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Protein

Heparanase

Gene

Hpse

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at transcript leveli

Functioni

Endoglycosidase that cleaves heparan sulfate proteoglycans (HSPGs) into heparan sulfate side chains and core proteoglycans. Participates in extracellular matrix (ECM) degradation and remodeling. Selectively cleaves the linkage between a glucuronic acid unit and an N-sulfo glucosamine unit carrying either a 3-O-sulfo or a 6-O-sulfo group. Can also cleave the linkage between a glucuronic acid unit and an N-sulfo glucosamine unit carrying a 2-O-sulfo group, but not linkages between a glucuronic acid unit and a 2-O-sulfated iduronic acid moiety. It is essentially inactive at neutral pH but becomes active under acidic conditions such as during tumor invasion and in inflammatory processes. Facilitates cell migration associated with metastasis, wound healing and inflammation. Enhances shedding of syndecans, and increases endothelial invasion and angiogenesis in myelomas. Acts as procoagulant by increasing the generation of activation factor X in the presence of tissue factor and activation factor VII. Increases cell adhesion to the extacellular matrix (ECM), independent of its enzymatic activity. Induces AKT1/PKB phosphorylation via lipid rafts increasing cell mobility and invasion. Heparin increases this AKT1/PKB activation. Regulates osteogenesis. Enhances angiogenesis through up-regulation of SRC-mediated activation of VEGF. Implicated in hair follicle inner root sheath differentiation and hair homeostasis (By similarity).By similarity1 Publication

Catalytic activityi

Endohydrolysis of (1->4)-beta-D-glycosidic bonds of heparan sulfate chains in heparan sulfate proteoglycan.

Enzyme regulationi

Inhibited by laminarin sulfate and, to a lower extent, by heparin and sulfamin (By similarity). Activated by calcium and magnesium. Inhibited by EDTA.By similarity1 Publication

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Active sitei218 – 2181Proton donorSequence analysis
Active sitei336 – 3361NucleophileSequence analysis

GO - Molecular functioni

  • heparanase activity Source: RGD

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Hydrolase

Keywords - Biological processi

Cell adhesion

Keywords - Ligandi

Calcium, Magnesium

Protein family/group databases

CAZyiGH79. Glycoside Hydrolase Family 79.

Names & Taxonomyi

Protein namesi
Recommended name:
Heparanase (EC:3.2.1.166)
Alternative name(s):
Endo-glucoronidase
Cleaved into the following 2 chains:
Gene namesi
Name:Hpse
Synonyms:Hep
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Unplaced

Organism-specific databases

RGDi61969. Hpse.

Subcellular locationi

  • Lysosome membrane By similarity; Peripheral membrane protein By similarity
  • Secreted By similarity
  • Nucleus By similarity

  • Note: Proheparanase is secreted via vesicles of the Golgi. Interacts with cell membrane heparan sulfate proteoglycans (HSPGs). Endocytosed and accumulates in endosomes. Transferred to lysosomes where it is proteolytically cleaved to produce the active enzyme. Under certain stimuli, transferred to the cell surface. Colocalizes with SDC1 in endosomal/lysosomal vesicles. Accumulates in perinuclear lysosomal vesicles. Heparin retains proheparanase in the extracellular medium. Associates with lipid rafts (By similarity).By similarity

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Lysosome, Membrane, Nucleus, Secreted

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Signal peptidei1 – 2828By similarityAdd
BLAST
Chaini29 – 10274Heparanase 8 kDa subunitPRO_0000042266Add
BLAST
Propeptidei103 – 15048Linker peptideBy similarityPRO_0000042267Add
BLAST
Chaini151 – 536386Heparanase 50 kDa subunitPRO_0000042268Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Glycosylationi155 – 1551N-linked (GlcNAc...)By similarity
Glycosylationi193 – 1931N-linked (GlcNAc...)By similarity
Glycosylationi210 – 2101N-linked (GlcNAc...)By similarity
Glycosylationi452 – 4521N-linked (GlcNAc...)By similarity

Post-translational modificationi

Proteolytically processed. The cleavage of the 65 kDa form leads to the generation of a linker peptide, and the 8 kDa and 50 kDa products. 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 (By similarity).By similarity
N-glycosylated. Glycosylation of the 50 kDa subunit appears to be essential for its solubility (By similarity).By similarity

Keywords - PTMi

Glycoprotein

Proteomic databases

PRIDEiQ71RP1.

Interactioni

Subunit structurei

Heterodimer; heterodimer formation between the 8 kDa and the 50 kDa subunits is required for enzyme activity (By similarity). Interacts with TF; the interaction, inhibited by heparin, enhances the generation of activated factor X and activates coagulation. Interacts with HRG; the interaction is enhanced at acidic pH, partially inhibits binding of HPSE to cell surface receptors and modulates its enzymatic activity. Interacts with SDC1; the interaction enhances the shedding of SDC1. Interacts with HPSE2 (By similarity).By similarity

Protein-protein interaction databases

MINTiMINT-4997517.

Structurei

3D structure databases

ProteinModelPortaliQ71RP1.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni151 – 1555Heparin/HS-bindingBy similarity
Regioni263 – 27311Heparin/HS-bindingBy similarityAdd
BLAST
Regioni520 – 53617Required for transferring proheparanase to the Golgi apparatus, secretion and subsequent enzyme activity and for enhancement of PKB/AKT1 phosphorylationBy similarityAdd
BLAST

Sequence similaritiesi

Belongs to the glycosyl hydrolase 79 family.Curated

Keywords - Domaini

Signal

Phylogenomic databases

HOVERGENiHBG081606.
InParanoidiQ71RP1.
KOiK07964.
PhylomeDBiQ71RP1.

Family and domain databases

Gene3Di3.20.20.80. 1 hit.
InterProiIPR005199. Glyco_hydro_79.
IPR013781. Glyco_hydro_catalytic_dom.
IPR017853. Glycoside_hydrolase_SF.
[Graphical view]
PANTHERiPTHR14363. PTHR14363. 2 hits.
PfamiPF03662. Glyco_hydro_79n. 1 hit.
[Graphical view]
SUPFAMiSSF51445. SSF51445. 2 hits.

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

Q71RP1-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MLRPLLLLWL WGRLGALTQG TPAGTAPTKD VVDLEFYTKR LFQSVSPSFL
60 70 80 90 100
SITIDASLAT DPRFLTFLGS PRLRALARGL SPAYLRFGGT KTDFLIFDPN
110 120 130 140 150
KEPTSEERSY WQSQDNNDIC GSERVSADVL RKLQMEWPFQ ELLLLREQYQ
160 170 180 190 200
REFKNSTYSR SSVDMLYSFA KCSRLDLIFG LNALLRTPDL RWNSSNAQLL
210 220 230 240 250
LNYCSSKGYN ISWELGNEPN SFWKKAHISI DGLQLGEDFV ELHKLLQKSA
260 270 280 290 300
FQNAKLYGPD IGQPRGKTVK LLRSFLKAGG EVIDSLTWHH YYLNGRVATK
310 320 330 340 350
EDFLSSDVLD TFILSVQKIL KVTKEMTPGK KVWLGETSSA YGGGAPLLSD
360 370 380 390 400
TFAAGFMWLD KLGLSAQLGI EVVMRQVFFG AGNYHLVDEN FEPLPDYWLS
410 420 430 440 450
LLFKKLVGPK VLMSRVKGPD RSKLRVYLHC TNVYHPRYRE GDLTLYVLNL
460 470 480 490 500
HNVTKHLKLP PPMFSRPVDK YLLKPFGSDG LLSKSVQLNG QTLKMVDEQT
510 520 530
LPALTEKPLP AGSSLSVPAF SYGFFVIRNA KIAACI
Length:536
Mass (Da):60,480
Last modified:July 5, 2004 - v1
Checksum:iC434E04CF536EA4D
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti15 – 151G → R in AAF04563 (PubMed:12077130).Curated
Sequence conflicti227 – 2271H → Q in AAF04563 (PubMed:12077130).Curated
Sequence conflicti350 – 3501D → N in AAF04563 (PubMed:12077130).Curated

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF359508 mRNA. Translation: AAQ15189.1.
AF184967 mRNA. Translation: AAF04563.1.
RefSeqiNP_072127.1. NM_022605.1.
UniGeneiRn.6392.

Genome annotation databases

GeneIDi64537.
KEGGirno:64537.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF359508 mRNA. Translation: AAQ15189.1.
AF184967 mRNA. Translation: AAF04563.1.
RefSeqiNP_072127.1. NM_022605.1.
UniGeneiRn.6392.

3D structure databases

ProteinModelPortaliQ71RP1.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

MINTiMINT-4997517.

Protein family/group databases

CAZyiGH79. Glycoside Hydrolase Family 79.

Proteomic databases

PRIDEiQ71RP1.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

GeneIDi64537.
KEGGirno:64537.

Organism-specific databases

CTDi10855.
RGDi61969. Hpse.

Phylogenomic databases

HOVERGENiHBG081606.
InParanoidiQ71RP1.
KOiK07964.
PhylomeDBiQ71RP1.

Miscellaneous databases

NextBioi613394.
PROiQ71RP1.

Family and domain databases

Gene3Di3.20.20.80. 1 hit.
InterProiIPR005199. Glyco_hydro_79.
IPR013781. Glyco_hydro_catalytic_dom.
IPR017853. Glycoside_hydrolase_SF.
[Graphical view]
PANTHERiPTHR14363. PTHR14363. 2 hits.
PfamiPF03662. Glyco_hydro_79n. 1 hit.
[Graphical view]
SUPFAMiSSF51445. SSF51445. 2 hits.
ProtoNetiSearch...

Publicationsi

  1. "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] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA].
    Tissue: Placenta.
  2. "Characterization of heparanase from a rat parathyroid cell line."
    Podyma-Inoue K.A., Yokote H., Sakaguchi K., Ikuta M., Yanagishita M.
    J. Biol. Chem. 277:32459-32465(2002) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA], ENZYME REGULATION.
  3. "Heparanase accelerates wound angiogenesis and wound healing in mouse and rat models."
    Zcharia E., Zilka R., Yaar A., Yacoby-Zeevi O., Zetser A., Metzger S., Sarid R., Naggi A., Casu B., Ilan N., Vlodavsky I., Abramovitch R.
    FASEB J. 19:211-221(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.

Entry informationi

Entry nameiHPSE_RAT
AccessioniPrimary (citable) accession number: Q71RP1
Secondary accession number(s): Q9QZF8
Entry historyi
Integrated into UniProtKB/Swiss-Prot: October 11, 2005
Last sequence update: July 5, 2004
Last modified: December 9, 2015
This is version 76 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Glycosyl hydrolases
    Classification of glycosyl hydrolase families and list of entries
  2. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.