ID APOE_DINBR Reviewed; 300 AA. AC P0DUY6; DT 23-FEB-2022, integrated into UniProtKB/Swiss-Prot. DT 23-FEB-2022, sequence version 1. DT 12-OCT-2022, entry version 4. DE RecName: Full=Apolipoprotein E; DE Short=Apo-E; DE Flags: Precursor; GN Name=APOE; OS Dinomys branickii (Pacarana). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Hystricomorpha; Dinomyidae; OC Dinomys. OX NCBI_TaxID=108858; RN [1] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Johnson J., Muren E., Swofford R., Turner-Maier J., Marinescu V., RA Genereux D., Birren B., Karlsson E.K., Lindblad-Toh K.; RT "The 200 mammals project: sequencing genomes by a novel cost-effective RT method, yielding a high resolution annotation of the human genome."; RL Submitted (FEB-2018) to the EMBL/GenBank/DDBJ databases. RN [2] RP IDENTIFICATION. RA Puppione D.L.; RL Unpublished observations (JUL-2021). CC -!- FUNCTION: APOE is an apolipoprotein, a protein associating with lipid CC particles, that mainly functions in lipoprotein-mediated lipid CC transport between organs via the plasma and interstitial fluids. APOE CC is a core component of plasma lipoproteins and is involved in their CC production, conversion and clearance. Apoliproteins are amphipathic CC molecules that interact both with lipids of the lipoprotein particle CC core and the aqueous environment of the plasma. As such, APOE CC associates with chylomicrons, chylomicron remnants, very low density CC lipoproteins (VLDL) and intermediate density lipoproteins (IDL) but CC shows a preferential binding to high-density lipoproteins (HDL). It CC also binds a wide range of cellular receptors including the LDL CC receptor/LDLR, the LDL receptor-related proteins LRP1, LRP2 and LRP8 CC and the very low-density lipoprotein receptor/VLDLR that mediate the CC cellular uptake of the APOE-containing lipoprotein particles. Finally, CC APOE has also a heparin-binding activity and binds heparan-sulfate CC proteoglycans on the surface of cells, a property that supports the CC capture and the receptor-mediated uptake of APOE-containing CC lipoproteins by cells. A main function of APOE is to mediate CC lipoprotein clearance through the uptake of chylomicrons, VLDLs, and CC HDLs by hepatocytes. APOE is also involved in the biosynthesis by the CC liver of VLDLs as well as their uptake by peripheral tissues ensuring CC the delivery of triglycerides and energy storage in muscle, heart and CC adipose tissues. By participating in the lipoprotein-mediated CC distribution of lipids among tissues, APOE plays a critical role in CC plasma and tissues lipid homeostasis. APOE is also involved in two CC steps of reverse cholesterol transport, the HDLs-mediated transport of CC cholesterol from peripheral tissues to the liver, and thereby plays an CC important role in cholesterol homeostasis. First, it is functionally CC associated with ABCA1 in the biogenesis of HDLs in tissues. Second, it CC is enriched in circulating HDLs and mediates their uptake by CC hepatocytes. APOE also plays an important role in lipid transport in CC the central nervous system, regulating neuron survival and sprouting. CC {ECO:0000250|UniProtKB:P02649}. CC -!- SUBUNIT: Homotetramer. May interact with ABCA1; functionally associated CC with ABCA1 in the biogenesis of HDLs. May interact with APP/A4 amyloid- CC beta peptide; the interaction is extremely stable in vitro but its CC physiological significance is unclear. May interact with MAPT. May CC interact with MAP2. In the cerebrospinal fluid, interacts with secreted CC SORL1. Interacts with PMEL; this allows the loading of PMEL luminal CC fragment on ILVs to induce fibril nucleation. CC {ECO:0000250|UniProtKB:P02649}. CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000250|UniProtKB:P02649}. CC Secreted, extracellular space {ECO:0000250|UniProtKB:P02649}. Secreted, CC extracellular space, extracellular matrix CC {ECO:0000250|UniProtKB:P02649}. Extracellular vesicle CC {ECO:0000250|UniProtKB:P02649}. Endosome, multivesicular body CC {ECO:0000250|UniProtKB:P02649}. Note=In the plasma, APOE is associated CC with chylomicrons, chylomicrons remnants, VLDL, LDL and HDL CC lipoproteins. Lipid poor oligomeric APOE is associated with the CC extracellular matrix in a calcium- and heparan-sulfate proteoglycans- CC dependent manner. Lipidation induces the release from the extracellular CC matrix. Colocalizes with CD63 and PMEL at exosomes and in intraluminal CC vesicles within multivesicular endosomes. CC {ECO:0000250|UniProtKB:P02649}. CC -!- PTM: APOE exists as multiple glycosylated and sialylated glycoforms CC within cells and in plasma. The extent of glycosylation and sialylation CC are tissue and context specific. {ECO:0000250|UniProtKB:P02649}. CC -!- PTM: Glycated in plasma VLDL. {ECO:0000250|UniProtKB:P02649}. CC -!- PTM: Phosphorylated by FAM20C in the extracellular medium. CC {ECO:0000250|UniProtKB:P02649}. CC -!- SIMILARITY: Belongs to the apolipoprotein A1/A4/E family. CC {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; PVLD010006399; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR GO; GO:0042627; C:chylomicron; IEA:UniProtKB-KW. DR GO; GO:0034364; C:high-density lipoprotein particle; IEA:UniProtKB-KW. DR GO; GO:0034361; C:very-low-density lipoprotein particle; IEA:UniProtKB-KW. DR GO; GO:0008201; F:heparin binding; IEA:UniProtKB-KW. DR GO; GO:0008289; F:lipid binding; IEA:UniProtKB-KW. DR GO; GO:0006869; P:lipid transport; IEA:UniProtKB-KW. DR GO; GO:0042157; P:lipoprotein metabolic process; IEA:InterPro. DR InterPro; IPR000074; ApoA_E. DR Pfam; PF01442; Apolipoprotein; 1. PE 3: Inferred from homology; KW Chylomicron; Endosome; Extracellular matrix; Glycoprotein; HDL; KW Heparin-binding; Lipid transport; Lipid-binding; Oxidation; Phosphoprotein; KW Repeat; Secreted; Signal; Transport; VLDL. FT SIGNAL 1..18 FT /evidence="ECO:0000255" FT CHAIN 19..300 FT /note="Apolipoprotein E" FT /id="PRO_0000454010" FT REPEAT 75..95 FT /note="1" FT REPEAT 96..117 FT /note="2" FT REPEAT 118..139 FT /note="3" FT REPEAT 140..161 FT /note="4" FT REPEAT 162..183 FT /note="5" FT REPEAT 184..205 FT /note="6" FT REPEAT 206..224 FT /note="7" FT REPEAT 225..243 FT /note="8" FT REGION 74..246 FT /note="8 X 22 AA approximate tandem repeats" FT REGION 152..162 FT /note="LDL and other lipoprotein receptors binding" FT /evidence="ECO:0000250|UniProtKB:P02649" FT REGION 204..274 FT /note="Lipid-binding and lipoprotein association" FT /evidence="ECO:0000250|UniProtKB:P02649" FT REGION 262..274 FT /note="Specificity for association with VLDL" FT /evidence="ECO:0000250|UniProtKB:P02649" FT BINDING 156..159 FT /ligand="heparin" FT /ligand_id="ChEBI:CHEBI:28304" FT /evidence="ECO:0000250|UniProtKB:P02649" FT BINDING 220..227 FT /ligand="heparin" FT /ligand_id="ChEBI:CHEBI:28304" FT /evidence="ECO:0000250|UniProtKB:P02649" FT MOD_RES 137 FT /note="Methionine sulfoxide" FT /evidence="ECO:0000250|UniProtKB:P08226" FT MOD_RES 141 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P02649" SQ SEQUENCE 300 AA; 34333 MW; 848B2E2274531117 CRC64; MKVLWAVLVV TLLAGCQADV EPELEAQEPA VWQNGQPWEL ALGRFWDYLR WVQTLSDQVQ EELLSSQVTQ ELTVLMEDTM KEVKAYKSEL EQELAPMAEE TKARLSKELK AAQARLGADM EEVRNRLSQY RGEVQSMLGH SAEELRARLA THLRKLRKRL LRDAEDLQKR LAVYKAGASE GAERSVSAIR ERLGSLVEQG RLRTAALTSQ PLQERAQAWG ERLRGRLEEV GSKARDRLDE VREQMEEVRL KVEEQAEAFQ ARLKGWFEPM MEDIRRQWAD LIEKMQAAVG TSTPAPTQKP //