ANGL3_HUMAN
ID ANGL3_HUMAN Reviewed; 460 AA.
AC Q9Y5C1; A0JLS0; B1ALJ0; B2RCW1;
DT 08-NOV-2002, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1999, sequence version 1.
DT 03-AUG-2022, entry version 188.
DE RecName: Full=Angiopoietin-related protein 3;
DE AltName: Full=Angiopoietin-5;
DE Short=ANG-5;
DE AltName: Full=Angiopoietin-like protein 3;
DE Contains:
DE RecName: Full=ANGPTL3(17-221);
DE Contains:
DE RecName: Full=ANGPTL3(17-224);
DE Flags: Precursor;
GN Name=ANGPTL3; Synonyms=ANGPT5; ORFNames=UNQ153/PRO179;
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 [MRNA], TISSUE SPECIFICITY, AND GLYCOSYLATION AT
RP ASN-115.
RC TISSUE=Liver;
RX PubMed=10644446; DOI=10.1006/geno.1999.6041;
RA Conklin D., Gilbertson D., Taft D.W., Maurer M.F., Whitmore T.E.,
RA Smith D.L., Walker K.M., Chen L.H., Wattler S., Nehls M., Lewis K.B.;
RT "Identification of a mammalian angiopoietin-related protein expressed
RT specifically in liver.";
RL Genomics 62:477-482(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=12975309; DOI=10.1101/gr.1293003;
RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J.,
RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P.,
RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S., Huang A.,
RA Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D.,
RA Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L.,
RA Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C.,
RA Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J.,
RA Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M.;
RT "The secreted protein discovery initiative (SPDI), a large-scale effort to
RT identify novel human secreted and transmembrane proteins: a bioinformatics
RT assessment.";
RL Genome Res. 13:2265-2270(2003).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Liver;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG SeattleSNPs variation discovery resource;
RL Submitted (MAR-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NHLBI resequencing and genotyping service (RS&G);
RL Submitted (FEB-2007) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Liver, and Skeletal muscle;
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 [8]
RP PROTEIN SEQUENCE OF 17-31.
RX PubMed=15340161; DOI=10.1110/ps.04682504;
RA Zhang Z., Henzel W.J.;
RT "Signal peptide prediction based on analysis of experimentally verified
RT cleavage sites.";
RL Protein Sci. 13:2819-2824(2004).
RN [9]
RP FUNCTION, GLYCOSYLATION, SUBCELLULAR LOCATION, AND DOMAIN.
RX PubMed=11877390; DOI=10.1074/jbc.m109768200;
RA Camenisch G., Pisabarro M.T., Sherman D., Kowalski J., Nagel M., Hass P.,
RA Xie M.H., Gurney A., Bodary S., Liang X.H., Clark K., Beresini M.,
RA Ferrara N., Gerber H.P.;
RT "ANGPTL3 stimulates endothelial cell adhesion and migration via integrin
RT alpha vbeta 3 and induces blood vessel formation in vivo.";
RL J. Biol. Chem. 277:17281-17290(2002).
RN [10]
RP FUNCTION.
RX PubMed=12097324; DOI=10.1074/jbc.m203215200;
RA Shimizugawa T., Ono M., Shimamura M., Yoshida K., Ando Y., Koishi R.,
RA Ueda K., Inaba T., Minekura H., Kohama T., Furukawa H.;
RT "ANGPTL3 decreases very low density lipoprotein triglyceride clearance by
RT inhibition of lipoprotein lipase.";
RL J. Biol. Chem. 277:33742-33748(2002).
RN [11]
RP FUNCTION.
RX PubMed=11788823; DOI=10.1038/ng814;
RA Koishi R., Ando Y., Ono M., Shimamura M., Yasumo H., Fujiwara T.,
RA Horikoshi H., Furukawa H.;
RT "Angptl3 regulates lipid metabolism in mice.";
RL Nat. Genet. 30:151-157(2002).
RN [12]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=12565906; DOI=10.1016/s0006-291x(02)03058-9;
RA Shimamura M., Matsuda M., Kobayashi S., Ando Y., Ono M., Koishi R.,
RA Furukawa H., Makishima M., Shimomura I.;
RT "Angiopoietin-like protein 3, a hepatic secretory factor, activates
RT lipolysis in adipocytes.";
RL Biochem. Biophys. Res. Commun. 301:604-609(2003).
RN [13]
RP PROTEOLYTIC CLEAVAGE, FUNCTION, AND MUTAGENESIS OF 62-HIS-LYS-63; LYS-65;
RP 204-ARG-ARG-205; ARG-221; ARG-224 AND ARG-235.
RX PubMed=12909640; DOI=10.1074/jbc.m302861200;
RA Ono M., Shimizugawa T., Shimamura M., Yoshida K., Noji-Sakikawa C.,
RA Ando Y., Koishi R., Furukawa H.;
RT "Protein region important for regulation of lipid metabolism in
RT angiopoietin-like 3 (ANGPTL3): ANGPTL3 is cleaved and activated in vivo.";
RL J. Biol. Chem. 278:41804-41809(2003).
RN [14]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-115; ASN-296 AND ASN-357.
RC TISSUE=Plasma;
RX PubMed=16335952; DOI=10.1021/pr0502065;
RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E., Moore R.J.,
RA Smith R.D.;
RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction,
RT hydrazide chemistry, and mass spectrometry.";
RL J. Proteome Res. 4:2070-2080(2005).
RN [15]
RP FUNCTION.
RX PubMed=17110602; DOI=10.1161/01.atv.0000252827.51626.89;
RA Shimamura M., Matsuda M., Yasumo H., Okazaki M., Fujimoto K., Kono K.,
RA Shimizugawa T., Ando Y., Koishi R., Kohama T., Sakai N., Kotani K.,
RA Komuro R., Ishida T., Hirata K., Yamashita S., Furukawa H., Shimomura I.;
RT "Angiopoietin-like protein3 regulates plasma HDL cholesterol through
RT suppression of endothelial lipase.";
RL Arterioscler. Thromb. Vasc. Biol. 27:366-372(2007).
RN [16]
RP POSSIBLE INVOLVEMENT IN ATHEROSCLEROSIS.
RX PubMed=17191020; DOI=10.1159/000098153;
RA Hatsuda S., Shoji T., Shinohara K., Kimoto E., Mori K., Fukumoto S.,
RA Koyama H., Emoto M., Nishizawa Y.;
RT "Association between plasma angiopoietin-like protein 3 and arterial wall
RT thickness in healthy subjects.";
RL J. Vasc. Res. 44:61-66(2007).
RN [17]
RP FUNCTION.
RX PubMed=18535744; DOI=10.1111/j.1745-7270.2008.00421.x;
RA Li Y., Sun L., Xu H., Fang Z., Yao W., Guo W., Rao J., Zha X.;
RT "Angiopoietin-like protein 3 modulates barrier properties of human
RT glomerular endothelial cells through a possible signaling pathway involving
RT phosphatidylinositol-3 kinase/protein kinase B and integrin alphaVbeta3.";
RL Acta Biochim. Biophys. Sin. 40:459-465(2008).
RN [18]
RP FUNCTION.
RX PubMed=19028676; DOI=10.1074/jbc.m808477200;
RA Shan L., Yu X.C., Liu Z., Hu Y., Sturgis L.T., Miranda M.L., Liu Q.;
RT "The angiopoietin-like proteins ANGPTL3 and ANGPTL4 inhibit lipoprotein
RT lipase activity through distinct mechanisms.";
RL J. Biol. Chem. 284:1419-1424(2009).
RN [19]
RP FUNCTION.
RX PubMed=19318355; DOI=10.1074/jbc.m807899200;
RA Lee E.C., Desai U., Gololobov G., Hong S., Feng X., Yu X.C., Gay J.,
RA Wilganowski N., Gao C., Du L.L., Chen J., Hu Y., Zhao S., Kirkpatrick L.,
RA Schneider M., Zambrowicz B.P., Landes G., Powell D.R., Sonnenburg W.K.;
RT "Identification of a new functional domain in angiopoietin-like 3 (ANGPTL3)
RT and angiopoietin-like 4 (ANGPTL4) involved in binding and inhibition of
RT lipoprotein lipase (LPL).";
RL J. Biol. Chem. 284:13735-13745(2009).
RN [20]
RP FUNCTION (ANGPTL3(17-221)).
RX PubMed=19542565; DOI=10.1194/jlr.m900145-jlr200;
RA Sonnenburg W.K., Yu D., Lee E.C., Xiong W., Gololobov G., Key B., Gay J.,
RA Wilganowski N., Hu Y., Zhao S., Schneider M., Ding Z.M., Zambrowicz B.P.,
RA Landes G., Powell D.R., Desai U.;
RT "GPIHBP1 stabilizes lipoprotein lipase and prevents its inhibition by
RT angiopoietin-like 3 and angiopoietin-like 4.";
RL J. Lipid Res. 50:2421-2429(2009).
RN [21]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-296.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of multiple
RT enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [22]
RP FUNCTION.
RX PubMed=20581395; DOI=10.1074/jbc.m110.144279;
RA Liu J., Afroza H., Rader D.J., Jin W.;
RT "Angiopoietin-like protein 3 inhibits lipoprotein lipase activity through
RT enhancing its cleavage by proprotein convertases.";
RL J. Biol. Chem. 285:27561-27570(2010).
RN [23]
RP GLYCOSYLATION AT THR-226.
RX PubMed=20837471; DOI=10.1074/jbc.m110.156950;
RA Schjoldager K.T., Vester-Christensen M.B., Bennett E.P., Levery S.B.,
RA Schwientek T., Yin W., Blixt O., Clausen H.;
RT "O-glycosylation modulates proprotein convertase activation of
RT angiopoietin-like protein 3: possible role of polypeptide GalNAc-
RT transferase-2 in regulation of concentrations of plasma lipids.";
RL J. Biol. Chem. 285:36293-36303(2010).
RN [24]
RP INVOLVEMENT IN FHBL2.
RX PubMed=20942659; DOI=10.1056/nejmoa1002926;
RA Musunuru K., Pirruccello J.P., Do R., Peloso G.M., Guiducci C., Sougnez C.,
RA Garimella K.V., Fisher S., Abreu J., Barry A.J., Fennell T., Banks E.,
RA Ambrogio L., Cibulskis K., Kernytsky A., Gonzalez E., Rudzicz N.,
RA Engert J.C., DePristo M.A., Daly M.J., Cohen J.C., Hobbs H.H.,
RA Altshuler D., Schonfeld G., Gabriel S.B., Yue P., Kathiresan S.;
RT "Exome sequencing, ANGPTL3 mutations, and familial combined
RT hypolipidemia.";
RL N. Engl. J. Med. 363:2220-2227(2010).
RN [25]
RP GLYCOSYLATION.
RX PubMed=22566642; DOI=10.1073/pnas.1203563109;
RA Schjoldager K.T., Vakhrushev S.Y., Kong Y., Steentoft C., Nudelman A.S.,
RA Pedersen N.B., Wandall H.H., Mandel U., Bennett E.P., Levery S.B.,
RA Clausen H.;
RT "Probing isoform-specific functions of polypeptide GalNAc-transferases
RT using zinc finger nuclease glycoengineered SimpleCells.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:9893-9898(2012).
RN [26]
RP INTERACTION WITH ANGPTL8.
RX PubMed=23150577; DOI=10.1073/pnas.1217552109;
RA Quagliarini F., Wang Y., Kozlitina J., Grishin N.V., Hyde R.,
RA Boerwinkle E., Valenzuela D.M., Murphy A.J., Cohen J.C., Hobbs H.H.;
RT "Atypical angiopoietin-like protein that regulates ANGPTL3.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:19751-19756(2012).
RN [27]
RP FUNCTION.
RX PubMed=23661675; DOI=10.1161/atvbaha.113.301397;
RA Robciuc M.R., Maranghi M., Lahikainen A., Rader D., Bensadoun A.,
RA Oeoerni K., Ooerni K., Metso J., Minicocci I., Ciociola E., Ceci F.,
RA Montali A., Arca M., Ehnholm C., Jauhiainen M.;
RT "Angptl3 deficiency is associated with increased insulin sensitivity,
RT lipoprotein lipase activity, and decreased serum free fatty acids.";
RL Arterioscler. Thromb. Vasc. Biol. 33:1706-1713(2013).
RN [28]
RP FUNCTION.
RX PubMed=25495645; DOI=10.1042/bsr20140115;
RA Tikka A., Soronen J., Laurila P.P., Metso J., Ehnholm C., Jauhiainen M.;
RT "Silencing of ANGPTL 3 (angiopoietin-like protein 3) in human hepatocytes
RT results in decreased expression of gluconeogenic genes and reduced
RT triacylglycerol-rich VLDL secretion upon insulin stimulation.";
RL Biosci. Rep. 34:E00160-E00160(2014).
RN [29]
RP TISSUE SPECIFICITY, AND INDUCTION.
RX PubMed=26204133; DOI=10.1210/jc.2015-1254;
RA Nidhina Haridas P.A., Soronen J., Saedevirta S., Mysore R., Quagliarini F.,
RA Pasternack A., Metso J., Perttilae J., Leivonen M., Smas C.M.,
RA Fischer-Posovszky P., Wabitsch M., Ehnholm C., Ritvos O., Jauhiainen M.,
RA Olkkonen V.M., Yki-Jaervinen H.;
RT "Regulation of Angiopoietin-Like Proteins (ANGPTLs) 3 and 8 by Insulin.";
RL J. Clin. Endocrinol. Metab. 100:E1299-E1307(2015).
RN [30] {ECO:0007744|PDB:6EUA}
RP X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) OF 242-460, DISULFIDE BONDS, AND
RP CHARACTERIZATION OF VARIANTS THR-259; GLN-288; PRO-292; SER-344 AND
RP LYS-375.
RX PubMed=29713054; DOI=10.1038/s41598-018-25237-7;
RA Biterova E., Esmaeeli M., Alanen H.I., Saaranen M., Ruddock L.W.;
RT "Structures of Angptl3 and Angptl4, modulators of triglyceride levels and
RT coronary artery disease.";
RL Sci. Rep. 8:6752-6752(2018).
RN [31]
RP VARIANT PHE-127.
RX PubMed=22095935; DOI=10.1002/humu.21660;
RA Huijgen R., Sjouke B., Vis K., de Randamie J.S., Defesche J.C.,
RA Kastelein J.J., Hovingh G.K., Fouchier S.W.;
RT "Genetic variation in APOB, PCSK9, and ANGPTL3 in carriers of pathogenic
RT autosomal dominant hypercholesterolemic mutations with unexpected low LDL-
RT Cl Levels.";
RL Hum. Mutat. 33:448-455(2012).
RN [32]
RP VARIANTS THR-63; GLY-91; PHE-164; SER-173; THR-259; GLN-288; PRO-292;
RP LYS-375 AND CYS-417, AND CHARACTERIZATION OF VARIANTS THR-63; GLY-91;
RP PHE-164; SER-173; THR-259; ARG-GLN; PRO-292; LYS-375 AND CYS-417.
RX PubMed=19075393; DOI=10.1172/jci37118;
RA Romeo S., Yin W., Kozlitina J., Pennacchio L.A., Boerwinkle E., Hobbs H.H.,
RA Cohen J.C.;
RT "Rare loss-of-function mutations in ANGPTL family members contribute to
RT plasma triglyceride levels in humans.";
RL J. Clin. Invest. 119:70-79(2009).
RN [33]
RP VARIANT SER-344, AND CHARACTERIZATION OF VARIANTS SER-173; SER-344 AND
RP LYS-375.
RX PubMed=25733326; DOI=10.1016/j.atherosclerosis.2015.02.031;
RA Wang X., Wang D., Shan Z.;
RT "Clinical and genetic analysis of a family diagnosed with familial
RT hypobetalipoproteinemia in which the proband was diagnosed with diabetes
RT mellitus.";
RL Atherosclerosis 239:552-556(2015).
RN [34]
RP TISSUE SPECIFICITY, SUBCELLULAR LOCATION, AND POSSIBLE INVOLVEMENT IN
RP NEPHROTIC SYNDROME.
RX PubMed=25710887; DOI=10.1038/pr.2015.38;
RA Liu J., Gao X., Zhai Y., Shen Q., Sun L., Feng C., Rao J., Liu H., Zha X.,
RA Guo M., Ma D., Zhang Z., Li R., Xu H.;
RT "A novel role of angiopoietin-like-3 associated with podocyte injury.";
RL Pediatr. Res. 77:732-739(2015).
CC -!- FUNCTION: Acts in part as a hepatokine that is involved in regulation
CC of lipid and glucose metabolism (PubMed:11788823, PubMed:12909640,
CC PubMed:23661675, PubMed:25495645). Proposed to play a role in the
CC trafficking of energy substrates to either storage or oxidative tissues
CC in response to food intake (By similarity). Has a stimulatory effect on
CC plasma triglycerides (TG), which is achieved by suppressing plasma TG
CC clearance via inhibition of LPL activity. The inhibition of LPL
CC activity appears to be an indirect mechanism involving recruitment of
CC proprotein convertases PCSK6 and FURIN to LPL leading to cleavage and
CC dissociation of LPL from the cell surface; the function does not
CC require ANGPTL3 proteolytic cleavage but seems to be mediated by the N-
CC terminal domain, and is not inhibited by GPIHBP1 (PubMed:12097324,
CC PubMed:19318355, PubMed:20581395). Can inhibit endothelial lipase,
CC causing increased plasma levels of high density lipoprotein (HDL)
CC cholesterol and phospholipids (PubMed:17110602, PubMed:19028676). Can
CC bind to adipocytes to activate lipolysis, releasing free fatty acids
CC and glycerol (PubMed:12565906). Suppresses LPL specifically in
CC oxidative tissues which is required to route very low density
CC lipoprotein (VLDL)-TG to white adipose tissue (WAT) for storage in
CC response to food; the function may involve cooperation with
CC circulating, liver-derived ANGPTL8 and ANGPTL4 expression in WAT (By
CC similarity). Contributes to lower plasma levels of low density
CC lipoprotein (LDL)-cholesterol by a mechanism that is independent of the
CC canonical pathway implicating APOE and LDLR. May stimulate hypothalamic
CC LPL activity (By similarity). {ECO:0000250|UniProtKB:Q9R182,
CC ECO:0000269|PubMed:11788823, ECO:0000269|PubMed:12097324,
CC ECO:0000269|PubMed:12565906, ECO:0000269|PubMed:12909640,
CC ECO:0000269|PubMed:17110602, ECO:0000269|PubMed:19028676,
CC ECO:0000269|PubMed:19318355, ECO:0000269|PubMed:20581395,
CC ECO:0000269|PubMed:23661675, ECO:0000269|PubMed:25495645,
CC ECO:0000305|PubMed:20581395}.
CC -!- FUNCTION: [ANGPTL3(17-221)]: In vitro inhibits LPL activity; not
CC effective on GPIHBP1-stabilized LPL. {ECO:0000269|PubMed:19542565}.
CC -!- FUNCTION: Involved in angiogenesis. Binds to endothelial cells via
CC integrin alpha-V/beta-3 (ITGAV:ITGB3), activates FAK, MAPK and Akt
CC signaling pathways and induces cell adhesion and cell migration
CC (PubMed:11877390). Secreted from podocytes, may modulate properties of
CC glomerular endothelial cells involving integrin alpha-V/beta-3 and Akt
CC signaling (PubMed:18535744). May increase the motility of podocytes.
CC May induce actin filament rearrangements in podocytes implicating
CC integrin alpha-V/beta-3 and Rac1 activation. Binds to hematopoietic
CC stem cells (HSC) and is involved in the regulation of HSC activity
CC probably implicating down-regulation of IKZF1/IKAROS (By similarity).
CC {ECO:0000250|UniProtKB:Q9R182, ECO:0000269|PubMed:11877390,
CC ECO:0000269|PubMed:18535744}.
CC -!- SUBUNIT: Interacts with ANGPTL8. Interacts with ITGB3 (By similarity).
CC {ECO:0000250|UniProtKB:Q9R182, ECO:0000269|PubMed:23150577}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000250,
CC ECO:0000305|PubMed:11877390}. Cell projection, lamellipodium
CC {ECO:0000250|UniProtKB:Q9R182}. Note=Colocalized with HSPG2 and
CC activated ITGB3 on podocytes. {ECO:0000250|UniProtKB:Q9R182}.
CC -!- TISSUE SPECIFICITY: Expressed principally in liver. Weakly expressed in
CC kidney. Binds to adipocytes. Increased expression and colocalization
CC with activated ITGB3 in glomeruli of patients with nephrotic syndrome
CC showing effaced podocyte foot processes (at protein level).
CC {ECO:0000269|PubMed:10644446, ECO:0000269|PubMed:25710887,
CC ECO:0000269|PubMed:26204133}.
CC -!- INDUCTION: Down-regulated by insulin. {ECO:0000269|PubMed:26204133}.
CC -!- DOMAIN: The fibrinogen C-terminal domain is sufficient to mediate
CC endothelial cell adhesion. {ECO:0000269|PubMed:11877390}.
CC -!- PTM: O-glycosylated at Thr-226 by GALNT2; blocks processing and
CC activation by proprotein convertases. {ECO:0000269|PubMed:20837471,
CC ECO:0000269|PubMed:22566642}.
CC -!- PTM: In part proteolytically cleaved by proprotein convertases;
CC proposed to be involved in activation. {ECO:0000269|PubMed:12909640,
CC ECO:0000269|PubMed:20837471}.
CC -!- DISEASE: Hypobetalipoproteinemia, familial, 2 (FHBL2) [MIM:605019]: A
CC disorder of lipid metabolism characterized by less than 5th percentile
CC age- and sex-specific levels of low density lipoproteins, and dietary
CC fat malabsorption. Affected individuals present with combined
CC hypolipidemia, consisting of extremely low plasma levels of LDL
CC cholesterol, HDL cholesterol, and triglycerides.
CC {ECO:0000269|PubMed:20942659}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Note=May be involved in atherosclerosis. Plasma levels are
CC closely associated with arterial wall thickness.
CC {ECO:0000305|PubMed:17191020}.
CC -!- DISEASE: Note=May be involved in nephrotic syndrome.
CC {ECO:0000305|PubMed:25710887}.
CC -!- MISCELLANEOUS: Was suggested to inhibit LPL through a direct mechanism;
CC however, the necessary concentration to achieve in vitro inhibition is
CC at least 30-fold higher than ANGPTL3 plasma concentration.
CC {ECO:0000305|PubMed:19028676, ECO:0000305|PubMed:20581395}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH07059.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence.; Evidence={ECO:0000305};
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DR EMBL; AF152562; AAD34156.1; -; mRNA.
DR EMBL; AY358273; AAQ88640.1; -; mRNA.
DR EMBL; AK315304; BAG37708.1; -; mRNA.
DR EMBL; AY569015; AAS66984.1; -; Genomic_DNA.
DR EMBL; FJ515851; ACS13743.1; -; Genomic_DNA.
DR EMBL; CH471059; EAX06583.1; -; Genomic_DNA.
DR EMBL; BC007059; AAH07059.1; ALT_SEQ; mRNA.
DR EMBL; BC058287; AAH58287.1; -; mRNA.
DR CCDS; CCDS622.1; -.
DR RefSeq; NP_055310.1; NM_014495.3.
DR PDB; 6EUA; X-ray; 2.10 A; A/B/C=242-460.
DR PDBsum; 6EUA; -.
DR AlphaFoldDB; Q9Y5C1; -.
DR SASBDB; Q9Y5C1; -.
DR SMR; Q9Y5C1; -.
DR BioGRID; 118143; 9.
DR IntAct; Q9Y5C1; 7.
DR STRING; 9606.ENSP00000360170; -.
DR ChEMBL; CHEMBL3710485; -.
DR DrugBank; DB15354; Evinacumab.
DR GlyConnect; 1010; 2 N-Linked glycans (3 sites).
DR GlyGen; Q9Y5C1; 8 sites, 2 N-linked glycans (3 sites), 3 O-linked glycans (3 sites).
DR iPTMnet; Q9Y5C1; -.
DR PhosphoSitePlus; Q9Y5C1; -.
DR BioMuta; ANGPTL3; -.
DR DMDM; 25008126; -.
DR MassIVE; Q9Y5C1; -.
DR PaxDb; Q9Y5C1; -.
DR PeptideAtlas; Q9Y5C1; -.
DR PRIDE; Q9Y5C1; -.
DR ProteomicsDB; 86339; -.
DR ABCD; Q9Y5C1; 1 sequenced antibody.
DR Antibodypedia; 19489; 492 antibodies from 39 providers.
DR DNASU; 27329; -.
DR Ensembl; ENST00000371129.4; ENSP00000360170.3; ENSG00000132855.5.
DR GeneID; 27329; -.
DR KEGG; hsa:27329; -.
DR MANE-Select; ENST00000371129.4; ENSP00000360170.3; NM_014495.4; NP_055310.1.
DR UCSC; uc001das.3; human.
DR CTD; 27329; -.
DR DisGeNET; 27329; -.
DR GeneCards; ANGPTL3; -.
DR HGNC; HGNC:491; ANGPTL3.
DR HPA; ENSG00000132855; Tissue enriched (liver).
DR MalaCards; ANGPTL3; -.
DR MIM; 604774; gene.
DR MIM; 605019; phenotype.
DR neXtProt; NX_Q9Y5C1; -.
DR OpenTargets; ENSG00000132855; -.
DR Orphanet; 426; NON RARE IN EUROPE: Familial hypobetalipoproteinemia.
DR PharmGKB; PA24796; -.
DR VEuPathDB; HostDB:ENSG00000132855; -.
DR eggNOG; KOG2579; Eukaryota.
DR GeneTree; ENSGT00940000156746; -.
DR HOGENOM; CLU_038628_2_0_1; -.
DR InParanoid; Q9Y5C1; -.
DR OMA; DWKEEKH; -.
DR OrthoDB; 357340at2759; -.
DR PhylomeDB; Q9Y5C1; -.
DR TreeFam; TF336658; -.
DR PathwayCommons; Q9Y5C1; -.
DR Reactome; R-HSA-8963889; Assembly of active LPL and LIPC lipase complexes.
DR Reactome; R-HSA-9029558; NR1H2 & NR1H3 regulate gene expression linked to lipogenesis.
DR SignaLink; Q9Y5C1; -.
DR BioGRID-ORCS; 27329; 32 hits in 1066 CRISPR screens.
DR ChiTaRS; ANGPTL3; human.
DR GeneWiki; ANGPTL3; -.
DR GenomeRNAi; 27329; -.
DR Pharos; Q9Y5C1; Tclin.
DR PRO; PR:Q9Y5C1; -.
DR Proteomes; UP000005640; Chromosome 1.
DR RNAct; Q9Y5C1; protein.
DR Bgee; ENSG00000132855; Expressed in right lobe of liver and 108 other tissues.
DR Genevisible; Q9Y5C1; HS.
DR GO; GO:0009986; C:cell surface; IDA:BHF-UCL.
DR GO; GO:0062023; C:collagen-containing extracellular matrix; IBA:GO_Central.
DR GO; GO:0005769; C:early endosome; IEA:Ensembl.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IDA:BHF-UCL.
DR GO; GO:0005794; C:Golgi apparatus; IEA:Ensembl.
DR GO; GO:0030027; C:lamellipodium; IEA:UniProtKB-SubCell.
DR GO; GO:0004857; F:enzyme inhibitor activity; ISS:UniProtKB.
DR GO; GO:0008083; F:growth factor activity; IDA:BHF-UCL.
DR GO; GO:0008201; F:heparin binding; IEA:UniProtKB-KW.
DR GO; GO:0005178; F:integrin binding; IPI:UniProtKB.
DR GO; GO:0004859; F:phospholipase inhibitor activity; IDA:BHF-UCL.
DR GO; GO:0005102; F:signaling receptor binding; IBA:GO_Central.
DR GO; GO:0055090; P:acylglycerol homeostasis; IDA:BHF-UCL.
DR GO; GO:0001525; P:angiogenesis; IEA:UniProtKB-KW.
DR GO; GO:0048844; P:artery morphogenesis; ISS:BHF-UCL.
DR GO; GO:0007160; P:cell-matrix adhesion; IPI:UniProtKB.
DR GO; GO:0042632; P:cholesterol homeostasis; IDA:BHF-UCL.
DR GO; GO:0008203; P:cholesterol metabolic process; IDA:BHF-UCL.
DR GO; GO:0006631; P:fatty acid metabolic process; IDA:BHF-UCL.
DR GO; GO:0006071; P:glycerol metabolic process; IDA:BHF-UCL.
DR GO; GO:0007229; P:integrin-mediated signaling pathway; NAS:UniProtKB.
DR GO; GO:0055088; P:lipid homeostasis; IDA:BHF-UCL.
DR GO; GO:0019915; P:lipid storage; IDA:BHF-UCL.
DR GO; GO:0051005; P:negative regulation of lipoprotein lipase activity; IDA:BHF-UCL.
DR GO; GO:0010519; P:negative regulation of phospholipase activity; IDA:BHF-UCL.
DR GO; GO:0009395; P:phospholipid catabolic process; IDA:BHF-UCL.
DR GO; GO:0055091; P:phospholipid homeostasis; IDA:BHF-UCL.
DR GO; GO:0006644; P:phospholipid metabolic process; IDA:BHF-UCL.
DR GO; GO:0045766; P:positive regulation of angiogenesis; IDA:UniProtKB.
DR GO; GO:0030335; P:positive regulation of cell migration; IDA:UniProtKB.
DR GO; GO:0050996; P:positive regulation of lipid catabolic process; IDA:BHF-UCL.
DR GO; GO:0009725; P:response to hormone; IEA:Ensembl.
DR GO; GO:0007165; P:signal transduction; IDA:BHF-UCL.
DR GO; GO:0070328; P:triglyceride homeostasis; IGI:MGI.
DR CDD; cd00087; FReD; 1.
DR DisProt; DP02665; -.
DR Gene3D; 3.90.215.10; -; 1.
DR InterPro; IPR036056; Fibrinogen-like_C.
DR InterPro; IPR014716; Fibrinogen_a/b/g_C_1.
DR InterPro; IPR002181; Fibrinogen_a/b/g_C_dom.
DR Pfam; PF00147; Fibrinogen_C; 1.
DR SMART; SM00186; FBG; 1.
DR SUPFAM; SSF56496; SSF56496; 1.
DR PROSITE; PS51406; FIBRINOGEN_C_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Angiogenesis; Cell adhesion; Cell projection; Coiled coil;
KW Direct protein sequencing; Disulfide bond; Glycoprotein; Heparin-binding;
KW Lipid metabolism; Reference proteome; Secreted; Signal.
FT SIGNAL 1..16
FT /evidence="ECO:0000269|PubMed:15340161"
FT CHAIN 17..460
FT /note="Angiopoietin-related protein 3"
FT /id="PRO_0000009122"
FT CHAIN 17..224
FT /note="ANGPTL3(17-224)"
FT /evidence="ECO:0000305|PubMed:12909640"
FT /id="PRO_0000435903"
FT CHAIN 17..221
FT /note="ANGPTL3(17-221)"
FT /evidence="ECO:0000305|PubMed:12909640"
FT /id="PRO_0000435904"
FT DOMAIN 237..455
FT /note="Fibrinogen C-terminal"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00739"
FT REGION 17..207
FT /note="Sufficient to inhibit LIPG/EL phospholipase
FT activity"
FT /evidence="ECO:0000269|PubMed:17110602"
FT REGION 17..165
FT /note="Sufficient to inhibit LPL lipase activity"
FT /evidence="ECO:0000269|PubMed:12909640"
FT REGION 32..56
FT /note="Required for inhibition of LPL lipase activity"
FT /evidence="ECO:0000269|PubMed:19318355"
FT COILED 85..210
FT /evidence="ECO:0000255"
FT CARBOHYD 115
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:10644446,
FT ECO:0000269|PubMed:16335952"
FT CARBOHYD 226
FT /note="O-linked (GalNAc) threonine"
FT /evidence="ECO:0000269|PubMed:20837471"
FT CARBOHYD 296
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:16335952,
FT ECO:0000269|PubMed:19159218"
FT CARBOHYD 357
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:16335952"
FT DISULFID 246..274
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00739"
FT DISULFID 394..408
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00739"
FT VARIANT 63
FT /note="K -> T (associated with low plasma triglyceride
FT level; fails to suppress LPL activity in vitro;
FT dbSNP:rs146749211)"
FT /evidence="ECO:0000269|PubMed:19075393"
FT /id="VAR_075670"
FT VARIANT 91
FT /note="E -> G (associated with low plasma triglyceride
FT level; fails to suppress LPL activity in vitro;
FT dbSNP:rs139334976)"
FT /evidence="ECO:0000269|PubMed:19075393"
FT /id="VAR_075671"
FT VARIANT 127
FT /note="L -> F (in dbSNP:rs72649573)"
FT /evidence="ECO:0000269|PubMed:22095935"
FT /id="VAR_067283"
FT VARIANT 164
FT /note="L -> F (associated with low plasma triglyceride
FT level; fails to suppress LPL activity in vitro;
FT dbSNP:rs775976787)"
FT /evidence="ECO:0000269|PubMed:19075393"
FT /id="VAR_075672"
FT VARIANT 173
FT /note="N -> S (associated with low plasma triglyceride
FT level; fails to suppress LPL activity in vitro; no effect
FT on protein secretion; dbSNP:rs149624466)"
FT /evidence="ECO:0000269|PubMed:19075393,
FT ECO:0000269|PubMed:25733326"
FT /id="VAR_075673"
FT VARIANT 259
FT /note="M -> T (common allele in African americans;
FT associated with low plasma triglyceride level; fails to
FT suppress LPL activity in vitro; no effect on protein
FT folding; dbSNP:rs77871363)"
FT /evidence="ECO:0000269|PubMed:19075393,
FT ECO:0000269|PubMed:29713054"
FT /id="VAR_075674"
FT VARIANT 288
FT /note="R -> Q (abolishes protein secretion; associated with
FT low plasma triglyceride level; dbSNP:rs763904695)"
FT /evidence="ECO:0000269|PubMed:19075393,
FT ECO:0000269|PubMed:29713054"
FT /id="VAR_075675"
FT VARIANT 288
FT /note="Missing (abolishes protein secretion; associated
FT with low plasma triglyceride level)"
FT /evidence="ECO:0000269|PubMed:19075393"
FT /id="VAR_075676"
FT VARIANT 292
FT /note="S -> P (abolishes protein secretion; associated with
FT low plasma triglyceride level; dbSNP:rs138899888)"
FT /evidence="ECO:0000269|PubMed:19075393,
FT ECO:0000269|PubMed:29713054"
FT /id="VAR_075677"
FT VARIANT 344
FT /note="Y -> S (abolishes protein secretion; associated with
FT low plasma triglyceride level; dbSNP:rs1334979946)"
FT /evidence="ECO:0000269|PubMed:25733326,
FT ECO:0000269|PubMed:29713054"
FT /id="VAR_075678"
FT VARIANT 375
FT /note="E -> K (abolishes protein secretion; associated with
FT low plasma triglyceride level; dbSNP:rs768802285)"
FT /evidence="ECO:0000269|PubMed:19075393,
FT ECO:0000269|PubMed:25733326, ECO:0000269|PubMed:29713054"
FT /id="VAR_075679"
FT VARIANT 417
FT /note="Y -> C (abolishes protein secretion; associated with
FT low plasma triglyceride level; dbSNP:rs376210525)"
FT /evidence="ECO:0000269|PubMed:19075393"
FT /id="VAR_075680"
FT VARIANT 418
FT /note="N -> Y (in dbSNP:rs4145257)"
FT /id="VAR_049071"
FT MUTAGEN 62..63
FT /note="HK->IN: Abolishes effect on plasma triglyceride
FT level; when associated with N-65."
FT /evidence="ECO:0000269|PubMed:12909640"
FT MUTAGEN 63
FT /note="K->N: Abolishes inhibitory effect on LIPG/EL
FT phospholipase activity; when associated with N-65."
FT /evidence="ECO:0000269|PubMed:17110602"
FT MUTAGEN 65
FT /note="K->N: Abolishes effect on plasma triglyceride level;
FT when associated with 62-I-N-63."
FT /evidence="ECO:0000269|PubMed:12909640"
FT MUTAGEN 65
FT /note="K->N: Abolishes inhibitory effect on LIPG/EL
FT phospholipase activity; when associated with N-63."
FT /evidence="ECO:0000269|PubMed:17110602"
FT MUTAGEN 204..205
FT /note="RR->TT: Abolishes proteolytical cleavage and effect
FT on plasma triglyceride levels, keeps in vitro inactivation
FT of LPL activity; when associated with S-221; S-224 and S-
FT 235."
FT /evidence="ECO:0000269|PubMed:12909640"
FT MUTAGEN 221
FT /note="R->ST: Abolishes proteolytical cleavage and effect
FT on plasma triglyceride levels, keeps in vitro inactivation
FT of LPL activity; when associated with 204-T-T-205; S-224
FT and S-235."
FT /evidence="ECO:0000269|PubMed:12909640"
FT MUTAGEN 224
FT /note="R->S: Abolishes proteolytical cleavage and effect on
FT plasma triglyceride levels, keeps in vitro inactivation of
FT LPL activity; when associated with 204-T-T-205; S-221 and
FT S-235."
FT /evidence="ECO:0000269|PubMed:12909640"
FT MUTAGEN 235
FT /note="R->T: Abolishes proteolytical cleavage and effect on
FT plasma triglyceride levels, keeps in vitro inactivation of
FT LPL activity; when associated with 204-T-T-205; S-221 and
FT S-224."
FT /evidence="ECO:0000269|PubMed:12909640"
FT CONFLICT 134
FT /note="L -> P (in Ref. 3; BAG37708)"
FT /evidence="ECO:0000305"
FT HELIX 246..251
FT /evidence="ECO:0007829|PDB:6EUA"
FT STRAND 256..262
FT /evidence="ECO:0007829|PDB:6EUA"
FT STRAND 270..277
FT /evidence="ECO:0007829|PDB:6EUA"
FT STRAND 280..291
FT /evidence="ECO:0007829|PDB:6EUA"
FT HELIX 299..304
FT /evidence="ECO:0007829|PDB:6EUA"
FT STRAND 306..308
FT /evidence="ECO:0007829|PDB:6EUA"
FT STRAND 311..314
FT /evidence="ECO:0007829|PDB:6EUA"
FT HELIX 317..324
FT /evidence="ECO:0007829|PDB:6EUA"
FT STRAND 329..337
FT /evidence="ECO:0007829|PDB:6EUA"
FT STRAND 342..351
FT /evidence="ECO:0007829|PDB:6EUA"
FT HELIX 354..356
FT /evidence="ECO:0007829|PDB:6EUA"
FT STRAND 360..369
FT /evidence="ECO:0007829|PDB:6EUA"
FT STRAND 375..377
FT /evidence="ECO:0007829|PDB:6EUA"
FT STRAND 379..383
FT /evidence="ECO:0007829|PDB:6EUA"
FT HELIX 395..397
FT /evidence="ECO:0007829|PDB:6EUA"
FT STRAND 398..400
FT /evidence="ECO:0007829|PDB:6EUA"
FT STRAND 402..404
FT /evidence="ECO:0007829|PDB:6EUA"
FT STRAND 431..435
FT /evidence="ECO:0007829|PDB:6EUA"
FT STRAND 437..439
FT /evidence="ECO:0007829|PDB:6EUA"
FT STRAND 441..453
FT /evidence="ECO:0007829|PDB:6EUA"
SQ SEQUENCE 460 AA; 53637 MW; 6279465FEEB91F56 CRC64;
MFTIKLLLFI VPLVISSRID QDNSSFDSLS PEPKSRFAML DDVKILANGL LQLGHGLKDF
VHKTKGQIND IFQKLNIFDQ SFYDLSLQTS EIKEEEKELR RTTYKLQVKN EEVKNMSLEL
NSKLESLLEE KILLQQKVKY LEEQLTNLIQ NQPETPEHPE VTSLKTFVEK QDNSIKDLLQ
TVEDQYKQLN QQHSQIKEIE NQLRRTSIQE PTEISLSSKP RAPRTTPFLQ LNEIRNVKHD
GIPAECTTIY NRGEHTSGMY AIRPSNSQVF HVYCDVISGS PWTLIQHRID GSQNFNETWE
NYKYGFGRLD GEFWLGLEKI YSIVKQSNYV LRIELEDWKD NKHYIEYSFY LGNHETNYTL
HLVAITGNVP NAIPENKDLV FSTWDHKAKG HFNCPEGYSG GWWWHDECGE NNLNGKYNKP
RAKSKPERRR GLSWKSQNGR LYSIKSTKML IHPTDSESFE
