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Apolipoprotein E (Apo-E)

 APOE_MACNE              Reviewed;         317 AA.
11-MAY-2016, integrated into UniProtKB/Swiss-Prot.
11-MAY-2016, sequence version 1.
16-JAN-2019, entry version 14.
RecName: Full=Apolipoprotein E;
Flags: Precursor;
Macaca nemestrina (Pig-tailed macaque).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
Catarrhini; Cercopithecidae; Cercopithecinae; Macaca.
Hughes D.S., Liu Y., Murali S., Raveendran M., Korchina V., Wang M.,
Jhangiani S., Bandaranaike D., Bellair M., Blankenburg K., Chao H.,
Dahdouli M., Dinh H., Doddapaneni H., English A., Gnanaolivu R.,
Gross S., Jayaseelan J., Jones J., Khan Z., Kovar C., Kurapati P.,
Le B., Lee S., Matakis S., Mathew T., Narasimhan A., Ngo D.,
Okwuonu G., Ongeri F., Osuji N., Otenyo P., Patel E., Qu C.,
Quiroz J., Raj R., Rajbhandari K., Reid J.G., Santibanez J.,
Skinner E., Vee V., Wang Y., Weissenberger G., Xin Y., Zou X., Han Y.,
Muzny D.M., Richards S., Worley K.C., Rogers J., Gibbs R.A.;
Submitted (MAR-2015) to the EMBL/GenBank/DDBJ databases.
Puppione D.L.;
Unpublished observations (MAR-2016).
-!- 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. APOE is a core component of plasma lipoproteins and is
involved in their production, conversion and clearance.
Apoliproteins are amphipathic molecules that interact both with
lipids of the lipoprotein particle core and the aqueous
environment of the plasma. 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). 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. 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. A main function
of APOE is to mediate lipoprotein clearance through the uptake of
chylomicrons, VLDLs, and HDLs by hepatocytes. 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. By participating to the lipoprotein-mediated distribution
of lipids among tissues, APOE plays a critical role in plasma and
tissues lipid homeostasis. 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. First, it is
functionally associated with ABCA1 in the biogenesis of HDLs in
tissues. Second, it is enriched in circulating HDLs and mediates
their uptake by hepatocytes. APOE also plays an important role in
lipid transport in the central nervous system, regulating neuron
survival and sprouting. {ECO:0000250|UniProtKB:P02649}.
-!- SUBUNIT: Homotetramer. {ECO:0000250|UniProtKB:P02649}.
-!- SUBCELLULAR LOCATION: Secreted {ECO:0000250|UniProtKB:P02649}.
Secreted, extracellular space {ECO:0000250|UniProtKB:P02649}.
Secreted, extracellular space, extracellular matrix
{ECO:0000250|UniProtKB:P02649}. Note=In the plasma, APOE is
associated with chylomicrons, chylomicrons remnants, VLDL, LDL and
HDL lipoproteins. Lipid poor oligomeric APOE is associated with
the extracellular matrix in a calcium- and heparan-sulfate
proteoglycans-dependent manner. Lipidation induces the release
from the extracellular matrix. {ECO:0000250|UniProtKB:P02649}.
-!- PTM: APOE exists as multiple glycosylated and sialylated
glycoforms within cells and in plasma. The extent of glycosylation
and sialylation are tissue and context specific.
-!- PTM: Glycated in plasma VLDL. {ECO:0000250|UniProtKB:P02649}.
-!- PTM: Phosphorylated by FAM20C in the extracellular medium.
-!- SIMILARITY: Belongs to the apolipoprotein A1/A4/E family.
Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
Distributed under the Creative Commons Attribution (CC BY 4.0) License
EMBL; JZLF01080368; -; NOT_ANNOTATED_CDS; Genomic_DNA.
SMR; P0DO94; -.
Ensembl; ENSMNET00000042220; ENSMNEP00000017988; ENSMNEG00000032951.
GeneTree; ENSGT00730000111315; -.
Proteomes; UP000233120; Whole Genome Shotgun Assembly.
GO; GO:0042627; C:chylomicron; IEA:UniProtKB-KW.
GO; GO:0005783; C:endoplasmic reticulum; IEA:Ensembl.
GO; GO:0031012; C:extracellular matrix; ISS:UniProtKB.
GO; GO:0005615; C:extracellular space; ISS:UniProtKB.
GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl.
GO; GO:0005794; C:Golgi apparatus; IEA:Ensembl.
GO; GO:0034364; C:high-density lipoprotein particle; ISS:UniProtKB.
GO; GO:0034363; C:intermediate-density lipoprotein particle; ISS:UniProtKB.
GO; GO:0034362; C:low-density lipoprotein particle; ISS:UniProtKB.
GO; GO:0005886; C:plasma membrane; IEA:GOC.
GO; GO:0043083; C:synaptic cleft; IEA:Ensembl.
GO; GO:0034361; C:very-low-density lipoprotein particle; ISS:UniProtKB.
GO; GO:0001540; F:amyloid-beta binding; IEA:Ensembl.
GO; GO:0016209; F:antioxidant activity; IEA:Ensembl.
GO; GO:0017127; F:cholesterol transporter activity; IEA:Ensembl.
GO; GO:0043395; F:heparan sulfate proteoglycan binding; ISS:UniProtKB.
GO; GO:0008201; F:heparin binding; ISS:UniProtKB.
GO; GO:0042802; F:identical protein binding; ISS:UniProtKB.
GO; GO:0071813; F:lipoprotein particle binding; IEA:Ensembl.
GO; GO:0050750; F:low-density lipoprotein particle receptor binding; ISS:UniProtKB.
GO; GO:0046911; F:metal chelating activity; IEA:Ensembl.
GO; GO:0060228; F:phosphatidylcholine-sterol O-acyltransferase activator activity; IEA:Ensembl.
GO; GO:0005543; F:phospholipid binding; IEA:Ensembl.
GO; GO:0042803; F:protein homodimerization activity; IEA:Ensembl.
GO; GO:0048156; F:tau protein binding; IEA:Ensembl.
GO; GO:0070326; F:very-low-density lipoprotein particle receptor binding; IEA:Ensembl.
GO; GO:0097113; P:AMPA glutamate receptor clustering; IEA:Ensembl.
GO; GO:0042982; P:amyloid precursor protein metabolic process; IEA:Ensembl.
GO; GO:0048844; P:artery morphogenesis; IEA:Ensembl.
GO; GO:0006874; P:cellular calcium ion homeostasis; IEA:Ensembl.
GO; GO:0019934; P:cGMP-mediated signaling; IEA:Ensembl.
GO; GO:0006707; P:cholesterol catabolic process; IEA:Ensembl.
GO; GO:0033344; P:cholesterol efflux; ISS:UniProtKB.
GO; GO:0042632; P:cholesterol homeostasis; IEA:Ensembl.
GO; GO:0034382; P:chylomicron remnant clearance; ISS:UniProtKB.
GO; GO:0055089; P:fatty acid homeostasis; IEA:Ensembl.
GO; GO:0007186; P:G protein-coupled receptor signaling pathway; IEA:Ensembl.
GO; GO:0034380; P:high-density lipoprotein particle assembly; ISS:UniProtKB.
GO; GO:0034384; P:high-density lipoprotein particle clearance; IEA:Ensembl.
GO; GO:0034375; P:high-density lipoprotein particle remodeling; IEA:Ensembl.
GO; GO:0071831; P:intermediate-density lipoprotein particle clearance; ISS:UniProtKB.
GO; GO:0010877; P:lipid transport involved in lipid storage; IEA:Ensembl.
GO; GO:0042158; P:lipoprotein biosynthetic process; ISS:UniProtKB.
GO; GO:0042159; P:lipoprotein catabolic process; IEA:Ensembl.
GO; GO:0035641; P:locomotory exploration behavior; IEA:Ensembl.
GO; GO:0015909; P:long-chain fatty acid transport; IEA:Ensembl.
GO; GO:0007616; P:long-term memory; IEA:Ensembl.
GO; GO:0034374; P:low-density lipoprotein particle remodeling; IEA:Ensembl.
GO; GO:0051651; P:maintenance of location in cell; IEA:Ensembl.
GO; GO:1902430; P:negative regulation of amyloid-beta formation; IEA:Ensembl.
GO; GO:0043537; P:negative regulation of blood vessel endothelial cell migration; IEA:Ensembl.
GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; IEA:Ensembl.
GO; GO:0045541; P:negative regulation of cholesterol biosynthetic process; IEA:Ensembl.
GO; GO:0001937; P:negative regulation of endothelial cell proliferation; IEA:Ensembl.
GO; GO:0010629; P:negative regulation of gene expression; IEA:Ensembl.
GO; GO:0050728; P:negative regulation of inflammatory response; IEA:Ensembl.
GO; GO:1900272; P:negative regulation of long-term synaptic potentiation; IEA:Ensembl.
GO; GO:0043407; P:negative regulation of MAP kinase activity; IEA:Ensembl.
GO; GO:1901215; P:negative regulation of neuron death; IEA:Ensembl.
GO; GO:0010977; P:negative regulation of neuron projection development; IEA:Ensembl.
GO; GO:0010544; P:negative regulation of platelet activation; IEA:Ensembl.
GO; GO:1901630; P:negative regulation of presynaptic membrane organization; IEA:Ensembl.
GO; GO:0090209; P:negative regulation of triglyceride metabolic process; IEA:Ensembl.
GO; GO:0031175; P:neuron projection development; ISS:UniProtKB.
GO; GO:0007263; P:nitric oxide mediated signal transduction; IEA:Ensembl.
GO; GO:0097114; P:NMDA glutamate receptor clustering; IEA:Ensembl.
GO; GO:0033700; P:phospholipid efflux; IEA:Ensembl.
GO; GO:0044794; P:positive regulation by host of viral process; IEA:Ensembl.
GO; GO:0010875; P:positive regulation of cholesterol efflux; IEA:Ensembl.
GO; GO:0010873; P:positive regulation of cholesterol esterification; IEA:Ensembl.
GO; GO:0060999; P:positive regulation of dendritic spine development; IEA:Ensembl.
GO; GO:1902952; P:positive regulation of dendritic spine maintenance; IEA:Ensembl.
GO; GO:0045807; P:positive regulation of endocytosis; IEA:Ensembl.
GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IEA:Ensembl.
GO; GO:1905855; P:positive regulation of heparan sulfate binding; IEA:Ensembl.
GO; GO:1905860; P:positive regulation of heparan sulfate proteoglycan binding; IEA:Ensembl.
GO; GO:0046889; P:positive regulation of lipid biosynthetic process; IEA:Ensembl.
GO; GO:1903002; P:positive regulation of lipid transport across blood-brain barrier; IEA:Ensembl.
GO; GO:0032805; P:positive regulation of low-density lipoprotein particle receptor catabolic process; IEA:Ensembl.
GO; GO:0051044; P:positive regulation of membrane protein ectodomain proteolysis; IEA:Ensembl.
GO; GO:0051000; P:positive regulation of nitric-oxide synthase activity; IEA:Ensembl.
GO; GO:1902995; P:positive regulation of phospholipid efflux; IEA:Ensembl.
GO; GO:1901628; P:positive regulation of postsynaptic membrane organization; IEA:Ensembl.
GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IEA:Ensembl.
GO; GO:0017038; P:protein import; IEA:Ensembl.
GO; GO:0006898; P:receptor-mediated endocytosis; IEA:Ensembl.
GO; GO:1905906; P:regulation of amyloid fibril formation; IEA:Ensembl.
GO; GO:1900221; P:regulation of amyloid-beta clearance; IEA:Ensembl.
GO; GO:0042981; P:regulation of apoptotic process; IEA:Ensembl.
GO; GO:2000822; P:regulation of behavioral fear response; IEA:Ensembl.
GO; GO:0032489; P:regulation of Cdc42 protein signal transduction; IEA:Ensembl.
GO; GO:1905890; P:regulation of cellular response to very-low-density lipoprotein particle stimulus; IEA:Ensembl.
GO; GO:0045088; P:regulation of innate immune response; IEA:Ensembl.
GO; GO:0061136; P:regulation of proteasomal protein catabolic process; IEA:Ensembl.
GO; GO:0032462; P:regulation of protein homooligomerization; IEA:Ensembl.
GO; GO:0061771; P:response to caloric restriction; IEA:Ensembl.
GO; GO:0002021; P:response to dietary excess; IEA:Ensembl.
GO; GO:0006979; P:response to oxidative stress; IEA:Ensembl.
GO; GO:0043691; P:reverse cholesterol transport; IEA:Ensembl.
GO; GO:0070328; P:triglyceride homeostasis; IEA:Ensembl.
GO; GO:0006641; P:triglyceride metabolic process; IEA:Ensembl.
GO; GO:0071830; P:triglyceride-rich lipoprotein particle clearance; ISS:UniProtKB.
GO; GO:0042311; P:vasodilation; IEA:Ensembl.
GO; GO:0034447; P:very-low-density lipoprotein particle clearance; ISS:UniProtKB.
GO; GO:0034372; P:very-low-density lipoprotein particle remodeling; IEA:Ensembl.
GO; GO:0019068; P:virion assembly; IEA:Ensembl.
InterPro; IPR000074; ApoA_E.
Pfam; PF01442; Apolipoprotein; 1.
3: Inferred from homology;
Chylomicron; Complete proteome; Extracellular matrix; Glycoprotein;
HDL; Heparin-binding; Lipid transport; Lipid-binding; Oxidation;
Phosphoprotein; Reference proteome; Repeat; Secreted; Signal;
Transport; VLDL.
SIGNAL 1 18 {ECO:0000250|UniProtKB:P02649}.
CHAIN 19 317 Apolipoprotein E.
REPEAT 80 101 1.
REPEAT 102 123 2.
REPEAT 124 145 3.
REPEAT 146 167 4.
REPEAT 168 189 5.
REPEAT 190 211 6.
REPEAT 212 233 7.
REPEAT 234 255 8.
REGION 80 255 8 X 22 AA approximate tandem repeats.
REGION 158 168 LDL and other lipoprotein receptors
binding. {ECO:0000250|UniProtKB:P02649}.
REGION 162 165 Heparin-binding.
REGION 210 290 Lipid-binding and lipoprotein
REGION 229 236 Heparin-binding.
REGION 266 317 Homooligomerization.
REGION 278 290 Specificity for association with VLDL.
MOD_RES 143 143 Methionine sulfoxide.
MOD_RES 147 147 Phosphoserine.
CARBOHYD 212 212 O-linked (GalNAc...) threonine.
SEQUENCE 317 AA; 35892 MW; 388E2AE1AF99E489 CRC64;

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