HPSE_HUMAN
ID HPSE_HUMAN Reviewed; 543 AA.
AC Q9Y251; A9JIG7; C7F7I3; C7F7I4; E9PCA9; E9PGR1; Q53GE5; Q9UL39;
DT 11-OCT-2005, integrated into UniProtKB/Swiss-Prot.
DT 18-MAY-2010, sequence version 2.
DT 03-AUG-2022, entry version 183.
DE RecName: Full=Heparanase;
DE EC=3.2.1.166;
DE AltName: Full=Endo-glucoronidase;
DE AltName: Full=Heparanase-1;
DE Short=Hpa1;
DE Contains:
DE RecName: Full=Heparanase 8 kDa subunit;
DE Contains:
DE RecName: Full=Heparanase 50 kDa subunit;
DE Flags: Precursor;
GN Name=HPSE; Synonyms=HEP, HPA, HPA1, HPR1, HPSE1, HSE1;
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), VARIANT ARG-307, AND TISSUE
RP SPECIFICITY.
RC TISSUE=Placenta;
RX PubMed=10405343; DOI=10.1006/bbrc.1999.0962;
RA Kussie P.H., Hulmes J.D., Ludwig D.L., Patel S., Navarro E.C., Seddon A.P.,
RA Giorgio N.A., Bohlen P.;
RT "Cloning and functional expression of a human heparanase gene.";
RL Biochem. Biophys. Res. Commun. 261:183-187(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), BIOPHYSICOCHEMICAL PROPERTIES,
RP PROTEIN SEQUENCE OF 158-168; 326-337 AND 447-491, AND VARIANT ARG-307.
RC TISSUE=Embryonic fibroblast;
RX PubMed=10446189; DOI=10.1074/jbc.274.34.24153;
RA Toyoshima M., Nakajima M.;
RT "Human heparanase. Purification, characterization, cloning, and
RT expression.";
RL J. Biol. Chem. 274:24153-24160(1999).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), GLYCOSYLATION, PROTEOLYTIC
RP PROCESSING, AND VARIANT ARG-307.
RX PubMed=10395325; DOI=10.1038/10518;
RA Vlodavsky I., Friedmann Y., Elkin M., Aingorn H., Atzmon R.,
RA Ishai-Michaeli R., Bitan M., Pappo O., Peretz T., Michal I., Spector L.,
RA Pecker I.;
RT "Mammalian heparanase: gene cloning, expression and function in tumor
RT progression and metastasis.";
RL Nat. Med. 5:793-802(1999).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, PROTEIN
RP SEQUENCE OF 158-174; 263-272; 326-337; 433-436; 438-443; 466-468 AND
RP 478-483, AND VARIANT ARG-307.
RC TISSUE=Placenta;
RX PubMed=10395326; DOI=10.1038/10525;
RA Hulett M.D., Freeman C., Hamdorf B.J., Baker R.T., Harris M.J.,
RA Parish C.R.;
RT "Cloning of mammalian heparanase, an important enzyme in tumor invasion and
RT metastasis.";
RL Nat. Med. 5:803-809(1999).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), BIOPHYSICOCHEMICAL PROPERTIES,
RP TISSUE SPECIFICITY, AND VARIANT ARG-307.
RC TISSUE=Placenta;
RX PubMed=10764835; DOI=10.1093/glycob/10.5.467;
RA Dempsey L.A., Plummer T.B., Coombes S.L., Platt J.L.;
RT "Heparanase expression in invasive trophoblasts and acute vascular
RT damage.";
RL Glycobiology 10:467-475(2000).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND SUBCELLULAR LOCATION.
RX PubMed=11547900; DOI=10.1023/a:1011375624902;
RA Zcharia E., Metzger S., Chajek-Shaul T., Friedmann Y., Pappo O., Aviv A.,
RA Elkin M., Pecker I., Peretz T., Vlodavsky I.;
RT "Molecular properties and involvement of heparanase in cancer progression
RT and mammary gland morphogenesis.";
RL J. Mammary Gland Biol. Neoplasia 6:311-322(2001).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PROTEIN SEQUENCE OF 36-41 AND
RP 158-163, SUBUNIT, GLYCOSYLATION, AND BIOPHYSICOCHEMICAL PROPERTIES.
RC TISSUE=Placenta;
RX PubMed=12713442; DOI=10.1042/bj20030318;
RA McKenzie E., Young K., Hircock M., Bennett J., Bhaman M., Felix R.,
RA Turner P., Stamps A., McMillan D., Saville G., Ng S., Mason S., Snell D.,
RA Schofield D., Gong H., Townsend R., Gallagher J., Page M., Parekh R.,
RA Stubberfield C.;
RT "Biochemical characterization of the active heterodimer form of human
RT heparanase (Hpa1) protein expressed in insect cells.";
RL Biochem. J. 373:423-435(2003).
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), ALTERNATIVE SPLICING, AND VARIANT
RP ARG-307.
RC TISSUE=Kidney;
RX PubMed=17208203; DOI=10.1016/j.bbrc.2006.12.189;
RA Nasser N.J., Avivi A., Shushy M., Vlodavsky I., Nevo E.;
RT "Cloning, expression, and characterization of an alternatively spliced
RT variant of human heparanase.";
RL Biochem. Biophys. Res. Commun. 354:33-38(2007).
RN [9]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT ARG-307.
RA Pinhal M.A., Semedo P.;
RT "Cloned heparanase from MCF-7 cells.";
RL Submitted (FEB-2005) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 3 AND 4), AND VARIANT ARG-307.
RA Jin S., Yu L., Gong F.;
RT "Two new transcript variants of Homo sapiens heparanase (HPSE).";
RL Submitted (JUN-2009) to the EMBL/GenBank/DDBJ databases.
RN [11]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT ARG-307.
RC TISSUE=Small intestine;
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 [12]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT 4.";
RL Nature 434:724-731(2005).
RN [13]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT ARG-307.
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 [14]
RP MUTAGENESIS OF GLU-225; GLU-343 AND ASP-367.
RX PubMed=11123890; DOI=10.1021/bi002080p;
RA Hulett M.D., Hornby J.R., Ohms S.J., Zuegg J., Freeman C., Gready J.E.,
RA Parish C.R.;
RT "Identification of active-site residues of the pro-metastatic
RT endoglycosidase heparanase.";
RL Biochemistry 39:15659-15667(2000).
RN [15]
RP SUBCELLULAR LOCATION, PROTEOLYTIC PROCESSING, AND INTERACTION WITH SDC1.
RX PubMed=12441129; DOI=10.1006/excr.2002.5651;
RA Goldshmidt O., Nadav L., Aingorn H., Irit C., Feinstein N., Ilan N.,
RA Zamir E., Geiger B., Vlodavsky I., Katz B.Z.;
RT "Human heparanase is localized within lysosomes in a stable form.";
RL Exp. Cell Res. 281:50-62(2002).
RN [16]
RP CATALYTIC ACTIVITY, AND FUNCTION.
RX PubMed=12213822; DOI=10.1074/jbc.m206510200;
RA Okada Y., Yamada S., Toyoshima M., Dong J., Nakajima M., Sugahara K.;
RT "Structural recognition by recombinant human heparanase that plays critical
RT roles in tumor metastasis. Hierarchical sulfate groups with different
RT effects and the essential target disulfated trisaccharide sequence.";
RL J. Biol. Chem. 277:42488-42495(2002).
RN [17]
RP PROTEOLYTIC PROCESSING, ENZYME ACTIVITY, AND SUBCELLULAR LOCATION.
RX PubMed=11973358; DOI=10.1242/jcs.115.10.2179;
RA Nadav L., Eldor A., Yacoby-Zeevi O., Zamir E., Pecker I., Ilan N.,
RA Geiger B., Vlodavsky I., Katz B.Z.;
RT "Activation, processing and trafficking of extracellular heparanase by
RT primary human fibroblasts.";
RL J. Cell Sci. 115:2179-2187(2002).
RN [18]
RP HETERODIMERIZATION, AND ENZYME ACTIVITY.
RX PubMed=12927802; DOI=10.1016/s0006-291x(03)01478-5;
RA Levy-Adam F., Miao H.Q., Heinrikson R.L., Vlodavsky I., Ilan N.;
RT "Heterodimer formation is essential for heparanase enzymatic activity.";
RL Biochem. Biophys. Res. Commun. 308:885-891(2003).
RN [19]
RP FUNCTION, AND MUTAGENESIS OF GLU-225.
RX PubMed=12773484; DOI=10.1096/fj.02-0773com;
RA Goldshmidt O., Zcharia E., Cohen M., Aingorn H., Cohen I., Nadav L.,
RA Katz B.Z., Geiger B., Vlodavsky I.;
RT "Heparanase mediates cell adhesion independent of its enzymatic activity.";
RL FASEB J. 17:1015-1025(2003).
RN [20]
RP GLYCOSYLATION AT ASN-162; ASN-178; ASN-200; ASN-217; ASN-238 AND ASN-459,
RP AND MUTAGENESIS OF ASN-162; ASN-178; ASN-200; ASN-217; ASN-238 AND ASN-459.
RX PubMed=14573609; DOI=10.1074/jbc.m300541200;
RA Simizu S., Ishida K., Wierzba M.K., Osada H.;
RT "Secretion of heparanase protein is regulated by glycosylation in human
RT tumor cell lines.";
RL J. Biol. Chem. 279:2697-2703(2004).
RN [21]
RP FUNCTION.
RX PubMed=15044433; DOI=10.1074/jbc.m400554200;
RA Gingis-Velitski S., Zetser A., Flugelman M.Y., Vlodavsky I., Ilan N.;
RT "Heparanase induces endothelial cell migration via protein kinase B/Akt
RT activation.";
RL J. Biol. Chem. 279:23536-23541(2004).
RN [22]
RP SUBCELLULAR LOCATION.
RX PubMed=15292202; DOI=10.1074/jbc.m402131200;
RA Gingis-Velitski S., Zetser A., Kaplan V., Ben-Zaken O., Cohen E.,
RA Levy-Adam F., Bashenko Y., Flugelman M.Y., Vlodavsky I., Ilan N.;
RT "Heparanase uptake is mediated by cell membrane heparan sulfate
RT proteoglycans.";
RL J. Biol. Chem. 279:44084-44092(2004).
RN [23]
RP PROTEOLYTIC PROCESSING, AND SUBCELLULAR LOCATION.
RX PubMed=15126626; DOI=10.1242/jcs.01068;
RA Zetser A., Levy-Adam F., Kaplan V., Gingis-Velitski S., Bashenko Y.,
RA Schubert S., Flugelman M.Y., Vlodavsky I., Ilan N.;
RT "Processing and activation of latent heparanase occurs in lysosomes.";
RL J. Cell Sci. 117:2249-2258(2004).
RN [24]
RP BIOPHYSICOCHEMICAL PROPERTIES, PROTEOLYTIC PROCESSING, AND SUBCELLULAR
RP LOCATION.
RX PubMed=15848168; DOI=10.1016/j.febslet.2005.03.030;
RA Cohen E., Atzmon R., Vlodavsky I., Ilan N.;
RT "Heparanase processing by lysosomal/endosomal protein preparation.";
RL FEBS Lett. 579:2334-2338(2005).
RN [25]
RP SUBCELLULAR LOCATION, PROTEOLYTIC PROCESSING, AND MUTAGENESIS OF TYR-156.
RX PubMed=15659389; DOI=10.1074/jbc.m413370200;
RA Abboud-Jarrous G., Rangini-Guetta Z., Aingorn H., Atzmon R., Elgavish S.,
RA Peretz T., Vlodavsky I.;
RT "Site-directed mutagenesis, proteolytic cleavage, and activation of human
RT proheparanase.";
RL J. Biol. Chem. 280:13568-13575(2005).
RN [26]
RP HEPARAN SULFATE-BINDING DOMAINS, AND MUTAGENESIS OF LYS-158 AND LYS-161.
RX PubMed=15760902; DOI=10.1074/jbc.m414546200;
RA Levy-Adam F., Abboud-Jarrous G., Guerrini M., Beccati D., Vlodavsky I.,
RA Ilan N.;
RT "Identification and characterization of heparin/heparan sulfate binding
RT domains of the endoglycosidase heparanase.";
RL J. Biol. Chem. 280:20457-20466(2005).
RN [27]
RP FUNCTION.
RX PubMed=16452201; DOI=10.1158/0008-5472.can-05-1811;
RA Zetser A., Bashenko Y., Edovitsky E., Levy-Adam F., Vlodavsky I., Ilan N.;
RT "Heparanase induces vascular endothelial growth factor expression:
RT correlation with p38 phosphorylation levels and Src activation.";
RL Cancer Res. 66:1455-1463(2006).
RN [28]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-217.
RC TISSUE=Platelet;
RX PubMed=16263699; DOI=10.1074/mcp.m500324-mcp200;
RA Lewandrowski U., Moebius J., Walter U., Sickmann A.;
RT "Elucidation of N-glycosylation sites on human platelet proteins: a
RT glycoproteomic approach.";
RL Mol. Cell. Proteomics 5:226-233(2006).
RN [29]
RP TISSUE SPECIFICITY, AND FUNCTION.
RX PubMed=18557927; DOI=10.1111/j.1600-0625.2008.00739.x;
RA Malgouries S., Donovan M., Thibaut S., Bernard B.A.;
RT "Heparanase 1: a key participant of inner root sheath differentiation
RT program and hair follicle homeostasis.";
RL Exp. Dermatol. 17:1017-1023(2008).
RN [30]
RP FUNCTION.
RX PubMed=18798279; DOI=10.1002/ijc.23898;
RA Cohen-Kaplan V., Naroditsky I., Zetser A., Ilan N., Vlodavsky I.,
RA Doweck I.;
RT "Heparanase induces VEGF C and facilitates tumor lymphangiogenesis.";
RL Int. J. Cancer 123:2566-2573(2008).
RN [31]
RP FUNCTION OF THE C-TERMINAL DOMAIN, SUBCELLULAR LOCATION, AND MUTAGENESIS OF
RP VAL-414; LYS-417; PRO-525; PHE-527; SER-528; TYR-529; PHE-531; VAL-533;
RP ILE-534; ARG-535; ASN-536; ALA-537; LYS-538; VAL-539; ALA-540; ALA-541 AND
RP CYS-542.
RX PubMed=19244131; DOI=10.1158/0008-5472.can-08-1837;
RA Fux L., Feibish N., Cohen-Kaplan V., Gingis-Velitski S., Feld S.,
RA Geffen C., Vlodavsky I., Ilan N.;
RT "Structure-function approach identifies a COOH-terminal domain that
RT mediates heparanase signaling.";
RL Cancer Res. 69:1758-1767(2009).
RN [32]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-217 AND ASN-238.
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 [33]
RP FUNCTION.
RX PubMed=20097882; DOI=10.1182/blood-2009-07-234757;
RA Purushothaman A., Uyama T., Kobayashi F., Yamada S., Sugahara K.,
RA Rapraeger A.C., Sanderson R.D.;
RT "Heparanase-enhanced shedding of syndecan-1 by myeloma cells promotes
RT endothelial invasion and angiogenesis.";
RL Blood 115:2449-2457(2010).
RN [34]
RP INTERACTION WITH TF, AND ENZYME ACTIVITY.
RX PubMed=20634491; DOI=10.3324/haematol.2010.023713;
RA Nadir Y., Brenner B., Fux L., Shafat I., Attias J., Vlodavsky I.;
RT "Heparanase enhances the generation of activated factor X in the presence
RT of tissue factor and activated factor VII.";
RL Haematologica 95:1927-1934(2010).
RN [35]
RP INTERACTION WITH HRG, ENZYME ACTIVITY, AND FUNCTION.
RX PubMed=20561914; DOI=10.1016/j.biocel.2010.05.008;
RA Poon I.K., Yee D.Y., Jones A.L., Wood R.J., Davis D.S., Freeman C.,
RA Parish C.R., Hulett M.D.;
RT "Histidine-rich glycoprotein binds heparanase and regulates its enzymatic
RT activity and cell surface interactions.";
RL Int. J. Biochem. Cell Biol. 42:1507-1516(2010).
RN [36]
RP CATALYTIC ACTIVITY, AND FUNCTION.
RX PubMed=20181948; DOI=10.1074/jbc.m110.104166;
RA Peterson S.B., Liu J.;
RT "Unraveling the specificity of heparanase utilizing synthetic substrates.";
RL J. Biol. Chem. 285:14504-14513(2010).
RN [37]
RP INTERACTION WITH HPSE2.
RX PubMed=20576607; DOI=10.1074/jbc.m110.116384;
RA Levy-Adam F., Feld S., Cohen-Kaplan V., Shteingauz A., Gross M., Arvatz G.,
RA Naroditsky I., Ilan N., Doweck I., Vlodavsky I.;
RT "Heparanase 2 interacts with heparan sulfate with high affinity and
RT inhibits heparanase activity.";
RL J. Biol. Chem. 285:28010-28019(2010).
RN [38]
RP FUNCTION, TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION.
RX PubMed=20309870; DOI=10.1002/jor.21138;
RA Smith P.N., Freeman C., Yu D., Chen M., Gatenby P.A., Parish C.R., Li R.W.;
RT "Heparanase in primary human osteoblasts.";
RL J. Orthop. Res. 28:1315-1322(2010).
RN [39]
RP FUNCTION.
RX PubMed=21131364; DOI=10.1074/jbc.m110.183277;
RA Ramani V.C., Yang Y., Ren Y., Nan L., Sanderson R.D.;
RT "Heparanase plays a dual role in driving hepatocyte growth factor (HGF)
RT signaling by enhancing HGF expression and activity.";
RL J. Biol. Chem. 286:6490-6499(2011).
RN [40] {ECO:0007744|PDB:5E8M, ECO:0007744|PDB:5E97, ECO:0007744|PDB:5E98, ECO:0007744|PDB:5E9B, ECO:0007744|PDB:5E9C}
RP X-RAY CRYSTALLOGRAPHY (1.63 ANGSTROMS) OF 158-543 AND 36-109 IN COMPLEX
RP WITH HEPARIN, GLYCOSYLATION AT ASN-162; ASN-200; ASN-217; ASN-238 AND
RP ASN-459, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=26575439; DOI=10.1038/nsmb.3136;
RA Wu L., Viola C.M., Brzozowski A.M., Davies G.J.;
RT "Structural characterization of human heparanase reveals insights into
RT substrate recognition.";
RL Nat. Struct. Mol. Biol. 22:1016-1022(2015).
RN [41]
RP ERRATUM OF PUBMED:26575439.
RX PubMed=26733221; DOI=10.1038/nsmb0116-91;
RA Wu L., Viola C.M., Brzozowski A.M., Davies G.J.;
RT "Corrigendum: Structural characterization of human heparanase reveals
RT insights into substrate recognition.";
RL Nat. Struct. Mol. Biol. 23:91-91(2016).
RN [42] {ECO:0007744|PDB:5L9Y, ECO:0007744|PDB:5L9Z, ECO:0007744|PDB:5LA4, ECO:0007744|PDB:5LA7}
RP X-RAY CRYSTALLOGRAPHY (1.57 ANGSTROMS) OF 36-543 OF PRECURSOR, AND X-RAY
RP CRYSTALLOGRAPHY (1.57 ANGSTROMS) OF 158-543 AND 36-109.
RX PubMed=28581485; DOI=10.1038/nchembio.2395;
RA Wu L., Jiang J., Jin Y., Kallemeijn W.W., Kuo C.L., Artola M., Dai W.,
RA van Elk C., van Eijk M., van der Marel G.A., Codee J.D.C., Florea B.I.,
RA Aerts J.M.F.G., Overkleeft H.S., Davies G.J.;
RT "Activity-based probes for functional interrogation of retaining beta-
RT glucuronidases.";
RL Nat. Chem. Biol. 13:867-873(2017).
RN [43]
RP VARIANT SER-260.
RX PubMed=15334672; DOI=10.3748/wjg.v10.i19.2795;
RA Chen X.P., Liu Y.B., Rui J., Peng S.Y., Peng C.H., Zhou Z.Y., Shi L.H.,
RA Shen H.W., Xu B.;
RT "Heparanase mRNA expression and point mutation in hepatocellular
RT carcinoma.";
RL World J. Gastroenterol. 10:2795-2799(2004).
CC -!- FUNCTION: Endoglycosidase that cleaves heparan sulfate proteoglycans
CC (HSPGs) into heparan sulfate side chains and core proteoglycans.
CC Participates in extracellular matrix (ECM) degradation and remodeling.
CC Selectively cleaves the linkage between a glucuronic acid unit and an
CC N-sulfo glucosamine unit carrying either a 3-O-sulfo or a 6-O-sulfo
CC group. Can also cleave the linkage between a glucuronic acid unit and
CC an N-sulfo glucosamine unit carrying a 2-O-sulfo group, but not
CC linkages between a glucuronic acid unit and a 2-O-sulfated iduronic
CC acid moiety. It is essentially inactive at neutral pH but becomes
CC active under acidic conditions such as during tumor invasion and in
CC inflammatory processes. Facilitates cell migration associated with
CC metastasis, wound healing and inflammation. Enhances shedding of
CC syndecans, and increases endothelial invasion and angiogenesis in
CC myelomas. Acts as procoagulant by increasing the generation of
CC activation factor X in the presence of tissue factor and activation
CC factor VII. Increases cell adhesion to the extracellular matrix (ECM),
CC independent of its enzymatic activity. Induces AKT1/PKB phosphorylation
CC via lipid rafts increasing cell mobility and invasion. Heparin
CC increases this AKT1/PKB activation. Regulates osteogenesis. Enhances
CC angiogenesis through up-regulation of SRC-mediated activation of VEGF.
CC Implicated in hair follicle inner root sheath differentiation and hair
CC homeostasis. {ECO:0000269|PubMed:12213822, ECO:0000269|PubMed:12773484,
CC ECO:0000269|PubMed:15044433, ECO:0000269|PubMed:16452201,
CC ECO:0000269|PubMed:18557927, ECO:0000269|PubMed:18798279,
CC ECO:0000269|PubMed:19244131, ECO:0000269|PubMed:20097882,
CC ECO:0000269|PubMed:20181948, ECO:0000269|PubMed:20309870,
CC ECO:0000269|PubMed:20561914, ECO:0000269|PubMed:21131364}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=endohydrolysis of (1->4)-beta-D-glycosidic bonds of heparan
CC sulfate chains in heparan sulfate proteoglycan.; EC=3.2.1.166;
CC Evidence={ECO:0000269|PubMed:11973358, ECO:0000269|PubMed:12213822,
CC ECO:0000269|PubMed:12927802, ECO:0000269|PubMed:20181948,
CC ECO:0000269|PubMed:20561914, ECO:0000269|PubMed:20634491};
CC -!- ACTIVITY REGULATION: Inhibited by EDTA, laminarin sulfate and, to a
CC lower extent, by heparin and sulfamin and activated by calcium and
CC magnesium. {ECO:0000250}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=7.7 uM for M09 S05a, a heparin sulfate analog with a
CC nonasaccharide with N-sulfation and a single GlcNS(6S) toward the
CC reducing end {ECO:0000269|PubMed:28581485};
CC Note=kcat is 0.53 sec(-1) for M09 S05a.
CC {ECO:0000269|PubMed:28581485};
CC pH dependence:
CC Optimum pH is 4-6. {ECO:0000269|PubMed:10446189,
CC ECO:0000269|PubMed:10764835, ECO:0000269|PubMed:12713442,
CC ECO:0000269|PubMed:15848168};
CC -!- SUBUNIT: Heterodimer; heterodimer formation between the 8 kDa and the
CC 50 kDa subunits is required for enzyme activity. Interacts with TF; the
CC interaction, inhibited by heparin, enhances the generation of activated
CC factor X and activates coagulation. Interacts with HRG; the interaction
CC is enhanced at acidic pH, partially inhibits binding of HPSE to cell
CC surface receptors and modulates its enzymatic activity. Interacts with
CC SDC1; the interaction enhances the shedding of SDC1. Interacts with
CC HPSE2. {ECO:0000269|PubMed:12441129, ECO:0000269|PubMed:12713442,
CC ECO:0000269|PubMed:20561914, ECO:0000269|PubMed:20576607,
CC ECO:0000269|PubMed:20634491}.
CC -!- SUBCELLULAR LOCATION: Lysosome membrane; Peripheral membrane protein.
CC Secreted. Nucleus. Note=Proheparanase is secreted via vesicles of the
CC Golgi. Interacts with cell membrane heparan sulfate proteoglycans
CC (HSPGs). Endocytosed and accumulates in endosomes. Transferred to
CC lysosomes where it is proteolytically cleaved to produce the active
CC enzyme. Under certain stimuli, transferred to the cell surface.
CC Associates with lipid rafts. Colocalizes with SDC1 in
CC endosomal/lysosomal vesicles. Accumulates in perinuclear lysosomal
CC vesicles. Heparin retains proheparanase in the extracellular medium (By
CC similarity). {ECO:0000250}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1;
CC IsoId=Q9Y251-1; Sequence=Displayed;
CC Name=2; Synonyms=55 kDa, splice 5;
CC IsoId=Q9Y251-2; Sequence=VSP_044537;
CC Name=3; Synonyms=ex9-10del;
CC IsoId=Q9Y251-3; Sequence=VSP_044664;
CC Name=4; Synonyms=ex10del;
CC IsoId=Q9Y251-4; Sequence=VSP_053730, VSP_053731;
CC -!- TISSUE SPECIFICITY: Highly expressed in placenta and spleen and weakly
CC expressed in lymph node, thymus, peripheral blood leukocytes, bone
CC marrow, endothelial cells, fetal liver and tumor tissues. Also
CC expressed in hair follicles, specifically in both Henle's and Huxley's
CC layers of inner the root sheath (IRS) at anagen phase.
CC {ECO:0000269|PubMed:10395326, ECO:0000269|PubMed:10405343,
CC ECO:0000269|PubMed:10764835, ECO:0000269|PubMed:18557927,
CC ECO:0000269|PubMed:20309870}.
CC -!- PTM: Proteolytically processed. The cleavage of the 65 kDa form leads
CC to the generation of a linker peptide, and 8 kDa and 50 kDa products.
CC The active form, the 8/50 kDa heterodimer, is resistant to degradation.
CC Complete removal of the linker peptide appears to be a prerequisite to
CC the complete activation of the enzyme. {ECO:0000269|PubMed:10395325,
CC ECO:0000269|PubMed:11973358, ECO:0000269|PubMed:12441129,
CC ECO:0000269|PubMed:15126626, ECO:0000269|PubMed:15659389,
CC ECO:0000269|PubMed:15848168}.
CC -!- PTM: N-glycosylated. Glycosylation of the 50 kDa subunit appears to be
CC essential for its solubility. {ECO:0000269|PubMed:10395325,
CC ECO:0000269|PubMed:12713442, ECO:0000269|PubMed:14573609,
CC ECO:0000269|PubMed:16263699, ECO:0000269|PubMed:19159218}.
CC -!- MISCELLANEOUS: [Isoform 2]: Escapes proteolytic cleavage, devoid of HS
CC degradation activity. {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the glycosyl hydrolase 79 family. {ECO:0000305}.
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DR EMBL; AF152376; AAD45669.1; -; mRNA.
DR EMBL; AF155510; AAD54941.1; -; mRNA.
DR EMBL; AF144325; AAD41342.1; -; mRNA.
DR EMBL; AF165154; AAD45379.1; -; mRNA.
DR EMBL; AF084467; AAD54516.1; -; mRNA.
DR EMBL; AM419200; CAL91960.1; -; mRNA.
DR EMBL; AY948074; AAX47106.1; -; mRNA.
DR EMBL; GQ337901; ACT98237.1; -; mRNA.
DR EMBL; GQ337902; ACT98238.1; -; mRNA.
DR EMBL; AK222986; BAD96706.1; -; mRNA.
DR EMBL; AC114781; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC051321; AAH51321.1; -; mRNA.
DR CCDS; CCDS3602.1; -. [Q9Y251-1]
DR CCDS; CCDS54774.1; -. [Q9Y251-3]
DR CCDS; CCDS56337.1; -. [Q9Y251-2]
DR RefSeq; NP_001092010.1; NM_001098540.2. [Q9Y251-1]
DR RefSeq; NP_001159970.1; NM_001166498.2. [Q9Y251-3]
DR RefSeq; NP_001186759.1; NM_001199830.1. [Q9Y251-2]
DR RefSeq; NP_006656.2; NM_006665.5. [Q9Y251-1]
DR PDB; 5E8M; X-ray; 1.75 A; A=158-543, B=36-109.
DR PDB; 5E97; X-ray; 1.63 A; A=158-543, B=36-109.
DR PDB; 5E98; X-ray; 1.63 A; A=158-543, B=36-109.
DR PDB; 5E9B; X-ray; 1.88 A; A=158-543, B=36-109.
DR PDB; 5E9C; X-ray; 1.73 A; A=158-543, B=36-109.
DR PDB; 5L9Y; X-ray; 1.88 A; A=158-543, B=36-109.
DR PDB; 5L9Z; X-ray; 1.57 A; A=158-543, B=36-109.
DR PDB; 5LA4; X-ray; 1.90 A; A=36-543.
DR PDB; 5LA7; X-ray; 1.94 A; A=36-543.
DR PDB; 6ZDM; X-ray; 1.71 A; AAA=158-543, BBB=36-109.
DR PDB; 7RG8; X-ray; 1.30 A; A=157-543, B=36-109.
DR PDBsum; 5E8M; -.
DR PDBsum; 5E97; -.
DR PDBsum; 5E98; -.
DR PDBsum; 5E9B; -.
DR PDBsum; 5E9C; -.
DR PDBsum; 5L9Y; -.
DR PDBsum; 5L9Z; -.
DR PDBsum; 5LA4; -.
DR PDBsum; 5LA7; -.
DR PDBsum; 6ZDM; -.
DR PDBsum; 7RG8; -.
DR AlphaFoldDB; Q9Y251; -.
DR SMR; Q9Y251; -.
DR BioGRID; 116066; 70.
DR ComplexPortal; CPX-362; Heparanase complex.
DR IntAct; Q9Y251; 27.
DR STRING; 9606.ENSP00000384262; -.
DR BindingDB; Q9Y251; -.
DR ChEMBL; CHEMBL3921; -.
DR DrugBank; DB06779; Dalteparin.
DR DrugBank; DB01109; Heparin.
DR DrugCentral; Q9Y251; -.
DR GuidetoPHARMACOLOGY; 2996; -.
DR CAZy; GH79; Glycoside Hydrolase Family 79.
DR GlyGen; Q9Y251; 7 sites.
DR iPTMnet; Q9Y251; -.
DR PhosphoSitePlus; Q9Y251; -.
DR BioMuta; HPSE; -.
DR DMDM; 296434532; -.
DR EPD; Q9Y251; -.
DR jPOST; Q9Y251; -.
DR MassIVE; Q9Y251; -.
DR MaxQB; Q9Y251; -.
DR PaxDb; Q9Y251; -.
DR PeptideAtlas; Q9Y251; -.
DR PRIDE; Q9Y251; -.
DR ProteomicsDB; 19409; -.
DR ProteomicsDB; 20372; -.
DR ProteomicsDB; 85653; -. [Q9Y251-1]
DR TopDownProteomics; Q9Y251-1; -. [Q9Y251-1]
DR ABCD; Q9Y251; 8 sequenced antibodies.
DR Antibodypedia; 4072; 562 antibodies from 34 providers.
DR DNASU; 10855; -.
DR Ensembl; ENST00000311412.10; ENSP00000308107.5; ENSG00000173083.16. [Q9Y251-1]
DR Ensembl; ENST00000405413.6; ENSP00000384262.2; ENSG00000173083.16. [Q9Y251-1]
DR Ensembl; ENST00000509906.5; ENSP00000421038.1; ENSG00000173083.16. [Q9Y251-4]
DR Ensembl; ENST00000512196.5; ENSP00000423265.1; ENSG00000173083.16. [Q9Y251-3]
DR Ensembl; ENST00000513463.1; ENSP00000421365.1; ENSG00000173083.16. [Q9Y251-2]
DR GeneID; 10855; -.
DR KEGG; hsa:10855; -.
DR MANE-Select; ENST00000311412.10; ENSP00000308107.5; NM_001098540.3; NP_001092010.1.
DR UCSC; uc003hoi.4; human. [Q9Y251-1]
DR CTD; 10855; -.
DR DisGeNET; 10855; -.
DR GeneCards; HPSE; -.
DR HGNC; HGNC:5164; HPSE.
DR HPA; ENSG00000173083; Low tissue specificity.
DR MIM; 604724; gene.
DR neXtProt; NX_Q9Y251; -.
DR OpenTargets; ENSG00000173083; -.
DR PharmGKB; PA29435; -.
DR VEuPathDB; HostDB:ENSG00000173083; -.
DR eggNOG; ENOG502QQST; Eukaryota.
DR GeneTree; ENSGT00390000004874; -.
DR HOGENOM; CLU_021823_0_1_1; -.
DR InParanoid; Q9Y251; -.
DR OMA; SGFMWLD; -.
DR OrthoDB; 1132327at2759; -.
DR PhylomeDB; Q9Y251; -.
DR TreeFam; TF328999; -.
DR BioCyc; MetaCyc:ENSG00000173083-MON; -.
DR BRENDA; 3.2.1.166; 2681.
DR PathwayCommons; Q9Y251; -.
DR Reactome; R-HSA-2024096; HS-GAG degradation.
DR Reactome; R-HSA-6798695; Neutrophil degranulation.
DR SignaLink; Q9Y251; -.
DR SIGNOR; Q9Y251; -.
DR BioGRID-ORCS; 10855; 13 hits in 1078 CRISPR screens.
DR ChiTaRS; HPSE; human.
DR GeneWiki; Heparanase; -.
DR GenomeRNAi; 10855; -.
DR Pharos; Q9Y251; Tchem.
DR PRO; PR:Q9Y251; -.
DR Proteomes; UP000005640; Chromosome 4.
DR RNAct; Q9Y251; protein.
DR Bgee; ENSG00000173083; Expressed in monocyte and 119 other tissues.
DR ExpressionAtlas; Q9Y251; baseline and differential.
DR Genevisible; Q9Y251; HS.
DR GO; GO:0005776; C:autophagosome; IC:ComplexPortal.
DR GO; GO:0005768; C:endosome; IDA:ComplexPortal.
DR GO; GO:0031012; C:extracellular matrix; IBA:GO_Central.
DR GO; GO:0005576; C:extracellular region; IMP:ComplexPortal.
DR GO; GO:0005615; C:extracellular space; IBA:GO_Central.
DR GO; GO:1904974; C:heparanase complex; IDA:UniProtKB.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:HPA.
DR GO; GO:0043202; C:lysosomal lumen; TAS:Reactome.
DR GO; GO:0005765; C:lysosomal membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005764; C:lysosome; IDA:UniProtKB.
DR GO; GO:0045121; C:membrane raft; IEA:Ensembl.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0035580; C:specific granule lumen; TAS:Reactome.
DR GO; GO:0004566; F:beta-glucuronidase activity; TAS:ProtInc.
DR GO; GO:0030305; F:heparanase activity; IDA:UniProtKB.
DR GO; GO:0045545; F:syndecan binding; IDA:UniProtKB.
DR GO; GO:0060055; P:angiogenesis involved in wound healing; IBA:GO_Central.
DR GO; GO:0007160; P:cell-matrix adhesion; IDA:UniProtKB.
DR GO; GO:0061028; P:establishment of endothelial barrier; IEA:Ensembl.
DR GO; GO:0002542; P:Factor XII activation; IDA:ComplexPortal.
DR GO; GO:0030200; P:heparan sulfate proteoglycan catabolic process; IDA:ComplexPortal.
DR GO; GO:0030202; P:heparin metabolic process; IEA:Ensembl.
DR GO; GO:0006954; P:inflammatory response; IDA:ComplexPortal.
DR GO; GO:0045766; P:positive regulation of angiogenesis; IMP:ComplexPortal.
DR GO; GO:0010508; P:positive regulation of autophagy; IDA:ComplexPortal.
DR GO; GO:0030194; P:positive regulation of blood coagulation; IDA:ComplexPortal.
DR GO; GO:0030335; P:positive regulation of cell migration; IDA:ComplexPortal.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; IMP:ComplexPortal.
DR GO; GO:0001954; P:positive regulation of cell-matrix adhesion; IMP:ComplexPortal.
DR GO; GO:0090091; P:positive regulation of extracellular matrix disassembly; IC:ComplexPortal.
DR GO; GO:0051798; P:positive regulation of hair follicle development; IEA:Ensembl.
DR GO; GO:0033690; P:positive regulation of osteoblast proliferation; IDA:UniProtKB.
DR GO; GO:0051897; P:positive regulation of protein kinase B signaling; IDA:UniProtKB.
DR GO; GO:1900026; P:positive regulation of substrate adhesion-dependent cell spreading; IMP:ComplexPortal.
DR GO; GO:0010575; P:positive regulation of vascular endothelial growth factor production; IDA:UniProtKB.
DR GO; GO:0071806; P:protein transmembrane transport; IEA:Ensembl.
DR GO; GO:0006029; P:proteoglycan metabolic process; TAS:ProtInc.
DR GO; GO:0051797; P:regulation of hair follicle development; IDA:UniProtKB.
DR GO; GO:0010033; P:response to organic substance; IEA:Ensembl.
DR GO; GO:0061042; P:vascular wound healing; IEA:Ensembl.
DR InterPro; IPR005199; Glyco_hydro_79.
DR InterPro; IPR017853; Glycoside_hydrolase_SF.
DR Pfam; PF03662; Glyco_hydro_79n; 1.
DR SUPFAM; SSF51445; SSF51445; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Calcium; Cell adhesion;
KW Direct protein sequencing; Disulfide bond; Glycoprotein; Hydrolase;
KW Lysosome; Magnesium; Membrane; Nucleus; Reference proteome; Secreted;
KW Signal.
FT SIGNAL 1..35
FT /evidence="ECO:0000269|PubMed:12713442"
FT CHAIN 36..109
FT /note="Heparanase 8 kDa subunit"
FT /id="PRO_0000042260"
FT PROPEP 110..157
FT /note="Linker peptide"
FT /evidence="ECO:0000269|PubMed:10395326,
FT ECO:0000269|PubMed:10446189, ECO:0000269|PubMed:12713442"
FT /id="PRO_0000042261"
FT CHAIN 158..543
FT /note="Heparanase 50 kDa subunit"
FT /id="PRO_0000042262"
FT REGION 288..417
FT /note="Required for heterodimerization with the heparanase
FT 8 kDa subunit"
FT /evidence="ECO:0000269|PubMed:12927802"
FT REGION 527..543
FT /note="Required for transferring proheparanase to the Golgi
FT apparatus, secretion and subsequent enzyme activity and for
FT enhancement of PKB/AKT1 phosphorylation"
FT ACT_SITE 225
FT /note="Proton donor"
FT /evidence="ECO:0000305|PubMed:28581485,
FT ECO:0007744|PDB:5E9B"
FT ACT_SITE 343
FT /note="Nucleophile"
FT /evidence="ECO:0000305|PubMed:28581485,
FT ECO:0007744|PDB:5E97, ECO:0007744|PDB:5E98,
FT ECO:0007744|PDB:5E9B"
FT BINDING 62..64
FT /ligand="heparan sulfate group"
FT /ligand_id="ChEBI:CHEBI:157750"
FT /evidence="ECO:0000269|PubMed:28581485,
FT ECO:0007744|PDB:5E97, ECO:0007744|PDB:5E98,
FT ECO:0007744|PDB:5E9B, ECO:0007744|PDB:5E9C"
FT BINDING 97
FT /ligand="heparan sulfate group"
FT /ligand_id="ChEBI:CHEBI:157750"
FT /evidence="ECO:0000269|PubMed:28581485,
FT ECO:0007744|PDB:5E97, ECO:0007744|PDB:5E98,
FT ECO:0007744|PDB:5E9B"
FT BINDING 158..162
FT /ligand="heparan sulfate group"
FT /ligand_id="ChEBI:CHEBI:157750"
FT /evidence="ECO:0000269|PubMed:15760902"
FT BINDING 270..280
FT /ligand="heparan sulfate group"
FT /ligand_id="ChEBI:CHEBI:157750"
FT /evidence="ECO:0000269|PubMed:15760902,
FT ECO:0000269|PubMed:28581485, ECO:0007744|PDB:5E9C"
FT BINDING 296
FT /ligand="heparan sulfate group"
FT /ligand_id="ChEBI:CHEBI:157750"
FT /evidence="ECO:0000269|PubMed:28581485,
FT ECO:0007744|PDB:5E9C"
FT BINDING 303
FT /ligand="heparan sulfate group"
FT /ligand_id="ChEBI:CHEBI:157750"
FT /evidence="ECO:0000269|PubMed:28581485,
FT ECO:0007744|PDB:5E9C"
FT BINDING 348..350
FT /ligand="heparan sulfate group"
FT /ligand_id="ChEBI:CHEBI:157750"
FT /evidence="ECO:0000269|PubMed:28581485,
FT ECO:0007744|PDB:5E97, ECO:0007744|PDB:5E98,
FT ECO:0007744|PDB:5E9B"
FT BINDING 389..391
FT /ligand="heparan sulfate group"
FT /ligand_id="ChEBI:CHEBI:157750"
FT /evidence="ECO:0000269|PubMed:28581485,
FT ECO:0007744|PDB:5E97, ECO:0007744|PDB:5E98,
FT ECO:0007744|PDB:5E9B"
FT CARBOHYD 162
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:14573609,
FT ECO:0000269|PubMed:28581485, ECO:0007744|PDB:5E8M,
FT ECO:0007744|PDB:5E97"
FT CARBOHYD 178
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:14573609"
FT CARBOHYD 200
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:14573609,
FT ECO:0000269|PubMed:28581485, ECO:0007744|PDB:5E8M,
FT ECO:0007744|PDB:5E97, ECO:0007744|PDB:5E98,
FT ECO:0007744|PDB:5E9B, ECO:0007744|PDB:5E9C"
FT CARBOHYD 217
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:14573609,
FT ECO:0000269|PubMed:16263699, ECO:0000269|PubMed:19159218,
FT ECO:0000269|PubMed:28581485, ECO:0007744|PDB:5E8M"
FT CARBOHYD 238
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:14573609,
FT ECO:0000269|PubMed:19159218, ECO:0000269|PubMed:28581485,
FT ECO:0007744|PDB:5E8M, ECO:0007744|PDB:5E97,
FT ECO:0007744|PDB:5E98, ECO:0007744|PDB:5E9B,
FT ECO:0007744|PDB:5E9C"
FT CARBOHYD 459
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:14573609,
FT ECO:0000269|PubMed:28581485, ECO:0007744|PDB:5E8M,
FT ECO:0007744|PDB:5E97, ECO:0007744|PDB:5E98,
FT ECO:0007744|PDB:5E9B, ECO:0007744|PDB:5E9C"
FT DISULFID 127..179
FT /evidence="ECO:0000269|PubMed:15334672,
FT ECO:0007744|PDB:5LA4, ECO:0007744|PDB:5LA7"
FT DISULFID 437..542
FT /evidence="ECO:0000269|PubMed:15334672,
FT ECO:0000269|PubMed:28581485, ECO:0007744|PDB:5E8M,
FT ECO:0007744|PDB:5E97, ECO:0007744|PDB:5E98,
FT ECO:0007744|PDB:5E9B, ECO:0007744|PDB:5E9C,
FT ECO:0007744|PDB:5L9Y, ECO:0007744|PDB:5L9Z,
FT ECO:0007744|PDB:5LA4, ECO:0007744|PDB:5LA7"
FT VAR_SEQ 167..225
FT /note="RSSVDVLYTFANCSGLDLIFGLNALLRTADLQWNSSNAQLLLDYCSSKGYNI
FT SWELGNE -> K (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:17208203"
FT /id="VSP_044537"
FT VAR_SEQ 329..402
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|Ref.10"
FT /id="VSP_044664"
FT VAR_SEQ 365..380
FT /note="WLDKLGLSARMGIEVV -> IIGYLFCSRNWWAPRC (in isoform 4)"
FT /evidence="ECO:0000303|Ref.10"
FT /id="VSP_053730"
FT VAR_SEQ 381..543
FT /note="Missing (in isoform 4)"
FT /evidence="ECO:0000303|Ref.10"
FT /id="VSP_053731"
FT VARIANT 260
FT /note="N -> S (in some hepatocellular carcinoma)"
FT /evidence="ECO:0000269|PubMed:15334672"
FT /id="VAR_023600"
FT VARIANT 307
FT /note="K -> R (in dbSNP:rs11099592)"
FT /evidence="ECO:0000269|PubMed:10395325,
FT ECO:0000269|PubMed:10395326, ECO:0000269|PubMed:10405343,
FT ECO:0000269|PubMed:10446189, ECO:0000269|PubMed:10764835,
FT ECO:0000269|PubMed:15489334, ECO:0000269|PubMed:17208203,
FT ECO:0000269|Ref.10, ECO:0000269|Ref.11, ECO:0000269|Ref.9"
FT /id="VAR_068907"
FT MUTAGEN 156
FT /note="Y->A,E: Alteration of the correct processing of
FT heparanase which results in the cleavage at an upstream
FT site in the linker peptide and no activation of
FT proheparanase."
FT /evidence="ECO:0000269|PubMed:15659389"
FT MUTAGEN 156
FT /note="Y->V: Normal processing."
FT /evidence="ECO:0000269|PubMed:15659389"
FT MUTAGEN 158
FT /note="K->A: No association with GS-modified heparin; when
FT associated with K-158."
FT /evidence="ECO:0000269|PubMed:15760902"
FT MUTAGEN 161
FT /note="K->A: Two-fold increase in the level of secretion
FT upon addition of GS-modified heparin. No association with
FT GS-modified heparin; when associated with K-161."
FT /evidence="ECO:0000269|PubMed:15760902"
FT MUTAGEN 162
FT /note="N->Q: Faster electrophoretic migration typical of a
FT size reduction and important decrease of secretion. Larger
FT size reduction; when associated with Q-178; Q-200; Q-217;
FT Q-238 and Q-459."
FT /evidence="ECO:0000269|PubMed:14573609"
FT MUTAGEN 178
FT /note="N->Q: Faster electrophoretic migration typical of a
FT size reduction and important decrease of secretion. Larger
FT size reduction; when associated with Q-162; Q-200; Q-217;
FT Q-238 and Q-459."
FT /evidence="ECO:0000269|PubMed:14573609"
FT MUTAGEN 200
FT /note="N->Q: Faster electrophoretic migration typical of a
FT size reduction and partial decrease in secretion. Larger
FT size reduction; when associated with Q-162; Q-178; Q-217;
FT Q-238 and Q-459."
FT /evidence="ECO:0000269|PubMed:14573609"
FT MUTAGEN 217
FT /note="N->Q: Faster electrophoretic migration typical of a
FT size reduction and partial decrease in secretion. Larger
FT size reduction; when associated with Q-162; Q-178; Q-200;
FT Q-238 and Q-459."
FT /evidence="ECO:0000269|PubMed:14573609"
FT MUTAGEN 225
FT /note="E->A: Loss of heparanase activity. No effect on
FT HPSE-mediated cell adhesion."
FT /evidence="ECO:0000269|PubMed:11123890,
FT ECO:0000269|PubMed:12773484"
FT MUTAGEN 238
FT /note="N->Q: Faster electrophoretic migration typical of a
FT size reduction. Larger size reduction and important
FT decrease of secretion; when associated with Q-162; Q-178;
FT Q-200; Q-217 and Q-459."
FT /evidence="ECO:0000269|PubMed:14573609"
FT MUTAGEN 343
FT /note="E->A: Loss of heparanase activity."
FT /evidence="ECO:0000269|PubMed:11123890"
FT MUTAGEN 367
FT /note="D->A: Strong decrease in heparanase activity."
FT /evidence="ECO:0000269|PubMed:11123890"
FT MUTAGEN 378
FT /note="E->A: No reduction in heparanase activity."
FT MUTAGEN 396
FT /note="E->A: No reduction in heparanase activity."
FT MUTAGEN 414
FT /note="V->K: Abolishes processing, secretion and enzyme
FT activity."
FT /evidence="ECO:0000269|PubMed:19244131"
FT MUTAGEN 417
FT /note="K->E: No effect on processing nor secretion. No
FT enzyme activity detected."
FT /evidence="ECO:0000269|PubMed:19244131"
FT MUTAGEN 459
FT /note="N->Q: Faster electrophoretic migration typical of a
FT size reduction. Larger size reduction and important
FT decrease of secretion; when associated with Q-162; Q-178;
FT Q-200; Q-217 and Q-238."
FT /evidence="ECO:0000269|PubMed:14573609"
FT MUTAGEN 525
FT /note="P->G: No effect on processing nor secretion. No
FT enzyme activity detected."
FT /evidence="ECO:0000269|PubMed:19244131"
FT MUTAGEN 527
FT /note="F->R: No effect on processing nor secretion. No
FT enzyme activity detected."
FT /evidence="ECO:0000269|PubMed:19244131"
FT MUTAGEN 528
FT /note="S->K: No effect on processing nor secretion. No
FT enzyme activity detected."
FT /evidence="ECO:0000269|PubMed:19244131"
FT MUTAGEN 529
FT /note="Y->A: No effect on processing nor secretion. No
FT enzyme activity detected."
FT /evidence="ECO:0000269|PubMed:19244131"
FT MUTAGEN 531
FT /note="F->R: Abolishes processing, secretion and enzyme
FT activity."
FT /evidence="ECO:0000269|PubMed:19244131"
FT MUTAGEN 533
FT /note="V->R: Abolishes processing, secretion and enzyme
FT activity."
FT /evidence="ECO:0000269|PubMed:19244131"
FT MUTAGEN 534
FT /note="I->D: Abolishes processing, secretion and enzyme
FT activity."
FT /evidence="ECO:0000269|PubMed:19244131"
FT MUTAGEN 535
FT /note="R->A: No effect on processing, secretion nor enzyme
FT activity."
FT /evidence="ECO:0000269|PubMed:19244131"
FT MUTAGEN 536
FT /note="N->A: No effect on processing, secretion nor enzyme
FT activity."
FT /evidence="ECO:0000269|PubMed:19244131"
FT MUTAGEN 537
FT /note="A->K: Abolishes processing, secretion and enzyme
FT activity."
FT /evidence="ECO:0000269|PubMed:19244131"
FT MUTAGEN 538
FT /note="K->A: No effect on processing, secretion nor enzyme
FT activity."
FT /evidence="ECO:0000269|PubMed:19244131"
FT MUTAGEN 539
FT /note="V->A: No effect on processing, secretion nor enzyme
FT activity."
FT /evidence="ECO:0000269|PubMed:19244131"
FT MUTAGEN 540
FT /note="A->K: No effect on processing, secretion nor enzyme
FT activity."
FT /evidence="ECO:0000269|PubMed:19244131"
FT MUTAGEN 541
FT /note="A->K: No effect on processing, secretion nor enzyme
FT activity."
FT /evidence="ECO:0000269|PubMed:19244131"
FT MUTAGEN 542
FT /note="C->A: Abolishes processing, secretion and enzyme
FT activity."
FT /evidence="ECO:0000269|PubMed:19244131"
FT CONFLICT 13
FT /note="L -> LL (in Ref. 5; AAD54516)"
FT /evidence="ECO:0000305"
FT CONFLICT 36
FT /note="Q -> QQ (in Ref. 5; AAD54516)"
FT /evidence="ECO:0000305"
FT CONFLICT 291
FT /note="D -> G (in Ref. 11; BAD96706)"
FT /evidence="ECO:0000305"
FT STRAND 38..44
FT /evidence="ECO:0007829|PDB:5L9Z"
FT STRAND 49..51
FT /evidence="ECO:0007829|PDB:5L9Z"
FT STRAND 57..61
FT /evidence="ECO:0007829|PDB:5L9Z"
FT HELIX 63..67
FT /evidence="ECO:0007829|PDB:5L9Z"
FT HELIX 71..76
FT /evidence="ECO:0007829|PDB:5L9Z"
FT HELIX 78..86
FT /evidence="ECO:0007829|PDB:5L9Z"
FT STRAND 89..94
FT /evidence="ECO:0007829|PDB:5L9Z"
FT HELIX 97..101
FT /evidence="ECO:0007829|PDB:5L9Z"
FT STRAND 102..104
FT /evidence="ECO:0007829|PDB:5L9Z"
FT HELIX 112..121
FT /evidence="ECO:0007829|PDB:5LA4"
FT HELIX 126..129
FT /evidence="ECO:0007829|PDB:5LA4"
FT HELIX 134..157
FT /evidence="ECO:0007829|PDB:5LA4"
FT STRAND 163..165
FT /evidence="ECO:0007829|PDB:5L9Z"
FT HELIX 167..179
FT /evidence="ECO:0007829|PDB:5L9Z"
FT STRAND 182..188
FT /evidence="ECO:0007829|PDB:5L9Z"
FT HELIX 202..213
FT /evidence="ECO:0007829|PDB:5L9Z"
FT STRAND 219..222
FT /evidence="ECO:0007829|PDB:5L9Z"
FT HELIX 226..228
FT /evidence="ECO:0007829|PDB:5L9Z"
FT HELIX 229..233
FT /evidence="ECO:0007829|PDB:5L9Z"
FT HELIX 239..254
FT /evidence="ECO:0007829|PDB:5L9Z"
FT STRAND 256..258
FT /evidence="ECO:0007829|PDB:5L9Z"
FT STRAND 263..268
FT /evidence="ECO:0007829|PDB:5L9Z"
FT HELIX 273..286
FT /evidence="ECO:0007829|PDB:5L9Z"
FT HELIX 287..289
FT /evidence="ECO:0007829|PDB:5L9Z"
FT STRAND 291..301
FT /evidence="ECO:0007829|PDB:5L9Z"
FT TURN 302..304
FT /evidence="ECO:0007829|PDB:5L9Z"
FT HELIX 307..310
FT /evidence="ECO:0007829|PDB:5L9Z"
FT HELIX 313..316
FT /evidence="ECO:0007829|PDB:5L9Z"
FT HELIX 318..331
FT /evidence="ECO:0007829|PDB:5L9Z"
FT STRAND 338..348
FT /evidence="ECO:0007829|PDB:5L9Z"
FT TURN 353..357
FT /evidence="ECO:0007829|PDB:5L9Z"
FT HELIX 359..361
FT /evidence="ECO:0007829|PDB:5L9Z"
FT HELIX 362..375
FT /evidence="ECO:0007829|PDB:5L9Z"
FT STRAND 380..383
FT /evidence="ECO:0007829|PDB:5L9Z"
FT STRAND 385..389
FT /evidence="ECO:0007829|PDB:5L9Z"
FT HELIX 402..413
FT /evidence="ECO:0007829|PDB:5L9Z"
FT STRAND 414..418
FT /evidence="ECO:0007829|PDB:5L9Z"
FT STRAND 420..423
FT /evidence="ECO:0007829|PDB:5L9Z"
FT STRAND 429..438
FT /evidence="ECO:0007829|PDB:5L9Z"
FT STRAND 450..456
FT /evidence="ECO:0007829|PDB:5L9Z"
FT STRAND 458..460
FT /evidence="ECO:0007829|PDB:5L9Z"
FT STRAND 462..465
FT /evidence="ECO:0007829|PDB:5L9Z"
FT STRAND 475..482
FT /evidence="ECO:0007829|PDB:5L9Z"
FT STRAND 484..486
FT /evidence="ECO:0007829|PDB:5L9Z"
FT HELIX 487..489
FT /evidence="ECO:0007829|PDB:5L9Z"
FT STRAND 493..495
FT /evidence="ECO:0007829|PDB:5L9Z"
FT STRAND 514..516
FT /evidence="ECO:0007829|PDB:5LA7"
FT STRAND 522..524
FT /evidence="ECO:0007829|PDB:5L9Z"
FT STRAND 528..534
FT /evidence="ECO:0007829|PDB:5L9Z"
FT HELIX 540..542
FT /evidence="ECO:0007829|PDB:5L9Z"
SQ SEQUENCE 543 AA; 61149 MW; A990F5AFD639CA1A CRC64;
MLLRSKPALP PPLMLLLLGP LGPLSPGALP RPAQAQDVVD LDFFTQEPLH LVSPSFLSVT
IDANLATDPR FLILLGSPKL RTLARGLSPA YLRFGGTKTD FLIFDPKKES TFEERSYWQS
QVNQDICKYG SIPPDVEEKL RLEWPYQEQL LLREHYQKKF KNSTYSRSSV DVLYTFANCS
GLDLIFGLNA LLRTADLQWN SSNAQLLLDY CSSKGYNISW ELGNEPNSFL KKADIFINGS
QLGEDFIQLH KLLRKSTFKN AKLYGPDVGQ PRRKTAKMLK SFLKAGGEVI DSVTWHHYYL
NGRTATKEDF LNPDVLDIFI SSVQKVFQVV ESTRPGKKVW LGETSSAYGG GAPLLSDTFA
AGFMWLDKLG LSARMGIEVV MRQVFFGAGN YHLVDENFDP LPDYWLSLLF KKLVGTKVLM
ASVQGSKRRK LRVYLHCTNT DNPRYKEGDL TLYAINLHNV TKYLRLPYPF SNKQVDKYLL
RPLGPHGLLS KSVQLNGLTL KMVDDQTLPP LMEKPLRPGS SLGLPAFSYS FFVIRNAKVA
ACI
