APOC3_HUMAN
ID APOC3_HUMAN Reviewed; 99 AA.
AC P02656; Q08E83; Q6Q786;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
DT 21-JUL-1986, sequence version 1.
DT 03-AUG-2022, entry version 207.
DE RecName: Full=Apolipoprotein C-III;
DE Short=Apo-CIII;
DE Short=ApoC-III;
DE AltName: Full=Apolipoprotein C3;
DE Flags: Precursor;
GN Name=APOC3;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
RX PubMed=6439535; DOI=10.1089/dna.1.1984.3.449;
RA Protter A.A., Levy-Wilson B., Miller J., Bencen G., White T.,
RA Seilhamer J.J.;
RT "Isolation and sequence analysis of the human apolipoprotein CIII gene and
RT the intergenic region between the apo AI and apo CIII genes.";
RL DNA 3:449-456(1984).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=6548954; DOI=10.1089/dna.1984.3.359;
RA Levy-Wilson B., Appleby V., Protter A.A., Auperin D., Seilhamer J.J.;
RT "Isolation and DNA sequence of full-length cDNA for human preapolipoprotein
RT CIII.";
RL DNA 3:359-364(1984).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
RX PubMed=2989400;
RA Karathanasis S.K., Zannis V.I., Breslow J.L.;
RT "Isolation and characterization of cDNA clones corresponding to two
RT different human apoC-III alleles.";
RL J. Lipid Res. 26:451-456(1985).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND TISSUE SPECIFICITY.
RX PubMed=6328445; DOI=10.1093/nar/12.9.3917;
RA Sharpe C.R., Sidoli A., Shelley C.S., Lucero M.A., Shoulders C.C.,
RA Baralle F.E.;
RT "Human apolipoproteins AI, AII, CII and CIII. cDNA sequences and mRNA
RT abundance.";
RL Nucleic Acids Res. 12:3917-3932(1984).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=15108119; DOI=10.1007/s00439-004-1106-x;
RA Fullerton S.M., Buchanan A.V., Sonpar V.A., Taylor S.L., Smith J.D.,
RA Carlson C.S., Salomaa V., Stengaard J.H., Boerwinkle E., Clark A.G.,
RA Nickerson D.A., Weiss K.M.;
RT "The effects of scale: variation in the APOA1/C3/A4/A5 gene cluster.";
RL Hum. Genet. 115:36-56(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Pancreas, and Spleen;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP PROTEIN SEQUENCE OF 21-99.
RX PubMed=3949020; DOI=10.1016/0014-5793(86)80300-3;
RA Hospattankar A.V., Brewer H.B. Jr., Ronan R., Fairwell T.;
RT "Amino acid sequence of human plasma apolipoprotein C-III from
RT normolipidemic subjects.";
RL FEBS Lett. 197:67-73(1986).
RN [8]
RP PROTEIN SEQUENCE OF 21-99.
RX PubMed=4846755; DOI=10.1016/s0021-9258(19)42416-2;
RA Brewer H.B. Jr., Shulman R., Herbert P., Ronan R., Wehrly K.;
RT "The complete amino acid sequence of alanine apolipoprotein (apoC-3), and
RT apolipoprotein from human plasma very low density lipoproteins.";
RL J. Biol. Chem. 249:4975-4984(1974).
RN [9]
RP REVIEW.
RX PubMed=18201179; DOI=10.1111/j.1742-1241.2007.01678.x;
RA Chan D.C., Chen M.M., Ooi E.M., Watts G.F.;
RT "An ABC of apolipoprotein C-III: a clinically useful new cardiovascular
RT risk factor?";
RL Int. J. Clin. Pract. 62:799-809(2008).
RN [10]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT THR-94, AND STRUCTURE OF
RP CARBOHYDRATES.
RC TISSUE=Cerebrospinal fluid;
RX PubMed=19838169; DOI=10.1038/nmeth.1392;
RA Nilsson J., Rueetschi U., Halim A., Hesse C., Carlsohn E., Brinkmalm G.,
RA Larson G.;
RT "Enrichment of glycopeptides for glycan structure and attachment site
RT identification.";
RL Nat. Methods 6:809-811(2009).
RN [11]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [12]
RP REVIEW.
RX PubMed=22510806; DOI=10.1097/mol.0b013e328352dc70;
RA Yao Z., Wang Y.;
RT "Apolipoprotein C-III and hepatic triglyceride-rich lipoprotein
RT production.";
RL Curr. Opin. Lipidol. 23:206-212(2012).
RN [13]
RP GLYCOSYLATION AT THR-94, STRUCTURE OF CARBOHYDRATES, AND IDENTIFICATION BY
RP MASS SPECTROMETRY.
RX PubMed=23527852; DOI=10.1021/pr400136p;
RA Nicolardi S., van der Burgt Y.E., Dragan I., Hensbergen P.J., Deelder A.M.;
RT "Identification of new apolipoprotein-CIII glycoforms with ultrahigh
RT resolution MALDI-FTICR mass spectrometry of human sera.";
RL J. Proteome Res. 12:2260-2268(2013).
RN [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [15]
RP STRUCTURE BY NMR IN COMPLEX WITH SDS MICELLES, AND FUNCTION.
RX PubMed=18408013; DOI=10.1074/jbc.m800756200;
RA Gangabadage C.S., Zdunek J., Tessari M., Nilsson S., Olivecrona G.,
RA Wijmenga S.S.;
RT "Structure and dynamics of human apolipoprotein CIII.";
RL J. Biol. Chem. 283:17416-17427(2008).
RN [16]
RP VARIANT C-III-0 ALA-94, AND GLYCOSYLATION AT THR-94.
RX PubMed=3123586;
RA Maeda H., Hashimoto R.K., Oguro T., Hiraga S., Uzawa H.;
RT "Molecular cloning of a human apoC-III variant: Thr 74-->Ala 74 mutation
RT prevents O-glycosylation.";
RL J. Lipid Res. 28:1405-1409(1987).
RN [17]
RP VARIANT HALP2 GLU-78.
RX PubMed=2022742; DOI=10.1172/jci115190;
RA von Eckardstein A., Holz H., Sandkamp M., Weng W., Funke H., Assmann G.;
RT "Apolipoprotein C-III(Lys-58-->Glu). Identification of an apolipoprotein C-
RT III variant in a family with hyperalphalipoproteinemia.";
RL J. Clin. Invest. 87:1724-1731(1991).
CC -!- FUNCTION: Component of triglyceride-rich very low density lipoproteins
CC (VLDL) and high density lipoproteins (HDL) in plasma (PubMed:18201179,
CC PubMed:22510806). Plays a multifaceted role in triglyceride homeostasis
CC (PubMed:18201179, PubMed:22510806). Intracellularly, promotes hepatic
CC very low density lipoprotein 1 (VLDL1) assembly and secretion;
CC extracellularly, attenuates hydrolysis and clearance of triglyceride-
CC rich lipoproteins (TRLs) (PubMed:18201179, PubMed:22510806). Impairs
CC the lipolysis of TRLs by inhibiting lipoprotein lipase and the hepatic
CC uptake of TRLs by remnant receptors (PubMed:18201179, PubMed:22510806).
CC Formed of several curved helices connected via semiflexible hinges, so
CC that it can wrap tightly around the curved micelle surface and easily
CC adapt to the different diameters of its natural binding partners
CC (PubMed:18408013). {ECO:0000269|PubMed:18408013,
CC ECO:0000303|PubMed:18201179, ECO:0000303|PubMed:22510806}.
CC -!- INTERACTION:
CC P02656; Q9Y282: ERGIC3; NbExp=3; IntAct=EBI-1220113, EBI-781551;
CC P02656; Q5JX71: FAM209A; NbExp=3; IntAct=EBI-1220113, EBI-18304435;
CC P02656; Q8TED1: GPX8; NbExp=3; IntAct=EBI-1220113, EBI-11721746;
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000303|PubMed:18201179,
CC ECO:0000303|PubMed:22510806}.
CC -!- TISSUE SPECIFICITY: Liver. {ECO:0000269|PubMed:6328445}.
CC -!- PTM: The most abundant glycoforms are characterized by an O-linked
CC disaccharide galactose linked to N-acetylgalactosamine (Gal-GalNAc),
CC further modified with up to 3 sialic acid residues. Less abundant
CC glycoforms are characterized by more complex and fucosylated glycan
CC moieties. O-glycosylated on Thr-94 with a core 1 or possibly core 8
CC glycan. {ECO:0000269|PubMed:19838169, ECO:0000269|PubMed:23527852,
CC ECO:0000269|PubMed:3123586}.
CC -!- DISEASE: Hyperalphalipoproteinemia 2 (HALP2) [MIM:614028]: A condition
CC characterized by high levels of high density lipoprotein (HDL) and
CC increased HDL cholesterol levels. {ECO:0000269|PubMed:2022742}.
CC Note=The disease is caused by variants affecting the gene represented
CC in this entry.
CC -!- SIMILARITY: Belongs to the apolipoprotein C3 family. {ECO:0000305}.
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DR EMBL; J00098; AAB59515.1; -; Genomic_DNA.
DR EMBL; M33043; AAB59372.1; -; Genomic_DNA.
DR EMBL; M33041; AAB59372.1; JOINED; Genomic_DNA.
DR EMBL; M33042; AAB59372.1; JOINED; Genomic_DNA.
DR EMBL; X01392; CAA25648.1; -; Genomic_DNA.
DR EMBL; X01388; CAA25644.1; -; mRNA.
DR EMBL; X03120; CAA26895.1; -; Genomic_DNA.
DR EMBL; V01513; CAA24757.1; -; mRNA.
DR EMBL; M28613; AAA51760.1; -; mRNA.
DR EMBL; M28614; AAA51761.1; -; mRNA.
DR EMBL; X00567; CAA25233.1; -; mRNA.
DR EMBL; AY422951; AAQ91810.1; -; Genomic_DNA.
DR EMBL; AY555191; AAS68230.1; -; Genomic_DNA.
DR EMBL; BC027977; AAH27977.1; -; mRNA.
DR EMBL; BC121081; AAI21082.1; -; mRNA.
DR CCDS; CCDS8377.1; -.
DR PIR; A90950; LPHUC3.
DR RefSeq; NP_000031.1; NM_000040.1.
DR PDB; 2JQ3; NMR; -; A=21-99.
DR PDBsum; 2JQ3; -.
DR AlphaFoldDB; P02656; -.
DR BMRB; P02656; -.
DR SMR; P02656; -.
DR BioGRID; 106842; 38.
DR IntAct; P02656; 12.
DR MINT; P02656; -.
DR STRING; 9606.ENSP00000227667; -.
DR ChEMBL; CHEMBL4523160; -.
DR DrugBank; DB09130; Copper.
DR DrugBank; DB11886; Infigratinib.
DR DrugBank; DB00877; Sirolimus.
DR DrugBank; DB15067; Volanesorsen.
DR DrugCentral; P02656; -.
DR CarbonylDB; P02656; -.
DR GlyConnect; 58; 4 O-Linked glycans (1 site).
DR GlyGen; P02656; 1 site, 8 O-linked glycans (1 site).
DR iPTMnet; P02656; -.
DR PhosphoSitePlus; P02656; -.
DR BioMuta; APOC3; -.
DR DMDM; 114026; -.
DR DOSAC-COBS-2DPAGE; P02656; -.
DR SWISS-2DPAGE; P02656; -.
DR CPTAC; non-CPTAC-1083; -.
DR EPD; P02656; -.
DR jPOST; P02656; -.
DR MassIVE; P02656; -.
DR MaxQB; P02656; -.
DR PaxDb; P02656; -.
DR PeptideAtlas; P02656; -.
DR PRIDE; P02656; -.
DR ProteomicsDB; 51541; -.
DR Antibodypedia; 32278; 381 antibodies from 36 providers.
DR DNASU; 345; -.
DR Ensembl; ENST00000227667.8; ENSP00000227667.2; ENSG00000110245.12.
DR GeneID; 345; -.
DR KEGG; hsa:345; -.
DR MANE-Select; ENST00000227667.8; ENSP00000227667.2; NM_000040.3; NP_000031.1.
DR UCSC; uc001ppt.2; human.
DR CTD; 345; -.
DR DisGeNET; 345; -.
DR GeneCards; APOC3; -.
DR HGNC; HGNC:610; APOC3.
DR HPA; ENSG00000110245; Tissue enriched (liver).
DR MalaCards; APOC3; -.
DR MIM; 107720; gene.
DR MIM; 614028; phenotype.
DR neXtProt; NX_P02656; -.
DR OpenTargets; ENSG00000110245; -.
DR Orphanet; 79506; Cholesterol-ester transfer protein deficiency.
DR Orphanet; 426; NON RARE IN EUROPE: Familial hypobetalipoproteinemia.
DR Orphanet; 33271; NON RARE IN EUROPE: Non-alcoholic fatty liver disease.
DR PharmGKB; PA53; -.
DR VEuPathDB; HostDB:ENSG00000110245; -.
DR eggNOG; ENOG502SZ00; Eukaryota.
DR GeneTree; ENSGT00390000015395; -.
DR HOGENOM; CLU_154694_0_0_1; -.
DR InParanoid; P02656; -.
DR OMA; YWSTFKG; -.
DR OrthoDB; 1613530at2759; -.
DR PhylomeDB; P02656; -.
DR TreeFam; TF338209; -.
DR PathwayCommons; P02656; -.
DR Reactome; R-HSA-8963888; Chylomicron assembly.
DR Reactome; R-HSA-8963901; Chylomicron remodeling.
DR Reactome; R-HSA-8964058; HDL remodeling.
DR Reactome; R-HSA-975634; Retinoid metabolism and transport.
DR SignaLink; P02656; -.
DR SIGNOR; P02656; -.
DR BioGRID-ORCS; 345; 10 hits in 1068 CRISPR screens.
DR ChiTaRS; APOC3; human.
DR EvolutionaryTrace; P02656; -.
DR GeneWiki; Apolipoprotein_C3; -.
DR GenomeRNAi; 345; -.
DR Pharos; P02656; Tclin.
DR PRO; PR:P02656; -.
DR Proteomes; UP000005640; Chromosome 11.
DR RNAct; P02656; protein.
DR Bgee; ENSG00000110245; Expressed in jejunal mucosa and 105 other tissues.
DR ExpressionAtlas; P02656; baseline and differential.
DR Genevisible; P02656; HS.
DR GO; GO:0042627; C:chylomicron; IDA:BHF-UCL.
DR GO; GO:0062023; C:collagen-containing extracellular matrix; HDA:BHF-UCL.
DR GO; GO:0005769; C:early endosome; TAS:Reactome.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IDA:BHF-UCL.
DR GO; GO:0034363; C:intermediate-density lipoprotein particle; IDA:BHF-UCL.
DR GO; GO:0034366; C:spherical high-density lipoprotein particle; IDA:BHF-UCL.
DR GO; GO:0034361; C:very-low-density lipoprotein particle; IDA:BHF-UCL.
DR GO; GO:0015485; F:cholesterol binding; IC:BHF-UCL.
DR GO; GO:0030234; F:enzyme regulator activity; IDA:BHF-UCL.
DR GO; GO:0070653; F:high-density lipoprotein particle receptor binding; IPI:BHF-UCL.
DR GO; GO:0055102; F:lipase inhibitor activity; IDA:BHF-UCL.
DR GO; GO:0005543; F:phospholipid binding; IDA:BHF-UCL.
DR GO; GO:0033344; P:cholesterol efflux; IDA:BHF-UCL.
DR GO; GO:0042632; P:cholesterol homeostasis; IMP:BHF-UCL.
DR GO; GO:0034382; P:chylomicron remnant clearance; IDA:BHF-UCL.
DR GO; GO:0007186; P:G protein-coupled receptor signaling pathway; IDA:BHF-UCL.
DR GO; GO:0034375; P:high-density lipoprotein particle remodeling; IMP:BHF-UCL.
DR GO; GO:0042157; P:lipoprotein metabolic process; IEA:InterPro.
DR GO; GO:0060621; P:negative regulation of cholesterol import; IMP:BHF-UCL.
DR GO; GO:0045717; P:negative regulation of fatty acid biosynthetic process; IDA:BHF-UCL.
DR GO; GO:0010987; P:negative regulation of high-density lipoprotein particle clearance; IMP:BHF-UCL.
DR GO; GO:0050995; P:negative regulation of lipid catabolic process; IDA:BHF-UCL.
DR GO; GO:0045833; P:negative regulation of lipid metabolic process; IDA:BHF-UCL.
DR GO; GO:0051005; P:negative regulation of lipoprotein lipase activity; IDA:BHF-UCL.
DR GO; GO:0010989; P:negative regulation of low-density lipoprotein particle clearance; IMP:BHF-UCL.
DR GO; GO:0048261; P:negative regulation of receptor-mediated endocytosis; IDA:BHF-UCL.
DR GO; GO:0010897; P:negative regulation of triglyceride catabolic process; IDA:BHF-UCL.
DR GO; GO:0010916; P:negative regulation of very-low-density lipoprotein particle clearance; IDA:BHF-UCL.
DR GO; GO:0010903; P:negative regulation of very-low-density lipoprotein particle remodeling; IDA:BHF-UCL.
DR GO; GO:0033700; P:phospholipid efflux; IDA:BHF-UCL.
DR GO; GO:0032489; P:regulation of Cdc42 protein signal transduction; IDA:BHF-UCL.
DR GO; GO:0043691; P:reverse cholesterol transport; IC:BHF-UCL.
DR GO; GO:0019433; P:triglyceride catabolic process; IDA:BHF-UCL.
DR GO; GO:0070328; P:triglyceride homeostasis; IMP:BHF-UCL.
DR GO; GO:0006641; P:triglyceride metabolic process; IMP:HGNC-UCL.
DR GO; GO:0034379; P:very-low-density lipoprotein particle assembly; TAS:BHF-UCL.
DR Gene3D; 6.10.90.10; -; 1.
DR InterPro; IPR008403; Apo-CIII.
DR InterPro; IPR038195; Apo_CIII_sf.
DR PANTHER; PTHR14225; PTHR14225; 1.
DR Pfam; PF05778; Apo-CIII; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Chylomicron; Direct protein sequencing; Disease variant;
KW Glycoprotein; Lipid degradation; Lipid metabolism; Lipid transport;
KW Reference proteome; Secreted; Sialic acid; Signal; Transport; VLDL.
FT SIGNAL 1..20
FT /evidence="ECO:0000269|PubMed:3949020,
FT ECO:0000269|PubMed:4846755"
FT CHAIN 21..99
FT /note="Apolipoprotein C-III"
FT /evidence="ECO:0000269|PubMed:3949020"
FT /id="PRO_0000002031"
FT REGION 68..99
FT /note="Lipid-binding"
FT SITE 37
FT /note="May interact with the LDL receptor"
FT /evidence="ECO:0000305|PubMed:18408013"
FT SITE 41
FT /note="May interact with the LDL receptor"
FT /evidence="ECO:0000305|PubMed:18408013"
FT SITE 44
FT /note="May interact with the LDL receptor"
FT /evidence="ECO:0000305|PubMed:18408013"
FT CARBOHYD 94
FT /note="O-linked (GalNAc...) threonine"
FT /evidence="ECO:0000269|PubMed:19838169,
FT ECO:0000269|PubMed:23527852, ECO:0000269|PubMed:3123586"
FT /id="CAR_000168"
FT VARIANT 78
FT /note="K -> E (in HALP2; dbSNP:rs121918382)"
FT /evidence="ECO:0000269|PubMed:2022742"
FT /id="VAR_000643"
FT VARIANT 94
FT /note="T -> A (in C-III-0; unglycosylated;
FT dbSNP:rs121918381)"
FT /evidence="ECO:0000269|PubMed:3123586"
FT /id="VAR_000644"
FT CONFLICT 52..53
FT /note="ES -> SQ (in Ref. 8; AA sequence)"
FT /evidence="ECO:0000305"
FT CONFLICT 57..59
FT /note="QQA -> AQQ (in Ref. 8; AA sequence)"
FT /evidence="ECO:0000305"
FT HELIX 29..39
FT /evidence="ECO:0007829|PDB:2JQ3"
FT HELIX 40..42
FT /evidence="ECO:0007829|PDB:2JQ3"
FT HELIX 43..48
FT /evidence="ECO:0007829|PDB:2JQ3"
FT HELIX 49..55
FT /evidence="ECO:0007829|PDB:2JQ3"
FT HELIX 56..62
FT /evidence="ECO:0007829|PDB:2JQ3"
FT TURN 63..68
FT /evidence="ECO:0007829|PDB:2JQ3"
FT HELIX 69..80
FT /evidence="ECO:0007829|PDB:2JQ3"
FT HELIX 83..85
FT /evidence="ECO:0007829|PDB:2JQ3"
FT HELIX 93..98
FT /evidence="ECO:0007829|PDB:2JQ3"
SQ SEQUENCE 99 AA; 10852 MW; D4E806339FAE4DA7 CRC64;
MQPRVLLVVA LLALLASARA SEAEDASLLS FMQGYMKHAT KTAKDALSSV QESQVAQQAR
GWVTDGFSSL KDYWSTVKDK FSEFWDLDPE VRPTSAVAA
