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Reviewed, UniProtKB/Swiss-Prot Q9Y251 (HPSE_HUMAN)

Last modified June 16, 2009. Version 66. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data | Customize display text xml rdf/xml gff fasta
Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Sequence annotation (Features) · Sequences · References · Cross-references · Entry information · Relevant documents

Names and origin

Protein namesRecommended 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
OrganismHomo sapiens (Human)
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length543 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence 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 componentLysosome
Membrane
Secreted
   Coding sequence diversityPolymorphism
   DomainSignal
   LigandCalcium
Magnesium
   Molecular functionHydrolase
   PTMGlycoprotein
   Technical termDirect protein sequencing
Gene Ontology (GO)
   Biological processproteoglycan metabolic process Ref.2

Traceable author statement. Source: ProtInc

   Cellular componentextracellular region

Inferred from electronic annotation. Source: UniProtKB-SubCell

lysosomal membrane

Inferred from electronic annotation. Source: UniProtKB-SubCell

   Molecular functionbeta-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 keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 3535 Ref.7
Chain36 – 10974Heparanase 8 kDa subunit
PRO_0000042260
Propeptide110 – 15748Linker peptide Ref.4 Ref.2
PRO_0000042261
Chain158 – 543386Heparanase 50 kDa subunit
PRO_0000042262

Regions

Region158 – 1625Heparin/HS-binding
Region270 – 28011Heparin/HS-binding

Sites

Active site2251Proton donor Potential
Active site3431Nucleophile Potential

Amino acid modifications

Glycosylation1621N-linked (GlcNAc...) Ref.12
Glycosylation1781N-linked (GlcNAc...) Ref.12
Glycosylation2001N-linked (GlcNAc...) Ref.12
Glycosylation2171N-linked (GlcNAc...) Ref.12 Ref.17
Glycosylation2381N-linked (GlcNAc...) Ref.12
Glycosylation4591N-linked (GlcNAc...) Ref.12

Natural variations

Natural variant2601N → S in some hepatocellular carcinoma. Ref.19
VAR_023600

Experimental info

Mutagenesis1561Y → 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
Mutagenesis1561Y → V: Normal processing. Ref.15
Mutagenesis1581K → A: No association with GS-modified heparin; when associated with K-158. Ref.16
Mutagenesis1611K → 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
Mutagenesis1621N → 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
Mutagenesis1781N → 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
Mutagenesis2001N → 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
Mutagenesis2171N → 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
Mutagenesis2251E → A: Loss of heparanase activity. Ref.11
Mutagenesis2381N → 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
Mutagenesis3431E → A: Loss of heparanase activity. Ref.11
Mutagenesis3671D → A: Strong decrease in heparanase activity. Ref.11
Mutagenesis3781E → A: No reduction in heparanase activity.
Mutagenesis3961E → A: No reduction in heparanase activity.
Mutagenesis4591N → 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 conflict131L → LL in AAD54516. Ref.5
Sequence conflict361Q → QQ in AAD54516. Ref.5
Sequence conflict2911D → G in BAD96706. Ref.9

Sequences

Sequence LengthMass (Da)Tools
Q9Y251-1 [UniParc].

Last modified November 1, 1999. Version 1.
Checksum: AD262EC267334AB2

FASTA54361,177
        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 

« Hide

References

« Hide '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

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.
IPIIPI00410297.
RefSeqNP_001092010.1.
NP_006656.2.
UniGeneHs.44227

3D structure databases

ModBaseSearch...

Protein family/group databases

CAZyGH79. Glycoside Hydrolase Family 79.

PTM databases

PhosphoSiteQ9Y251.

Proteomic databases

PRIDEQ9Y251.

Genome annotation databases

EnsemblENSG00000173083. Homo sapiens. [Contig view]
GeneID10855.
KEGGhsa:10855.

Organism-specific databases

GeneCardsGC04M084507.
H-InvDBHIX0004342.
HGNCHGNC:5164. HPSE.
HPACAB009813.
MIM604724. gene.
PharmGKBPA29435.
GenAtlasSearch...

Phylogenomic databases

HOGENOMQ9Y251.
HOVERGENQ9Y251.

Enzyme and pathway databases

Pathway_Interaction_DBsyndecan_1_pathway. Syndecan-1-mediated signaling events.

Gene expression databases

ArrayExpressQ9Y251.
BgeeQ9Y251.
CleanExHS_HPSE.
GermOnlineENSG00000173083. Homo sapiens.

Family and domain databases

InterProIPR005199. Glyco_hydro_79_N.
[Graphical view]
PANTHERPTHR14363. Glyco_hydro_79_N. 1 hit.
PfamPF03662. Glyco_hydro_79n. 1 hit.
[Graphical view]
ProtoNetSearch...

Other Resources

DrugBankDB01109. Heparin.
NextBio41205.
SOURCESearch...

Entry information

Entry nameHPSE_HUMAN
AccessionPrimary (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 statusReviewed (UniProtKB/Swiss-Prot)
Annotation projectHPI (Human Proteome Initiative)

Relevant documents

Glycosyl hydrolases

Classification of glycosyl hydrolase families and list of entries

Human chromosome 4

Human chromosome 4: entries, gene names and cross-references to MIM

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

SIMILARITY comments

Index of protein domains and families

Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Sequence annotation (Features) · Sequences · References · Cross-references · Entry information · Relevant documents