ANGL4_HUMAN
ID ANGL4_HUMAN Reviewed; 406 AA.
AC Q9BY76; A8MY84; B4E089; D6W670; F5H0I2; Q53HQ6; Q53HU1; Q6UXN0; Q9HBV4;
AC Q9NZU4; Q9Y5B3;
DT 08-NOV-2002, integrated into UniProtKB/Swiss-Prot.
DT 08-NOV-2002, sequence version 2.
DT 03-AUG-2022, entry version 185.
DE RecName: Full=Angiopoietin-related protein 4;
DE AltName: Full=Angiopoietin-like protein 4;
DE AltName: Full=Hepatic fibrinogen/angiopoietin-related protein {ECO:0000303|PubMed:10698685};
DE Short=HFARP {ECO:0000303|PubMed:10698685};
DE Contains:
DE RecName: Full=ANGPTL4 N-terminal chain;
DE Contains:
DE RecName: Full=ANGPTL4 C-terminal chain;
DE Flags: Precursor;
GN Name=ANGPTL4; Synonyms=ARP4, HFARP, PGAR {ECO:0000303|PubMed:10866690};
GN ORFNames=PP1158 {ECO:0000303|PubMed:12015030}, PSEC0166, UNQ171/PRO197;
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] (ISOFORM 1), TISSUE SPECIFICITY, SUBCELLULAR
RP LOCATION, GLYCOSYLATION, AND VARIANT MET-266.
RX PubMed=10698685; DOI=10.1042/bj3460603;
RA Kim I., Kim H.-G., Kim H., Kim H.-H., Park S.K., Uhm C.-S., Lee Z.H.,
RA Koh G.Y.;
RT "Hepatic expression, synthesis and secretion of a novel
RT fibrinogen/angiopoietin-related protein that prevents endothelial-cell
RT apoptosis.";
RL Biochem. J. 346:603-610(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND TISSUE SPECIFICITY.
RC TISSUE=Aortic endothelium;
RX PubMed=10866690; DOI=10.1128/mcb.20.14.5343-5349.2000;
RA Yoon J.C., Chickering T.W., Rosen E.D., Dussault B., Qin Y., Soukas A.,
RA Friedman J.M., Holmes W.E., Spiegelman B.M.;
RT "Peroxisome proliferator-activated receptor gamma target gene encoding a
RT novel angiopoietin-related protein associated with adipose
RT differentiation.";
RL Mol. Cell. Biol. 20:5343-5349(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Placenta;
RX PubMed=11953136;
RA Zhu H., Li J., Qin W., Yang Y., He X., Wan D., Gu J.;
RT "Cloning of a novel gene, ANGPTL4 and the functional study in
RT angiogenesis.";
RL Zhonghua Yi Xue Za Zhi 82:94-99(2002).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, AND SUBCELLULAR LOCATION.
RC TISSUE=Placenta;
RX PubMed=14583458;
RA Ito Y., Oike Y., Yasunaga K., Hamada K., Miyata K., Matsumoto S.,
RA Sugano S., Tanihara H., Masuho Y., Suda T.;
RT "Inhibition of angiogenesis and vascular leakiness by angiopoietin-related
RT protein 4.";
RL Cancer Res. 63:6651-6657(2003).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Hair follicle dermal papilla;
RA Kim M.K., Kim Y.H., Seo J.M., Lee H.M., Chung H.J., Sohn M.Y., Hwang S.Y.,
RA Im S.U., Jung E.J., Lee J.H., Kim J.C.;
RT "A catalogue of genes in the human dermal papilla cells as identified by
RT expressed sequence tags.";
RL Submitted (MAY-1999) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
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 [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Thymus;
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 [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT MET-266.
RC TISSUE=Adipose tissue;
RA Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y.,
RA Tanaka A., Yokoyama S.;
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057824; DOI=10.1038/nature02399;
RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E.,
RA Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A.,
RA Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S.,
RA Carrano A.V., Caoile C., Chan Y.M., Christensen M., Cleland C.A.,
RA Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J.,
RA Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M.,
RA Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W.,
RA Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V.,
RA Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D.,
RA McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I.,
RA Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L.,
RA Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A.,
RA She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J.,
RA Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA Rubin E.M., Lucas S.M.;
RT "The DNA sequence and biology of human chromosome 19.";
RL Nature 428:529-535(2004).
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.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 [11]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Pancreas;
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 [12]
RP TISSUE SPECIFICITY.
RX PubMed=12015030;
RA Zhu H., Li J., Wan D., Yang Y., Qin W., Ge C., Yao M., Gu J.;
RT "Expression and function of hepatocellular carcinoma-related gene pp1158.";
RL Zhonghua Zhong Liu Za Zhi 24:123-125(2002).
RN [13]
RP FUNCTION, INDUCTION BY ISCHEMIA, SUBCELLULAR LOCATION, AND PROTEOLYTIC
RP CLEAVAGE.
RX PubMed=17068295; DOI=10.1161/01.res.0000250758.63358.91;
RA Cazes A., Galaup A., Chomel C., Bignon M., Brechot N., Le Jan S., Weber H.,
RA Corvol P., Muller L., Germain S., Monnot C.;
RT "Extracellular matrix-bound angiopoietin-like 4 inhibits endothelial cell
RT adhesion, migration, and sprouting and alters actin cytoskeleton.";
RL Circ. Res. 99:1207-1215(2006).
RN [14]
RP SUBCELLULAR LOCATION, SUBUNIT, PROTEOLYTIC CLEAVAGE, CHARACTERIZATION OF
RP VARIANT LYS-40, MUTAGENESIS OF GLU-40; CYS-76; CYS-80 AND 161-ARG--ARG-164,
RP AND DISULFIDE BONDS.
RX PubMed=19270337; DOI=10.1074/jbc.m900553200;
RA Yin W., Romeo S., Chang S., Grishin N.V., Hobbs H.H., Cohen J.C.;
RT "Genetic variation in ANGPTL4 provides insights into protein processing and
RT function.";
RL J. Biol. Chem. 284:13213-13222(2009).
RN [15]
RP SUBCELLULAR LOCATION, PARTIAL PROTEIN SEQUENCE, PROTEOLYTIC CLEAVAGE, AND
RP MUTAGENESIS OF ARG-161 AND ARG-164.
RX PubMed=21398697; DOI=10.1074/jbc.m110.217638;
RA Lei X., Shi F., Basu D., Huq A., Routhier S., Day R., Jin W.;
RT "Proteolytic processing of angiopoietin-like protein 4 by proprotein
RT convertases modulates its inhibitory effects on lipoprotein lipase
RT activity.";
RL J. Biol. Chem. 286:15747-15756(2011).
RN [16]
RP FUNCTION, AND CHARACTERIZATION OF VARIANT LYS-40.
RX PubMed=27929370; DOI=10.7554/elife.20958;
RA Mysling S., Kristensen K.K., Larsson M., Kovrov O., Bensadouen A.,
RA Joergensen T.J., Olivecrona G., Young S.G., Ploug M.;
RT "The angiopoietin-like protein ANGPTL4 catalyzes unfolding of the hydrolase
RT domain in lipoprotein lipase and the endothelial membrane protein GPIHBP1
RT counteracts this unfolding.";
RL Elife 5:0-0(2016).
RN [17]
RP FUNCTION.
RX PubMed=29899144; DOI=10.1073/pnas.1806774115;
RA Kristensen K.K., Midtgaard S.R., Mysling S., Kovrov O., Hansen L.B.,
RA Skar-Gislinge N., Beigneux A.P., Kragelund B.B., Olivecrona G., Young S.G.,
RA Joergensen T.J.D., Fong L.G., Ploug M.;
RT "A disordered acidic domain in GPIHBP1 harboring a sulfated tyrosine
RT regulates lipoprotein lipase.";
RL Proc. Natl. Acad. Sci. U.S.A. 115:E6020-E6029(2018).
RN [18] {ECO:0007744|PDB:6EUB}
RP X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) OF 184-406, DISULFIDE BONDS,
RP CHARACTERIZATION OF VARIANTS CYS-336; CYS-349 AND SER-361, AND MUTAGENESIS
RP OF GLY-223.
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 [19]
RP ASSOCIATION WITH TGQTL, AND VARIANTS LEU-5; LYS-40; ILE-41; ARG-67; LEU-72;
RP ARG-77; LYS-167; SER-174; GLN-190; LYS-196; CYS-230; ARG-233; VAL-237;
RP THR-251; MET-266; GLN-278; MET-291; MET-293; VAL-296; SER-307; MET-308;
RP CYS-336; GLU-338; CYS-349; SER-361; ARG-361; GLN-371 AND TRP-384.
RX PubMed=17322881; DOI=10.1038/ng1984;
RA Romeo S., Pennacchio L.A., Fu Y., Boerwinkle E., Tybjaerg-Hansen A.,
RA Hobbs H.H., Cohen J.C.;
RT "Population-based resequencing of ANGPTL4 uncovers variations that reduce
RT triglycerides and increase HDL.";
RL Nat. Genet. 39:513-516(2007).
RN [20]
RP VARIANT LYS-40, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=29899519; DOI=10.1038/s41467-018-04611-z;
RA Gusarova V., O'Dushlaine C., Teslovich T.M., Benotti P.N., Mirshahi T.,
RA Gottesman O., Van Hout C.V., Murray M.F., Mahajan A., Nielsen J.B.,
RA Fritsche L., Wulff A.B., Gudbjartsson D.F., Sjoegren M., Emdin C.A.,
RA Scott R.A., Lee W.J., Small A., Kwee L.C., Dwivedi O.P., Prasad R.B.,
RA Bruse S., Lopez A.E., Penn J., Marcketta A., Leader J.B., Still C.D.,
RA Kirchner H.L., Mirshahi U.L., Wardeh A.H., Hartle C.M., Habegger L.,
RA Fetterolf S.N., Tusie-Luna T., Morris A.P., Holm H., Steinthorsdottir V.,
RA Sulem P., Thorsteinsdottir U., Rotter J.I., Chuang L.M., Damrauer S.,
RA Birtwell D., Brummett C.M., Khera A.V., Natarajan P., Orho-Melander M.,
RA Flannick J., Lotta L.A., Willer C.J., Holmen O.L., Ritchie M.D.,
RA Ledbetter D.H., Murphy A.J., Borecki I.B., Reid J.G., Overton J.D.,
RA Hansson O., Groop L., Shah S.H., Kraus W.E., Rader D.J., Chen Y.I.,
RA Hveem K., Wareham N.J., Kathiresan S., Melander O., Stefansson K.,
RA Nordestgaard B.G., Tybjaerg-Hansen A., Abecasis G.R., Altshuler D.,
RA Florez J.C., Boehnke M., McCarthy M.I., Yancopoulos G.D., Carey D.J.,
RA Shuldiner A.R., Baras A., Dewey F.E., Gromada J.;
RT "Genetic inactivation of ANGPTL4 improves glucose homeostasis and is
RT associated with reduced risk of diabetes.";
RL Nat. Commun. 9:2252-2252(2018).
CC -!- FUNCTION: Mediates inactivation of the lipoprotein lipase LPL, and
CC thereby plays a role in the regulation of triglyceride clearance from
CC the blood serum and in lipid metabolism (PubMed:19270337,
CC PubMed:21398697, PubMed:27929370, PubMed:29899144). May also play a
CC role in regulating glucose homeostasis and insulin sensitivity
CC (Probable). Inhibits proliferation, migration, and tubule formation of
CC endothelial cells and reduces vascular leakage (PubMed:14583458,
CC PubMed:17068295). Upon heterologous expression, inhibits the adhesion
CC of endothelial cell to the extracellular matrix (ECM), and inhibits the
CC reorganization of the actin cytoskeleton, formation of actin stress
CC fibers and focal adhesions in endothelial cells that have adhered to
CC ANGPTL4-containing ECM (in vitro) (PubMed:17068295). Depending on
CC context, may modulate tumor-related angiogenesis (By similarity).
CC {ECO:0000250|UniProtKB:Q9Z1P8, ECO:0000269|PubMed:14583458,
CC ECO:0000269|PubMed:17068295, ECO:0000269|PubMed:19270337,
CC ECO:0000269|PubMed:21398697, ECO:0000269|PubMed:27929370,
CC ECO:0000269|PubMed:29899144, ECO:0000305|PubMed:29899519}.
CC -!- FUNCTION: [ANGPTL4 N-terminal chain]: Mediates inactivation of the
CC lipoprotein lipase LPL, and thereby plays an important role in the
CC regulation of triglyceride clearance from the blood serum and in lipid
CC metabolism (PubMed:19270337, PubMed:21398697, PubMed:27929370,
CC PubMed:29899144). Has higher activity in LPL inactivation than the
CC uncleaved protein (PubMed:19270337, PubMed:21398697).
CC {ECO:0000269|PubMed:19270337, ECO:0000269|PubMed:21398697,
CC ECO:0000269|PubMed:27929370, ECO:0000269|PubMed:29899144}.
CC -!- SUBUNIT: Homooligomer; disulfide-linked via Cys residues in the N-
CC terminal part of the protein (PubMed:19270337). The homooligomer
CC undergoes proteolytic processing to release the ANGPTL4 C-terminal
CC chain, which circulates as a monomer (PubMed:19270337). The
CC homooligomer unprocessed form is able to interact with the
CC extracellular matrix (PubMed:21398697). {ECO:0000250,
CC ECO:0000269|PubMed:19270337, ECO:0000269|PubMed:21398697}.
CC -!- INTERACTION:
CC Q9BY76; Q9BY76: ANGPTL4; NbExp=3; IntAct=EBI-2968146, EBI-2968146;
CC Q9BY76; P05556: ITGB1; NbExp=2; IntAct=EBI-2968146, EBI-703066;
CC Q9BY76; P18084: ITGB5; NbExp=3; IntAct=EBI-2968146, EBI-1223434;
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:10698685,
CC ECO:0000269|PubMed:14583458, ECO:0000269|PubMed:17068295,
CC ECO:0000269|PubMed:19270337, ECO:0000269|PubMed:21398697,
CC ECO:0000269|PubMed:29899519}. Secreted, extracellular space,
CC extracellular matrix {ECO:0000269|PubMed:17068295,
CC ECO:0000269|PubMed:21398697}. Note=The unprocessed form interacts with
CC the extracellular matrix (PubMed:17068295, PubMed:21398697). This may
CC constitute a dynamic reservoir, a regulatory mechanism of the
CC bioavailability of ANGPTL4 (Probable). {ECO:0000269|PubMed:17068295,
CC ECO:0000269|PubMed:21398697, ECO:0000305|PubMed:17068295}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q9BY76-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9BY76-2; Sequence=VSP_047045;
CC Name=3;
CC IsoId=Q9BY76-3; Sequence=VSP_055092;
CC -!- TISSUE SPECIFICITY: Detected in blood plasma (at protein level)
CC (PubMed:29899519). Detected in liver (PubMed:10698685). Detected in
CC white fat tissue and placenta (PubMed:10866690). Expressed at high
CC levels in the placenta, heart, liver, muscle, pancreas and lung but
CC expressed poorly in the brain and kidney. {ECO:0000269|PubMed:10698685,
CC ECO:0000269|PubMed:10866690, ECO:0000269|PubMed:12015030,
CC ECO:0000269|PubMed:29899519}.
CC -!- INDUCTION: Up-regulated when cells are exposed to severe hypoxia (in
CC vitro). {ECO:0000269|PubMed:17068295}.
CC -!- PTM: N-glycosylated. {ECO:0000269|PubMed:10698685}.
CC -!- PTM: [ANGPTL4 N-terminal chain]: Forms disulfide-linked dimers and
CC tetramers. {ECO:0000269|PubMed:19270337}.
CC -!- PTM: Cleaved into a smaller N-terminal chain and a larger chain that
CC contains the fibrinogen C-terminal domain; both cleaved and uncleaved
CC forms are detected in the extracellular space. The cleaved form is not
CC present within the cell. {ECO:0000269|PubMed:17068295,
CC ECO:0000269|PubMed:19270337, ECO:0000269|PubMed:21398697}.
CC -!- POLYMORPHISM: Genetic variations in ANGPTL4 are associated with low
CC plasma triglyceride levels and define the plasma triglyceride level
CC quantitative trait locus (TGQTL) [MIM:615881].
CC {ECO:0000269|PubMed:17322881}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAQ88642.1; Type=Erroneous initiation; Evidence={ECO:0000305};
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DR EMBL; AF169312; AAF62868.1; -; mRNA.
DR EMBL; AF202636; AAG22490.1; -; mRNA.
DR EMBL; AB056477; BAB40692.1; -; mRNA.
DR EMBL; AF153606; AAD41088.1; -; mRNA.
DR EMBL; AY358275; AAQ88642.1; ALT_INIT; mRNA.
DR EMBL; AK303269; BAG64351.1; -; mRNA.
DR EMBL; AK222489; BAD96209.1; -; mRNA.
DR EMBL; AK222524; BAD96244.1; -; mRNA.
DR EMBL; AC136469; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471139; EAW68930.1; -; Genomic_DNA.
DR EMBL; CH471139; EAW68931.1; -; Genomic_DNA.
DR EMBL; BC023647; AAH23647.1; -; mRNA.
DR CCDS; CCDS12200.1; -. [Q9BY76-1]
DR CCDS; CCDS42493.1; -. [Q9BY76-2]
DR RefSeq; NP_001034756.1; NM_001039667.2. [Q9BY76-2]
DR RefSeq; NP_647475.1; NM_139314.2. [Q9BY76-1]
DR PDB; 6EUB; X-ray; 2.30 A; A=184-406.
DR PDB; 6U0A; X-ray; 2.11 A; A=185-400.
DR PDB; 6U1U; X-ray; 1.75 A; A=185-400.
DR PDB; 6U73; X-ray; 2.38 A; A=185-400.
DR PDBsum; 6EUB; -.
DR PDBsum; 6U0A; -.
DR PDBsum; 6U1U; -.
DR PDBsum; 6U73; -.
DR AlphaFoldDB; Q9BY76; -.
DR SASBDB; Q9BY76; -.
DR SMR; Q9BY76; -.
DR BioGRID; 119316; 36.
DR CORUM; Q9BY76; -.
DR IntAct; Q9BY76; 24.
DR MINT; Q9BY76; -.
DR STRING; 9606.ENSP00000301455; -.
DR GlyConnect; 1918; 11 N-Linked glycans (1 site).
DR GlyGen; Q9BY76; 4 sites, 11 N-linked glycans (1 site), 3 O-linked glycans (3 sites).
DR iPTMnet; Q9BY76; -.
DR PhosphoSitePlus; Q9BY76; -.
DR BioMuta; ANGPTL4; -.
DR DMDM; 25008123; -.
DR EPD; Q9BY76; -.
DR jPOST; Q9BY76; -.
DR MassIVE; Q9BY76; -.
DR MaxQB; Q9BY76; -.
DR PaxDb; Q9BY76; -.
DR PeptideAtlas; Q9BY76; -.
DR PRIDE; Q9BY76; -.
DR ProteomicsDB; 2383; -.
DR ProteomicsDB; 25349; -.
DR ProteomicsDB; 79597; -. [Q9BY76-1]
DR ABCD; Q9BY76; 17 sequenced antibodies.
DR Antibodypedia; 1649; 524 antibodies from 38 providers.
DR DNASU; 51129; -.
DR Ensembl; ENST00000301455.7; ENSP00000301455.1; ENSG00000167772.12. [Q9BY76-1]
DR Ensembl; ENST00000393962.6; ENSP00000377534.1; ENSG00000167772.12. [Q9BY76-2]
DR Ensembl; ENST00000593998.5; ENSP00000472551.1; ENSG00000167772.12. [Q9BY76-1]
DR GeneID; 51129; -.
DR KEGG; hsa:51129; -.
DR MANE-Select; ENST00000301455.7; ENSP00000301455.1; NM_139314.3; NP_647475.1.
DR UCSC; uc002mjq.3; human. [Q9BY76-1]
DR CTD; 51129; -.
DR DisGeNET; 51129; -.
DR GeneCards; ANGPTL4; -.
DR HGNC; HGNC:16039; ANGPTL4.
DR HPA; ENSG00000167772; Tissue enhanced (adipose tissue, breast, liver).
DR MalaCards; ANGPTL4; -.
DR MIM; 605910; gene.
DR MIM; 615881; phenotype.
DR neXtProt; NX_Q9BY76; -.
DR OpenTargets; ENSG00000167772; -.
DR PharmGKB; PA24797; -.
DR VEuPathDB; HostDB:ENSG00000167772; -.
DR eggNOG; KOG2579; Eukaryota.
DR GeneTree; ENSGT00940000159478; -.
DR HOGENOM; CLU_038628_2_1_1; -.
DR InParanoid; Q9BY76; -.
DR OMA; INCAKHL; -.
DR OrthoDB; 357340at2759; -.
DR PhylomeDB; Q9BY76; -.
DR TreeFam; TF329953; -.
DR PathwayCommons; Q9BY76; -.
DR Reactome; R-HSA-1989781; PPARA activates gene expression.
DR Reactome; R-HSA-381340; Transcriptional regulation of white adipocyte differentiation.
DR Reactome; R-HSA-8963889; Assembly of active LPL and LIPC lipase complexes.
DR SignaLink; Q9BY76; -.
DR BioGRID-ORCS; 51129; 15 hits in 1073 CRISPR screens.
DR ChiTaRS; ANGPTL4; human.
DR GeneWiki; ANGPTL4; -.
DR GenomeRNAi; 51129; -.
DR Pharos; Q9BY76; Tbio.
DR PRO; PR:Q9BY76; -.
DR Proteomes; UP000005640; Chromosome 19.
DR RNAct; Q9BY76; protein.
DR Bgee; ENSG00000167772; Expressed in pericardium and 158 other tissues.
DR ExpressionAtlas; Q9BY76; baseline and differential.
DR Genevisible; Q9BY76; HS.
DR GO; GO:0072562; C:blood microparticle; HDA:UniProtKB.
DR GO; GO:0062023; C:collagen-containing extracellular matrix; IBA:GO_Central.
DR GO; GO:0005576; C:extracellular region; IDA:UniProtKB.
DR GO; GO:0005615; C:extracellular space; IDA:MGI.
DR GO; GO:0004857; F:enzyme inhibitor activity; ISS:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0005102; F:signaling receptor binding; IBA:GO_Central.
DR GO; GO:0001525; P:angiogenesis; IEA:UniProtKB-KW.
DR GO; GO:0072577; P:endothelial cell apoptotic process; IEA:Ensembl.
DR GO; GO:0006629; P:lipid metabolic process; IEA:UniProtKB-KW.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IDA:UniProtKB.
DR GO; GO:2000352; P:negative regulation of endothelial cell apoptotic process; IEA:Ensembl.
DR GO; GO:0051005; P:negative regulation of lipoprotein lipase activity; IDA:BHF-UCL.
DR GO; GO:0045766; P:positive regulation of angiogenesis; TAS:UniProtKB.
DR GO; GO:0043335; P:protein unfolding; IDA:ARUK-UCL.
DR GO; GO:0001666; P:response to hypoxia; NAS:UniProtKB.
DR GO; GO:0070328; P:triglyceride homeostasis; ISS:BHF-UCL.
DR CDD; cd00087; FReD; 1.
DR Gene3D; 3.90.215.10; -; 1.
DR InterPro; IPR028793; ANGPTL4.
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 InterPro; IPR020837; Fibrinogen_CS.
DR PANTHER; PTHR19143:SF256; PTHR19143:SF256; 2.
DR Pfam; PF00147; Fibrinogen_C; 1.
DR SMART; SM00186; FBG; 1.
DR SUPFAM; SSF56496; SSF56496; 1.
DR PROSITE; PS00514; FIBRINOGEN_C_1; 1.
DR PROSITE; PS51406; FIBRINOGEN_C_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Angiogenesis; Coiled coil;
KW Direct protein sequencing; Disulfide bond; Extracellular matrix;
KW Glycoprotein; Lipid metabolism; Reference proteome; Secreted; Signal.
FT SIGNAL 1..25
FT /evidence="ECO:0000255"
FT CHAIN 26..406
FT /note="Angiopoietin-related protein 4"
FT /id="PRO_0000009124"
FT CHAIN 26..163
FT /note="ANGPTL4 N-terminal chain"
FT /evidence="ECO:0000305"
FT /id="PRO_0000446859"
FT CHAIN 164..406
FT /note="ANGPTL4 C-terminal chain"
FT /evidence="ECO:0000305"
FT /id="PRO_0000446860"
FT DOMAIN 179..401
FT /note="Fibrinogen C-terminal"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00739"
FT COILED 100..143
FT /evidence="ECO:0000255"
FT SITE 164..165
FT /note="Cleavage"
FT /evidence="ECO:0000269|PubMed:21398697"
FT CARBOHYD 177
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 188..216
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00739,
FT ECO:0000269|PubMed:29713054, ECO:0007744|PDB:6EUB"
FT DISULFID 341..354
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00739,
FT ECO:0000269|PubMed:29713054, ECO:0007744|PDB:6EUB"
FT VAR_SEQ 1..167
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_055092"
FT VAR_SEQ 183..221
FT /note="RLPRDCQELFQVGERQSGLFEIQPQGSPPFLVNCKMTSD -> H (in
FT isoform 2)"
FT /evidence="ECO:0000305"
FT /id="VSP_047045"
FT VARIANT 5
FT /note="P -> L (in dbSNP:rs761583091)"
FT /evidence="ECO:0000269|PubMed:17322881"
FT /id="VAR_032642"
FT VARIANT 40
FT /note="E -> K (associated with lower plasma levels of
FT triglyceride and higher levels of HDL cholesterol; strongly
FT reduced inactivation of lipoprotein lipase LPL; no effect
FT on protein secretion and stability of monomers; abolishes
FT accumulation of oligomers; dbSNP:rs116843064)"
FT /evidence="ECO:0000269|PubMed:17322881,
FT ECO:0000269|PubMed:19270337, ECO:0000269|PubMed:27929370,
FT ECO:0000269|PubMed:29899519"
FT /id="VAR_032643"
FT VARIANT 41
FT /note="M -> I (in dbSNP:rs186754194)"
FT /evidence="ECO:0000269|PubMed:17322881"
FT /id="VAR_032644"
FT VARIANT 67
FT /note="S -> R (in dbSNP:rs538554190)"
FT /evidence="ECO:0000269|PubMed:17322881"
FT /id="VAR_032645"
FT VARIANT 72
FT /note="R -> L (in dbSNP:rs141831018)"
FT /evidence="ECO:0000269|PubMed:17322881"
FT /id="VAR_032646"
FT VARIANT 77
FT /note="G -> R (in dbSNP:rs568624939)"
FT /evidence="ECO:0000269|PubMed:17322881"
FT /id="VAR_032647"
FT VARIANT 167
FT /note="E -> K (in dbSNP:rs140640857)"
FT /evidence="ECO:0000269|PubMed:17322881"
FT /id="VAR_032648"
FT VARIANT 174
FT /note="P -> S (in dbSNP:rs1008363865)"
FT /evidence="ECO:0000269|PubMed:17322881"
FT /id="VAR_032649"
FT VARIANT 190
FT /note="E -> Q (in dbSNP:rs77938377)"
FT /evidence="ECO:0000269|PubMed:17322881"
FT /id="VAR_032650"
FT VARIANT 196
FT /note="E -> K (in dbSNP:rs1192364228)"
FT /evidence="ECO:0000269|PubMed:17322881"
FT /id="VAR_032651"
FT VARIANT 230
FT /note="R -> C (in dbSNP:rs201026877)"
FT /evidence="ECO:0000269|PubMed:17322881"
FT /id="VAR_032652"
FT VARIANT 233
FT /note="G -> R"
FT /evidence="ECO:0000269|PubMed:17322881"
FT /id="VAR_032653"
FT VARIANT 237
FT /note="F -> V (in dbSNP:rs768374046)"
FT /evidence="ECO:0000269|PubMed:17322881"
FT /id="VAR_032654"
FT VARIANT 251
FT /note="P -> T (in dbSNP:rs376328756)"
FT /evidence="ECO:0000269|PubMed:17322881"
FT /id="VAR_032655"
FT VARIANT 266
FT /note="T -> M (in dbSNP:rs1044250)"
FT /evidence="ECO:0000269|PubMed:10698685,
FT ECO:0000269|PubMed:17322881, ECO:0000269|Ref.8"
FT /id="VAR_020428"
FT VARIANT 278
FT /note="R -> Q (in dbSNP:rs35061979)"
FT /evidence="ECO:0000269|PubMed:17322881"
FT /id="VAR_032656"
FT VARIANT 291
FT /note="V -> M (in dbSNP:rs150000287)"
FT /evidence="ECO:0000269|PubMed:17322881"
FT /id="VAR_032657"
FT VARIANT 293
FT /note="L -> M (in dbSNP:rs775667046)"
FT /evidence="ECO:0000269|PubMed:17322881"
FT /id="VAR_032658"
FT VARIANT 296
FT /note="E -> V"
FT /evidence="ECO:0000269|PubMed:17322881"
FT /id="VAR_032659"
FT VARIANT 307
FT /note="P -> S (in dbSNP:rs751249880)"
FT /evidence="ECO:0000269|PubMed:17322881"
FT /id="VAR_032660"
FT VARIANT 308
FT /note="V -> M (in dbSNP:rs139998264)"
FT /evidence="ECO:0000269|PubMed:17322881"
FT /id="VAR_032661"
FT VARIANT 336
FT /note="R -> C (no effect on protein folding;
FT dbSNP:rs140744493)"
FT /evidence="ECO:0000269|PubMed:17322881,
FT ECO:0000269|PubMed:29713054"
FT /id="VAR_032662"
FT VARIANT 338
FT /note="D -> E (in dbSNP:rs780121474)"
FT /evidence="ECO:0000269|PubMed:17322881"
FT /id="VAR_032663"
FT VARIANT 349
FT /note="W -> C (impaired protein folding;
FT dbSNP:rs1033145581)"
FT /evidence="ECO:0000269|PubMed:17322881,
FT ECO:0000269|PubMed:29713054"
FT /id="VAR_032664"
FT VARIANT 361
FT /note="G -> R (in dbSNP:rs755737249)"
FT /evidence="ECO:0000269|PubMed:17322881"
FT /id="VAR_032665"
FT VARIANT 361
FT /note="G -> S (impaired protein folding;
FT dbSNP:rs755737249)"
FT /evidence="ECO:0000269|PubMed:17322881,
FT ECO:0000269|PubMed:29713054"
FT /id="VAR_032666"
FT VARIANT 371
FT /note="R -> Q (in dbSNP:rs779488814)"
FT /evidence="ECO:0000269|PubMed:17322881"
FT /id="VAR_032667"
FT VARIANT 384
FT /note="R -> W (impaired protein folding;
FT dbSNP:rs146942305)"
FT /evidence="ECO:0000269|PubMed:17322881,
FT ECO:0000269|PubMed:29713054"
FT /id="VAR_032668"
FT MUTAGEN 40
FT /note="E->A: Loss of inactivation of lipoprotein lipase
FT LPL."
FT /evidence="ECO:0000269|PubMed:19270337"
FT MUTAGEN 40
FT /note="E->D: Decreased inactivation of lipoprotein lipase
FT LPL."
FT /evidence="ECO:0000269|PubMed:19270337"
FT MUTAGEN 76
FT /note="C->A: No effect on secretion and proteolytic
FT cleavage. Loss of oligomerization; when associated with A-
FT 80."
FT /evidence="ECO:0000269|PubMed:19270337"
FT MUTAGEN 80
FT /note="C->A: No effect on secretion and proteolytic
FT cleavage. Loss of oligomerization; when associated with A-
FT 76."
FT /evidence="ECO:0000269|PubMed:19270337"
FT MUTAGEN 161..164
FT /note="RRKR->GSGS: Loss of proteolytic cleavage. No effect
FT on the ability to inactivate lipoprotein lipase LPL."
FT /evidence="ECO:0000269|PubMed:19270337"
FT MUTAGEN 161
FT /note="R->A: Loss of proteolytic cleavage. Decreased
FT ability to inactivate lipoprotein lipase LPL."
FT /evidence="ECO:0000269|PubMed:21398697"
FT MUTAGEN 164
FT /note="R->A: Loss of proteolytic cleavage."
FT /evidence="ECO:0000269|PubMed:21398697"
FT MUTAGEN 223
FT /note="G->R: Impaired protein folding."
FT /evidence="ECO:0000269|PubMed:29713054"
FT CONFLICT 55..71
FT /note="LREHAERTRSQLSALER -> CANTGAHPQSAERAGA (in Ref. 5;
FT AAD41088)"
FT /evidence="ECO:0000305"
FT CONFLICT 60
FT /note="E -> G (in Ref. 4; BAB40692)"
FT /evidence="ECO:0000305"
FT CONFLICT 175
FT /note="A -> P (in Ref. 1; AAF62868)"
FT /evidence="ECO:0000305"
FT CONFLICT 237
FT /note="F -> S (in Ref. 7; BAG64351)"
FT /evidence="ECO:0000305"
FT CONFLICT 251
FT /note="P -> S (in Ref. 8; BAD96209)"
FT /evidence="ECO:0000305"
FT CONFLICT 270
FT /note="N -> D (in Ref. 7; BAG64351 and 8; BAD96209)"
FT /evidence="ECO:0000305"
FT CONFLICT 277
FT /note="L -> R (in Ref. 8; BAD96244)"
FT /evidence="ECO:0000305"
FT CONFLICT 304
FT /note="L -> F (in Ref. 1; AAF62868)"
FT /evidence="ECO:0000305"
FT CONFLICT 363
FT /note="Y -> H (in Ref. 8; BAD96209)"
FT /evidence="ECO:0000305"
FT CONFLICT 389
FT /note="P -> S (in Ref. 1; AAF62868)"
FT /evidence="ECO:0000305"
FT HELIX 188..193
FT /evidence="ECO:0007829|PDB:6U1U"
FT STRAND 200..204
FT /evidence="ECO:0007829|PDB:6U1U"
FT STRAND 212..219
FT /evidence="ECO:0007829|PDB:6U1U"
FT STRAND 222..233
FT /evidence="ECO:0007829|PDB:6U1U"
FT HELIX 241..246
FT /evidence="ECO:0007829|PDB:6U1U"
FT STRAND 253..256
FT /evidence="ECO:0007829|PDB:6U1U"
FT HELIX 259..266
FT /evidence="ECO:0007829|PDB:6U1U"
FT STRAND 271..278
FT /evidence="ECO:0007829|PDB:6U1U"
FT STRAND 284..293
FT /evidence="ECO:0007829|PDB:6U1U"
FT HELIX 296..298
FT /evidence="ECO:0007829|PDB:6U1U"
FT STRAND 302..304
FT /evidence="ECO:0007829|PDB:6U1U"
FT HELIX 306..311
FT /evidence="ECO:0007829|PDB:6U1U"
FT STRAND 322..324
FT /evidence="ECO:0007829|PDB:6U1U"
FT HELIX 341..344
FT /evidence="ECO:0007829|PDB:6U1U"
FT STRAND 352..358
FT /evidence="ECO:0007829|PDB:6U1U"
FT HELIX 371..374
FT /evidence="ECO:0007829|PDB:6U1U"
FT HELIX 381..384
FT /evidence="ECO:0007829|PDB:6U1U"
FT STRAND 391..399
FT /evidence="ECO:0007829|PDB:6U1U"
SQ SEQUENCE 406 AA; 45214 MW; 219E56FEB3F602AF CRC64;
MSGAPTAGAA LMLCAATAVL LSAQGGPVQS KSPRFASWDE MNVLAHGLLQ LGQGLREHAE
RTRSQLSALE RRLSACGSAC QGTEGSTDLP LAPESRVDPE VLHSLQTQLK AQNSRIQQLF
HKVAQQQRHL EKQHLRIQHL QSQFGLLDHK HLDHEVAKPA RRKRLPEMAQ PVDPAHNVSR
LHRLPRDCQE LFQVGERQSG LFEIQPQGSP PFLVNCKMTS DGGWTVIQRR HDGSVDFNRP
WEAYKAGFGD PHGEFWLGLE KVHSITGDRN SRLAVQLRDW DGNAELLQFS VHLGGEDTAY
SLQLTAPVAG QLGATTVPPS GLSVPFSTWD QDHDLRRDKN CAKSLSGGWW FGTCSHSNLN
GQYFRSIPQQ RQKLKKGIFW KTWRGRYYPL QATTMLIQPM AAEAAS
