproteinemia type III; isoforms E1 Weisgraber, isoform E2 and isoform E3**. dbSNP rs7412. Ref.6 Ref.26 Ref.32

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.25

VAR_000667

Natural variant

262 – 263

2

EE → KK in hyperlipoproteinemia type III; isoform E7 Suita.

VAR_000668

Natural variant

269

1

R → G in isoform E3 H.B. and isoform E4/3. Ref.28 Ref.25

VAR_000669

Natural variant

270

1

L → E in isoform E1 H.E.; requires 2 nucleotide substitutions. Ref.25

VAR_000670

Natural variant

292

1

R → H in isoform E4 P.D.. Ref.25

VAR_000671

Natural variant

314

1

S → R in isoform E4 H.G.. dbSNP rs28931579. Ref.25

VAR_000672

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

317

Helix Strand Turn

Details...

Helix

43 – 59

17

Helix

63 – 69

7

Beta strand

70 – 72

3

Helix

73 – 96

24

Helix

105 – 142

38

Turn

143 – 145

3

Helix

149 – 179

31

Helix

286 – 303

18

Sequences

	Sequence		Length	Mass (Da)
	P02649-1 [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: 6325438] [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: 6327682] [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: 2987927] [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: 3243553] [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: 10520737] [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: 11042151] [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: 14702039] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Cerebellum.
[8]	"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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Eye.
[9]	"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.
[10]	"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: 6897404] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 99-317 (VARIANT E3).
[11]	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)
[12]	"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: 7068630] [Abstract] Cited for: PROTEIN SEQUENCE OF 19-317 (VARIANT E2).
[13]	"Apolipoprotein E: cholesterol transport protein with expanding role in cell biology." Mahley R.W. Science 240:622-630(1988) [PubMed: 3283935] [Abstract] Cited for: REVIEW.
[14]	"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: 3947350] [Abstract] Cited for: HEPARIN-BINDING SITES.
[15]	"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: 8346443] [Abstract] Cited for: ASSOCIATION OF APOE*4 WITH ALZHEIMER DISEASE.
[16]	"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: 10452964] [Abstract] Cited for: GLYCATION AT LYS-93, MASS SPECTROMETRY.
[17]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[18]	"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: 2063194] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.25 ANGSTROMS) OF 41-184.
[19]	"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: 8756331] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 41-181.
[20]	"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: 10850798] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF 22-165.
[21]	"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: 7833947] [Abstract] Cited for: REVIEW ON VARIANTS.
[22]	"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: 2760009] [Abstract] Cited for: VARIANT E5 LYS-21.
[23]	"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: 2556398] [Abstract] Cited for: VARIANT HYPOLIPOPROTEINEMIA TYPE III E3 LEIDEN GLU-VAL-GLN-ALA-MET-LEU-GLY-145 INS.
[24]	"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: 1674745] [Abstract] Cited for: VARIANTS HYPOLIPOPROTEINEMIA TYPE III E4 PHILADELPHIA LYS-31 AND CYS-163.
[25]	"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: 8488843] [Abstract] Cited for: VARIANTS GLU-254; GLY-269; GLU-270; HIS-292 AND ARG-314.
[26]	"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: 8287539] [Abstract] Cited for: VARIANTS HYPOLIPOPROTEINEMIA TYPE III ARG-130; ASP-145; SER-154; CYS-160 AND CYS-176.
[27]	"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: 9176854] [Abstract] Cited for: VARIANT LPG PRO-163.
[28]	"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: 9360638] [Abstract] Cited for: VARIANTS E4/3 ARG-130 AND GLY-269.
[29]	"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: 10432380] [Abstract] Cited for: VARIANT LPG CYS-43.
[30]	"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: 11095479] [Abstract] Cited for: VARIANT SEA-BLUE HISTIOCYTE DISEASE LEU-167 DEL.
[31]	"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: 12864777] [Abstract] Cited for: VARIANT E3 BASEL VAL-124.
[32]	"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: 12966036] [Abstract] Cited for: VARIANTS ARG-130 AND CYS-176.
[33]	"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: 16094309] [Abstract] Cited for: VARIANT SEA-BLUE HISTIOCYTE DISEASE LEU-167 DEL.
[34]	"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: 18077821] [Abstract] Cited for: VARIANT LPG CYS-43.
+	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

EMBLGenBankDDBJ

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.
BC003557 mRNA. Translation: AAH03557.1.
AB035149 Genomic DNA. Translation: BAA96080.1.

IPI

IPI00021842.

PIR

LPHUE. A92478.

RefSeq

NP_000032.1.

UniGene

Hs.654439

3D structure databases

PDBPDBe

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	[»]

DisProt

DP00355.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP:1120N.

PTM databases

PhosphoSite

P02649.

2-D gel databases

SWISS-2DPAGE

P02649.

DOSAC-COBS-2DPAGE

P02649.

Proteomic databases

PeptideAtlas

P02649.

PRIDE

P02649.

Genome annotation databases

Ensembl

ENSG00000130203. Homo sapiens. [Contig view]

GeneID

348.

KEGG

hsa:348.

Organism-specific databases

GeneCards

GC19P050100.

HGNC

HGNC:613. APOE.

HPA

CAB008363.

MIM

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

Orphanet

1020. Alzheimer disease, familial.
158029. Histiocytosis, sea-blue.
412. Hyperlipidemia type 3.

PharmGKB

PA55.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

P02649.

HOVERGEN

P02649.

OMA

P02649. YQAGARE.

Enzyme and pathway databases

Reactome

REACT_602. Lipid and lipoprotein metabolism.

Gene expression databases

ArrayExpress

P02649.

Bgee

P02649.

CleanEx

HS_APOE.

GermOnline

ENSG00000130203. Homo sapiens.

Family and domain databases

InterPro

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

Gene3D

G3DSA:1.20.120.20. ApoA/E_ApoLp. 1 hit.

Pfam

PF01442. Apolipoprotein. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

DrugBank

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

NextBio

1435.

PMAP-CutDB

P02649.

SOURCE

Search...

Entry information

Entry name

APOE_HUMAN

Accession

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

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 21, 1986
Last sequence update:	July 21, 1986
Last modified:	June 16, 2009
This is version 131 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)