Reviewed, UniProtKB/Swiss-Prot Q9Y251 (HPSE_HUMAN)

Names and origin

Protein names

Recommended name:
    Heparanase
    EC=3.2.-.-
Alternative name(s):
    Heparanase-1
      Short name=Hpa1
    Endo-glucoronidase
Cleaved into the following 2 chains:
    1- Recommended name:
            Heparanase 8 kDa subunit
    2- Recommended name:
            Heparanase 50 kDa subunit

Gene names

Name:	HPSE
Synonyms:	HEP, HPA, HPA1, HPR1, HPSE1, HSE1

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	543 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Endoglycosidase which is a cell surface and extracellular matrix-degrading enzyme. Cleaves heparan sulfate proteoglycans (HSPGs) into heparan sulfate side chains and core proteoglycans. Also implicated in the extravasation of leukocytes and tumor cell lines. Due to its contribution to metastasis and angiogenesis, it is considered to be a potential target for anti-cancer therapies.
Enzyme regulation	Inhibited by EDTA, laminarin sulfate and, to a lower extent, by heparin and sulfamin and activated by calcium and magnesium By similarity.
Subunit structure	The active heterodimer is composed of the 8 and 50 kDa subunits, the proteolytic products. Ref.7
Subcellular location	Lysosome membrane; Peripheral membrane protein. Secreted. Note: Secreted, internalised and transferred to late endosomes/lysosomes as a proheparanase. In lysosomes, it is processed into the active form, the heparanase. The uptake or internalisation of proheparanase is mediated by HSPGs. Heparin appears to be a competitor and retain proheparanase in the extracellular medium. Ref.6 Ref.13 Ref.14 Ref.15
Tissue specificity	Highly expressed in placenta and spleen and weakly expressed in lymph node, thymus, peripheral blood leukocytes, bone marrow, endothelial cells, fetal liver and tumor tissues. Ref.1 Ref.4 Ref.5
Post-translational modification	Proteolytically processed. The cleavage of the 65 kDa form leads to the generation of a linker peptide, 8 kDa and 50 kDa product. The active form, the 8/50 kDa heterodimer, is resistant to degradation. Complete removal of the linker peptide appears to be a prerequisite to the complete activation of the enzyme. N-glycosylated. Glycosylation of the 50 kDa subunit appears to be essential for its solubility. Ref.7 Ref.3 Ref.12 Ref.17
Sequence similarities	Belongs to the glycosyl hydrolase 79 family.
biophysicochemical properties	pH dependence: Optimum pH is 4-6.

Ontologies

Keywords
Cellular component	Lysosome Membrane Secreted
Coding sequence diversity	Polymorphism
Domain	Signal
Ligand	Calcium Magnesium
Molecular function	Hydrolase
PTM	Glycoprotein
Technical term	Direct protein sequencing
Gene Ontology (GO)
Biological process	proteoglycan metabolic process Ref.2 Traceable author statement. Source: ProtInc
Cellular component	extracellular region Inferred from electronic annotation. Source: UniProtKB-SubCell lysosomal membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	beta-glucuronidase activity Ref.3 Traceable author statement. Source: ProtInc calcium ion binding Inferred from electronic annotation. Source: UniProtKB-KW magnesium ion binding Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 35	35	Ref.7
	Chain	36 – 109	74	Heparanase 8 kDa subunit		PRO_0000042260
	Propeptide	110 – 157	48	Linker peptide Ref.4 Ref.2		PRO_0000042261
	Chain	158 – 543	386	Heparanase 50 kDa subunit		PRO_0000042262
Regions
	Region	158 – 162	5	Heparin/HS-binding
	Region	270 – 280	11	Heparin/HS-binding
Sites
	Active site	225	1	Proton donor Potential
	Active site	343	1	Nucleophile Potential
Amino acid modifications
	Glycosylation	162	1	N-linked (GlcNAc...) Ref.12
	Glycosylation	178	1	N-linked (GlcNAc...) Ref.12
	Glycosylation	200	1	N-linked (GlcNAc...) Ref.12
	Glycosylation	217	1	N-linked (GlcNAc...) Ref.12 Ref.17
	Glycosylation	238	1	N-linked (GlcNAc...) Ref.12
	Glycosylation	459	1	N-linked (GlcNAc...) Ref.12
Natural variations
	Natural variant	260	1	N → S in some hepatocellular carcinoma. Ref.19		VAR_023600
Experimental info
	Mutagenesis	156	1	Y → A or E: Alteration of the correct processing of heparanase which results in the cleavage at an upstream site in the linker peptide and no activation of proheparanase. Ref.15
	Mutagenesis	156	1	Y → V: Normal processing. Ref.15
	Mutagenesis	158	1	K → A: No association with GS-modified heparin; when associated with K-158. Ref.16
	Mutagenesis	161	1	K → A: Two-fold increase in the level of secretion upon addition of GS-modified heparin. No association with GS-modified heparin; when associated with K-161. Ref.16
	Mutagenesis	162	1	N → Q: Faster electrophoretic migration typical of a size reduction and important decrease of secretion. Larger size reduction; when associated with Q-178; Q-200; Q-217; Q-238 and Q-459. Ref.12
	Mutagenesis	178	1	N → Q: Faster electrophoretic migration typical of a size reduction and important decrease of secretion. Larger size reduction; when associated with Q-162; Q-200; Q-217; Q-238 and Q-459. Ref.12
	Mutagenesis	200	1	N → Q: Faster electrophoretic migration typical of a size reduction and partial decrease in secretion. Larger size reduction; when associated with Q-162; Q-178; Q-217; Q-238 and Q-459. Ref.12
	Mutagenesis	217	1	N → Q: Faster electrophoretic migration typical of a size reduction and partial decrease in secretion. Larger size reduction; when associated with Q-162; Q-178; Q-200; Q-238 and Q-459. Ref.12
	Mutagenesis	225	1	E → A: Loss of heparanase activity. Ref.11
	Mutagenesis	238	1	N → Q: Faster electrophoretic migration typical of a size reduction. Larger size reduction and important decrease of secretion; when associated with Q-162; Q-178; Q-200; Q-217 and Q-459. Ref.12
	Mutagenesis	343	1	E → A: Loss of heparanase activity. Ref.11
	Mutagenesis	367	1	D → A: Strong decrease in heparanase activity. Ref.11
	Mutagenesis	378	1	E → A: No reduction in heparanase activity.
	Mutagenesis	396	1	E → A: No reduction in heparanase activity.
	Mutagenesis	459	1	N → Q: Faster electrophoretic migration typical of a size reduction. Larger size reduction and important decrease of secretion; when associated with Q-162; Q-178; Q-200; Q-217 and Q-238. Ref.12
	Sequence conflict	13	1	L → LL in AAD54516. Ref.5
	Sequence conflict	36	1	Q → QQ in AAD54516. Ref.5
	Sequence conflict	291	1	D → G in BAD96706. Ref.9

Sequences

	Sequence		Length	Mass (Da)
	Q9Y251-1 [UniParc]. Last modified November 1, 1999. Version 1. Checksum: AD262EC267334AB2	FASTA	543	61,177
	10 20 30 40 50 60 MLLRSKPALP PPLMLLLLGP LGPLSPGALP RPAQAQDVVD LDFFTQEPLH LVSPSFLSVT 70 80 90 100 110 120 IDANLATDPR FLILLGSPKL RTLARGLSPA YLRFGGTKTD FLIFDPKKES TFEERSYWQS 130 140 150 160 170 180 QVNQDICKYG SIPPDVEEKL RLEWPYQEQL LLREHYQKKF KNSTYSRSSV DVLYTFANCS 190 200 210 220 230 240 GLDLIFGLNA LLRTADLQWN SSNAQLLLDY CSSKGYNISW ELGNEPNSFL KKADIFINGS 250 260 270 280 290 300 QLGEDFIQLH KLLRKSTFKN AKLYGPDVGQ PRRKTAKMLK SFLKAGGEVI DSVTWHHYYL 310 320 330 340 350 360 NGRTATREDF LNPDVLDIFI SSVQKVFQVV ESTRPGKKVW LGETSSAYGG GAPLLSDTFA 370 380 390 400 410 420 AGFMWLDKLG LSARMGIEVV MRQVFFGAGN YHLVDENFDP LPDYWLSLLF KKLVGTKVLM 430 440 450 460 470 480 ASVQGSKRRK LRVYLHCTNT DNPRYKEGDL TLYAINLHNV TKYLRLPYPF SNKQVDKYLL 490 500 510 520 530 540 RPLGPHGLLS KSVQLNGLTL KMVDDQTLPP LMEKPLRPGS SLGLPAFSYS FFVIRNAKVA ACI

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Cloning and functional expression of a human heparanase gene." Kussie P.H., Hulmes J.D., Ludwig D.L., Patel S., Navarro E.C., Seddon A.P., Giorgio N.A., Bohlen P. Biochem. Biophys. Res. Commun. 261:183-187(1999) [PubMed: 10405343] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY. Tissue: Placenta.
[2]	"Human heparanase. Purification, characterization, cloning, and expression." Toyoshima M., Nakajima M. J. Biol. Chem. 274:24153-24160(1999) [PubMed: 10446189] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], BIOPHYSICOCHEMICAL PROPERTIES, PROTEIN SEQUENCE OF 158-168; 326-337 AND 447-491. Tissue: Embryonic fibroblast.
[3]	"Mammalian heparanase: gene cloning, expression and function in tumor progression and metastasis." Vlodavsky I., Friedmann Y., Elkin M., Aingorn H., Atzmon R., Ishai-Michaeli R., Bitan M., Pappo O., Peretz T., Michal I., Spector L., Pecker I. Nat. Med. 5:793-802(1999) [PubMed: 10395325] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], GLYCOSYLATION, PROTEOLYTIC PROCESSING.
[4]	"Cloning of mammalian heparanase, an important enzyme in tumor invasion and metastasis." Hulett M.D., Freeman C., Hamdorf B.J., Baker R.T., Harris M.J., Parish C.R. Nat. Med. 5:803-809(1999) [PubMed: 10395326] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, PROTEIN SEQUENCE OF 158-174; 263-272; 326-337; 433-436; 438-443; 466-468 AND 478-483. Tissue: Placenta.
[5]	"Heparanase expression in invasive trophoblasts and acute vascular damage." Dempsey L.A., Plummer T.B., Coombes S.L., Platt J.L. Glycobiology 10:467-475(2000) [PubMed: 10764835] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], BIOPHYSICOCHEMICAL PROPERTIES, TISSUE SPECIFICITY. Tissue: Placenta.
[6]	"Molecular properties and involvement of heparanase in cancer progression and mammary gland morphogenesis." Zcharia E., Metzger S., Chajek-Shaul T., Friedmann Y., Pappo O., Aviv A., Elkin M., Pecker I., Peretz T., Vlodavsky I. J. Mammary Gland Biol. Neoplasia 6:311-322(2001) [PubMed: 11547900] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], SUBCELLULAR LOCATION.
[7]	"Biochemical characterization of the active heterodimer form of human heparanase (Hpa1) protein expressed in insect cells." McKenzie E., Young K., Hircock M., Bennett J., Bhaman M., Felix R., Turner P., Stamps A., McMillan D., Saville G., Ng S., Mason S., Snell D., Schofield D., Gong H., Townsend R., Gallagher J., Page M., Parekh R., Stubberfield C. Biochem. J. 373:423-435(2003) [PubMed: 12713442] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], PROTEIN SEQUENCE OF 36-41 AND 158-163, SUBUNIT, GLYCOSYLATION, BIOPHYSICOCHEMICAL PROPERTIES. Tissue: Placenta.
[8]	"Cloned heparanase from MCF-7 cells." Pinhal M.A., Semedo P. Submitted (FEB-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[9]	Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S. Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Small intestine.
[10]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Pancreas.
[11]	"Identification of active-site residues of the pro-metastatic endoglycosidase heparanase." Hulett M.D., Hornby J.R., Ohms S.J., Zuegg J., Freeman C., Gready J.E., Parish C.R. Biochemistry 39:15659-15667(2000) [PubMed: 11123890] [Abstract] Cited for: MUTAGENESIS OF GLU-225; GLU-343 AND ASP-367.
[12]	"Secretion of heparanase protein is regulated by glycosylation in human tumor cell lines." Simizu S., Ishida K., Wierzba M.K., Osada H. J. Biol. Chem. 279:2697-2703(2004) [PubMed: 14573609] [Abstract] Cited for: GLYCOSYLATION AT ASN-162; ASN-178; ASN-200; ASN-217; ASN-238 AND ASN-459, MUTAGENESIS OF ASN-162; ASN-178; ASN-200; ASN-217; ASN-238 AND ASN-459.
[13]	"Heparanase uptake is mediated by cell membrane heparan sulfate proteoglycans." Gingis-Velitski S., Zetser A., Kaplan V., Ben-Zaken O., Cohen E., Levy-Adam F., Bashenko Y., Flugelman M.Y., Vlodavsky I., Ilan N. J. Biol. Chem. 279:44084-44092(2004) [PubMed: 15292202] [Abstract] Cited for: SUBCELLULAR LOCATION.
[14]	"Heparanase processing by lysosomal/endosomal protein preparation." Cohen E., Atzmon R., Vlodavsky I., Ilan N. FEBS Lett. 579:2334-2338(2005) [PubMed: 15848168] [Abstract] Cited for: BIOPHYSICOCHEMICAL PROPERTIES, PROTEOLYTIC PROCESSING, SUBCELLULAR LOCATION.
[15]	"Site-directed mutagenesis, proteolytic cleavage, and activation of human proheparanase." Abboud-Jarrous G., Rangini-Guetta Z., Aingorn H., Atzmon R., Elgavish S., Peretz T., Vlodavsky I. J. Biol. Chem. 280:13568-13575(2005) [PubMed: 15659389] [Abstract] Cited for: SUBCELLULAR LOCATION, PROTEOLYTIC PROCESSING, MUTAGENESIS OF TYR-156.
[16]	"Identification and characterization of heparin/heparan sulfate binding domains of the endoglycosidase heparanase." Levy-Adam F., Abboud-Jarrous G., Guerrini M., Beccati D., Vlodavsky I., Ilan N. J. Biol. Chem. 280:20457-20466(2005) [PubMed: 15760902] [Abstract] Cited for: DOMAINS, MUTAGENESIS OF LYS-158 AND LYS-161.
[17]	"Elucidation of N-glycosylation sites on human platelet proteins: a glycoproteomic approach." Lewandrowski U., Moebius J., Walter U., Sickmann A. Mol. Cell. Proteomics 5:226-233(2006) [PubMed: 16263699] [Abstract] Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-217, MASS SPECTROMETRY. Tissue: Platelet.
[18]	"Glycoproteomics analysis of human liver tissue by combination of multiple enzyme digestion and hydrazide chemistry." Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H. J. Proteome Res. 8:651-661(2009) [PubMed: 19159218] [Abstract] Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-217 AND ASN-238, MASS SPECTROMETRY. Tissue: Liver.
[19]	"Heparanase mRNA expression and point mutation in hepatocellular carcinoma." Chen X.P., Liu Y.B., Rui J., Peng S.Y., Peng C.H., Zhou Z.Y., Shi L.H., Shen H.W., Xu B. World J. Gastroenterol. 10:2795-2799(2004) [PubMed: 15334672] [Abstract] Cited for: VARIANT SER-260.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBLGenBankDDBJ	AF152376 mRNA. Translation: AAD45669.1. AF155510 mRNA. Translation: AAD54941.1. AF165154 mRNA. Translation: AAD45379.1. AF084467 mRNA. Translation: AAD54516.1. AF144325 mRNA. Translation: AAD41342.1. AY948074 mRNA. Translation: AAX47106.1. AK222986 mRNA. Translation: BAD96706.1. BC051321 mRNA. Translation: AAH51321.1.
IPI	IPI00410297.
RefSeq	NP_001092010.1. NP_006656.2.
UniGene	Hs.44227
3D structure databases
ModBase	Search...
Protein family/group databases
CAZy	GH79. Glycoside Hydrolase Family 79.
PTM databases
PhosphoSite	Q9Y251.
Proteomic databases
PRIDE	Q9Y251.
Genome annotation databases
Ensembl	ENSG00000173083. Homo sapiens. [Contig view]
GeneID	10855.
KEGG	hsa:10855.
Organism-specific databases
GeneCards	GC04M084507.
H-InvDB	HIX0004342.
HGNC	HGNC:5164. HPSE.
HPA	CAB009813.
MIM	604724. gene.
PharmGKB	PA29435.
GenAtlas	Search...
Phylogenomic databases
HOGENOM	Q9Y251.
HOVERGEN	Q9Y251.
Enzyme and pathway databases
Pathway_Interaction_DB	syndecan_1_pathway. Syndecan-1-mediated signaling events.
Gene expression databases
ArrayExpress	Q9Y251.
Bgee	Q9Y251.
CleanEx	HS_HPSE.
GermOnline	ENSG00000173083. Homo sapiens.
Family and domain databases
InterPro	IPR005199. Glyco_hydro_79_N. [Graphical view]
PANTHER	PTHR14363. Glyco_hydro_79_N. 1 hit.
Pfam	PF03662. Glyco_hydro_79n. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
DrugBank	DB01109. Heparin.
NextBio	41205.
SOURCE	Search...

Entry information

Entry name

HPSE_HUMAN

Accession

Primary (citable) accession number: Q9Y251
Secondary accession number(s): Q53GE5, Q9UL39

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 11, 2005
Last sequence update:	November 1, 1999
Last modified:	June 16, 2009
This is version 66 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)