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Protein

Histidine-rich glycoprotein

Gene

Hrg

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Plasma glycoprotein that binds a number of ligands such as heme, heparin, heparan sulfate, thrombospondin, plasminogen, and divalent metal ions. Binds heparin and heparin/glycosaminoglycans in a zinc-dependent manner. Binds heparan sulfate on the surface of liver, lung, kidney and heart endothelial cells. Binds to N-sulfated polysaccharide chains on the surface of liver endothelial cells. Inhibits rosette formation. Acts as an adapter protein and is implicated in regulating many processes such as immune complex and pathogen clearance, cell chemotaxis, cell adhesion, angiogenesis, coagulation and fibrinolysis. Mediates clearance of necrotic cells through enhancing the phagocytosis of necrotic cells in a heparan sulfate-dependent pathway. This process can be regulated by the presence of certain HRG ligands such as heparin and zinc ions. Binds to IgG subclasses of immunoglobins containing kappa and lambda light chains with different affinities regulating their clearance and inhibiting the formation of insoluble immune complexes. Tethers plasminogen to the cell surface. Binds T-cells and alters the cell morphology. Acts as a regulator of the vascular endothelial growth factor (VEGF) signaling pathway; inhibits endothelial cell motility by reducing VEGF-induced complex formation between PXN/paxillin and ILK/integrin-linked protein kinase and by promoting inhibition of VEGF-induced tyrosine phosphorylation of focal adhesion kinases and alpha-actinins in endothelial cells. Also plays a role in the regulation of tumor angiogenesis and tumor immune surveillance. Normalizes tumor vessels and promotes antitumor immunity by polarizing tumor-associated macrophages, leading to decreased tumor growth and metastasis (By similarity). Modulates angiogenesis by blocking the CD6-mediated antiangiongenic effect of thrombospondins, THBS1 and THBS2.By similarity5 Publications

Cofactori

Zn2+By similarity

GO - Molecular functioni

GO - Biological processi

  • angiogenesis Source: UniProtKB-KW
  • chemotaxis Source: UniProtKB-KW
  • defense response to fungus Source: UniProtKB
  • fibrinolysis Source: UniProtKB-KW
  • heme export Source: MGI
  • heme transport Source: MGI
  • negative regulation of angiogenesis Source: UniProtKB
  • negative regulation of blood vessel endothelial cell migration Source: UniProtKB
  • negative regulation of cell adhesion Source: UniProtKB
  • negative regulation of cell adhesion mediated by integrin Source: UniProtKB
  • negative regulation of cell growth Source: UniProtKB
  • negative regulation of cell proliferation Source: UniProtKB
  • negative regulation of endopeptidase activity Source: GOC
  • negative regulation of endothelial cell chemotaxis Source: UniProtKB
  • negative regulation of fibrinolysis Source: MGI
  • negative regulation of lamellipodium assembly Source: UniProtKB
  • negative regulation of vascular endothelial growth factor signaling pathway Source: UniProtKB
  • platelet activation Source: UniProtKB
  • positive regulation of apoptotic process Source: UniProtKB
  • positive regulation of blood vessel remodeling Source: UniProtKB
  • positive regulation of focal adhesion assembly Source: UniProtKB
  • positive regulation of immune response to tumor cell Source: UniProtKB
  • regulation of actin cytoskeleton organization Source: UniProtKB
  • regulation of blood coagulation Source: UniProtKB
  • regulation of gene expression Source: UniProtKB
  • regulation of peptidyl-tyrosine phosphorylation Source: UniProtKB
  • regulation of platelet activation Source: UniProtKB
  • regulation of protein complex assembly Source: UniProtKB
  • regulation of transcription from RNA polymerase II promoter in response to iron Source: MGI
  • response to organic cyclic compound Source: MGI
Complete GO annotation...

Keywords - Biological processi

Angiogenesis, Blood coagulation, Chemotaxis, Fibrinolysis, Hemostasis

Keywords - Ligandi

Copper, Heparin-binding, Metal-binding, Zinc

Protein family/group databases

MEROPSiI25.022.

Names & Taxonomyi

Protein namesi
Recommended name:
Histidine-rich glycoprotein
Alternative name(s):
Histidine-proline-rich glycoprotein
Short name:
HPRG
Gene namesi
Name:Hrg
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Unplaced

Organism-specific databases

MGIiMGI:2146636. Hrg.

Subcellular locationi

GO - Cellular componenti

  • endolysosome Source: MGI
  • extracellular region Source: UniProtKB-SubCell
  • phagolysosome membrane Source: MGI
  • vesicle Source: MGI
Complete GO annotation...

Keywords - Cellular componenti

Secreted

Pathology & Biotechi

Disruption phenotypei

Null mice are viable and fertile, but have enhanced coagulation resulting in decreased bleeding times. The observed enhanced platelet activation mediates the accelerated angiogenic switch. Also enhanced fibrinolysis. Animals are unprotected against Candida fungal infection. Also show larger tumor volume in cancerous state, an excessive stimulation of tumor angiogenesis, a suppression of tumor immune respons and an increased tumor growth and metastatic spread.5 Publications

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Signal peptidei1 – 1818By similarityAdd
BLAST
Chaini19 – 525507Histidine-rich glycoproteinPRO_0000408507Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Disulfide bondi24 ↔ 504By similarity
Disulfide bondi78 ↔ 89By similarity
Disulfide bondi103 ↔ 124By similarity
Glycosylationi112 – 1121N-linked (GlcNAc...)Sequence analysis
Glycosylationi123 – 1231N-linked (GlcNAc...)Sequence analysis
Glycosylationi200 – 2001N-linked (GlcNAc...)1 Publication
Disulfide bondi201 ↔ 414By similarity
Disulfide bondi216 ↔ 239By similarity
Glycosylationi322 – 3221N-linked (GlcNAc...)Sequence analysis
Glycosylationi330 – 3301N-linked (GlcNAc...)Sequence analysis
Modified residuei438 – 4381PhosphoserineBy similarity

Post-translational modificationi

Proteolytic cleavage produces several HRG fragments which are mostly disulfide-linked and, therefore, not released. Cleavage by plasmin is inhibited in the presence of heparin, zinc ions or in an acidic environment. Cleavage reduces binding of HRG to heparan sulfate, but enhances the ability of HRG to bind and tether plasminogen to the cell surface. On platelet activation, releases a 33 kDa antiangiogenic peptide which encompasses the HRR. Also cleaved in the C-terminal by plasmin (By similarity).By similarity
N-glycosylated.1 Publication

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sitei439 – 4402Cleavage; by plasminBy similarity

Keywords - PTMi

Cleavage on pair of basic residues, Disulfide bond, Glycoprotein, Phosphoprotein

Proteomic databases

EPDiQ9ESB3.
MaxQBiQ9ESB3.
PaxDbiQ9ESB3.
PRIDEiQ9ESB3.

PTM databases

SwissPalmiQ9ESB3.

Expressioni

Tissue specificityi

Expressed in liver, blood plasma, serum and in platelets. Also present in fibrin clots, wound fluid from acute wounds and chronic leg ulcers.2 Publications

Gene expression databases

BgeeiQ9ESB3.

Interactioni

Subunit structurei

Interacts with THBS1 (via the TSP type I repeats); the interaction blocks the antiangiogenic effect of THBS1 with CD36. Interacts with HPSE; the interaction is enhanced at acidic pH, partially inhibits binding of HPSE to cell surface receptors and modulates its enzymatic activity. Interacts (via the HRR domain) with TMP1; the interaction partially mediates the antiangiogenic properties of HRG. Interacts with kappa and lambda light chains of IgG molecules. Interacts with ATP5A1; the interaction occurs on the surface of T-cells and alters their cell morphology in concert with CONA. Binds IgG molecules containing kappa and lambda light chains and inhibits the formation of insoluble immunoglobulin complexes. Interacts with F12; the interaction, which is enhanced in the presence of zinc ions and inhibited by heparin-binding to HRG, inhibits factor XII autoactivation and contact-initiated coagulation (By similarity). Interacts with PLG (via its Kringle domains); the interaction tethers PLG to the cell surface and enhances its activation. Interacts (via the HRR domain) with TPM1; the interaction appears to contribute to the antiangiogenic properties of the HRR domain (By similarity). Interacts with THBS2; the interaction blocks the antiangiogenic effect of THBS2 with CD36.By similarity1 Publication

GO - Molecular functioni

Protein-protein interaction databases

MINTiMINT-1857803.
STRINGi10090.ENSMUSP00000023590.

Structurei

3D structure databases

ProteinModelPortaliQ9ESB3.
SMRiQ9ESB3. Positions 139-254.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini19 – 122104Cystatin 1Add
BLAST
Domaini135 – 240106Cystatin 2Add
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni41 – 8444Interaction with ATP5A1By similarityAdd
BLAST
Regioni345 – 37935Necessary for endothelial cell focal adhesions and anti-angiogenic activitiesBy similarityAdd
BLAST

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi267 – 31246Pro-richAdd
BLAST
Compositional biasi337 – 497161His/Pro-rich (HRR)Add
BLAST
Compositional biasi341 – 40666His/Pro-rich (HRR)Add
BLAST
Compositional biasi413 – 524112Pro-richAdd
BLAST

Domaini

The His-rich (HRR) region contains approximately 12 tandem internal repeats of the 5-residue G[H/P][H/P]PH consensus sequence. HRR binds heparan sulfate and possesses antiangiogenic, antibacterial and antifungal properties through binding Candida cells, and preferentially lysing the ergosterol-containing liposomes at low pH. The tandem repeats also bind divalent metal ions and heme.
The cystatin domains can also bind heparan sulfate. Binding is enhanced in the presence of zinc ions (By similarity).By similarity

Sequence similaritiesi

Contains 2 cystatin domains.Curated

Keywords - Domaini

Repeat, Signal

Phylogenomic databases

eggNOGiENOG410IVJP. Eukaryota.
ENOG41117FH. LUCA.
HOGENOMiHOG000090255.
HOVERGENiHBG004597.
InParanoidiQ9ESB3.
OrthoDBiEOG7HXCSK.
TreeFamiTF333729.

Family and domain databases

InterProiIPR000010. Cystatin_dom.
[Graphical view]
SMARTiSM00043. CY. 2 hits.
[Graphical view]

Sequencei

Sequence statusi: Complete.

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

Q9ESB3-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MKVLTTALLL VTLQCSHALS PTNCDASEPL AEKVLDLINK GRRSGYVFEL
60 70 80 90 100
LRVSDAHLDR AGTATVYYLA LDVIESDCWV LSTKAQDDCL PSRWQSEIVI
110 120 130 140 150
GQCKVIATRY SNESQDLSVN GYNCTTSSVS SALRNTKDSP VLLDFFEDSE
160 170 180 190 200
LYRKQARKAL DKYKTDNGDF ASFRVERAER VIRARGGERT NYYVEFSMRN
210 220 230 240 250
CSTQHFPRSP LVFGFCRALL SYSIETSDLE TPDSIDINCE VFNIEDHKDT
260 270 280 290 300
SDMKPHWGHE RPLCDKHLCK LSGSRDHHHT HKTDKLGCPP PPEGKDNSDR
310 320 330 340 350
PRLQEGALPQ LPPGYPPHSG ANRTHRPSYN HSCNEHPCHG HRPHGHHPHS
360 370 380 390 400
HHPPGHHSHG HHPHGHHPHS HHSHGHHPPG HHPHGHHPHG HHPHGHHPHG
410 420 430 440 450
HHPHGHDFLD YGPCDPPSNS QELKGQYHRG YGPPHGHSRK RGPGKGLFPF
460 470 480 490 500
HHQQIGYVYR LPPLNIGEVL TLPEANFPSF SLPNCNRSLQ PEIQPFPQTA
510 520
SRSCPGKFES EFPQISKFFG YTPPK
Length:525
Mass (Da):59,163
Last modified:May 31, 2011 - v2
Checksum:iA83E93A439CFB126
GO

Sequence cautioni

The sequence AAN10183.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.Curated
The sequence AAN27996.1 differs from that shown. Reason: Erroneous gene model prediction. Curated

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti6 – 61T → A in AAG28416 (PubMed:10849117).Curated
Sequence conflicti511 – 5111E → G in BAB33094 (PubMed:15869579).Curated

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF194028 mRNA. Translation: AAG28416.1.
AY135662 mRNA. Translation: AAN10183.1. Different initiation.
AY137504 Genomic DNA. Translation: AAN27996.1. Sequence problems.
AB055897 mRNA. Translation: BAB33094.1.
AB055898 Genomic DNA. Translation: BAB33095.1.
BC011168 mRNA. Translation: AAH11168.1.
RefSeqiNP_444406.2. NM_053176.2.
UniGeneiMm.358794.

Genome annotation databases

GeneIDi94175.
KEGGimmu:94175.
UCSCiuc007ysw.2. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF194028 mRNA. Translation: AAG28416.1.
AY135662 mRNA. Translation: AAN10183.1. Different initiation.
AY137504 Genomic DNA. Translation: AAN27996.1. Sequence problems.
AB055897 mRNA. Translation: BAB33094.1.
AB055898 Genomic DNA. Translation: BAB33095.1.
BC011168 mRNA. Translation: AAH11168.1.
RefSeqiNP_444406.2. NM_053176.2.
UniGeneiMm.358794.

3D structure databases

ProteinModelPortaliQ9ESB3.
SMRiQ9ESB3. Positions 139-254.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

MINTiMINT-1857803.
STRINGi10090.ENSMUSP00000023590.

Protein family/group databases

MEROPSiI25.022.

PTM databases

SwissPalmiQ9ESB3.

Proteomic databases

EPDiQ9ESB3.
MaxQBiQ9ESB3.
PaxDbiQ9ESB3.
PRIDEiQ9ESB3.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

GeneIDi94175.
KEGGimmu:94175.
UCSCiuc007ysw.2. mouse.

Organism-specific databases

CTDi3273.
MGIiMGI:2146636. Hrg.

Phylogenomic databases

eggNOGiENOG410IVJP. Eukaryota.
ENOG41117FH. LUCA.
HOGENOMiHOG000090255.
HOVERGENiHBG004597.
InParanoidiQ9ESB3.
OrthoDBiEOG7HXCSK.
TreeFamiTF333729.

Miscellaneous databases

PROiQ9ESB3.
SOURCEiSearch...

Gene expression databases

BgeeiQ9ESB3.

Family and domain databases

InterProiIPR000010. Cystatin_dom.
[Graphical view]
SMARTiSM00043. CY. 2 hits.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "Murine histidine-rich glycoprotein: cloning, characterization and cellular origin."
    Hulett M.D., Parish C.R.
    Immunol. Cell Biol. 78:280-287(2000) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY.
    Strain: 129.
  2. "Identification of fetuin-B as a member of a cystatin-like gene family on mouse chromosome 16 with tumor suppressor activity."
    Hsu S.J., Nagase H., Balmain A.
    Genome 47:931-946(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
    Strain: NIH/Ola.
  3. "Enhanced blood coagulation and fibrinolysis in mice lacking histidine-rich glycoprotein (HRG)."
    Tsuchida-Straeten N., Ensslen S., Schafer C., Woltje M., Denecke B., Moser M., Graber S., Wakabayashi S., Koide T., Jahnen-Dechent W.
    J. Thromb. Haemost. 3:865-872(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA], DISRUPTION PHENOTYPE, FUNCTION.
    Strain: BALB/cJ.
    Tissue: Liver.
  4. "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] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    Strain: FVB/N.
    Tissue: Liver.
  5. "The antiangiogenic effect of thrombospondin-2 is mediated by CD36 and modulated by histidine-rich glycoprotein."
    Simantov R., Febbraio M., Silverstein R.L.
    Matrix Biol. 24:27-34(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH THBS2, FUNCTION.
  6. "Enhanced analysis of the mouse plasma proteome using cysteine-containing tryptic glycopeptides."
    Bernhard O.K., Kapp E.A., Simpson R.J.
    J. Proteome Res. 6:987-995(2007) [PubMed] [Europe PMC] [Abstract]
    Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-200.
    Strain: C57BL/6J.
    Tissue: Plasma.
  7. Cited for: DISRUPTION PHENOTYPE, TISSUE SPECIFICITY, FUNCTION.
  8. "Activated platelets provide a functional microenvironment for the antiangiogenic fragment of histidine-rich glycoprotein."
    Thulin A., Ringvall M., Dimberg A., Karehed K., Vaisanen T., Vaisanen M.R., Hamad O., Wang J., Bjerkvig R., Nilsson B., Pihlajaniemi T., Akerud H., Pietras K., Jahnen-Dechent W., Siegbahn A., Olsson A.K.
    Mol. Cancer Res. 7:1792-1802(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: DISRUPTION PHENOTYPE, FUNCTION.
  9. Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    Tissue: Brown adipose tissue, Heart, Liver, Lung, Spleen and Testis.
  10. "Genetic deficiency in plasma protein HRG enhances tumor growth and metastasis by exacerbating immune escape and vessel abnormalization."
    Tugues S., Honjo S., Konig C., Noguer O., Hedlund M., Botling J., Deschoemaeker S., Wenes M., Rolny C., Jahnen-Dechent W., Mazzone M., Claesson-Welsh L.
    Cancer Res. 72:1953-1963(2012) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, DISRUPTION PHENOTYPE.
  11. "Enhanced platelet activation mediates the accelerated angiogenic switch in mice lacking histidine-rich glycoprotein."
    Ringvall M., Thulin A., Zhang L., Cedervall J., Tsuchida-Straeten N., Jahnen-Dechent W., Siegbahn A., Olsson A.K.
    PLoS ONE 6:E14526-E14526(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: DISRUPTION PHENOTYPE.

Entry informationi

Entry nameiHRG_MOUSE
AccessioniPrimary (citable) accession number: Q9ESB3
Secondary accession number(s): Q6YK32
, Q6YKA2, Q99PS5, Q99PS6
Entry historyi
Integrated into UniProtKB/Swiss-Prot: May 31, 2011
Last sequence update: May 31, 2011
Last modified: June 8, 2016
This is version 84 of the entry and version 2 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. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  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.