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Protein

Histidine-rich glycoprotein

Gene

HRG

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -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. Modulates angiogenesis by blocking the CD6-mediated antiangiongenic effect of thrombospondins, THBS1 and THBS2. 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.14 Publications

Cofactori

Zn2+1 Publication

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionHeparin-binding
Biological processAngiogenesis, Blood coagulation, Chemotaxis, Fibrinolysis, Hemostasis
LigandCopper, Metal-binding, Zinc

Enzyme and pathway databases

ReactomeiR-HSA-114608 Platelet degranulation
R-HSA-75205 Dissolution of Fibrin Clot

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
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 3

Organism-specific databases

EuPathDBiHostDB:ENSG00000113905.4
HGNCiHGNC:5181 HRG
MIMi142640 gene
neXtProtiNX_P04196

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Secreted

Pathology & Biotechi

Involvement in diseasei

Thrombophilia due to histidine-rich glycoprotein deficiency (THPH11)2 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA hemostatic disorder characterized by a tendency to thrombosis.
See also OMIM:613116
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_063000103G → E in THPH11; HRG Tokushima 1; results in increased intracellular degradation and reduced protein secretion. 1 PublicationCorresponds to variant dbSNP:rs121918122EnsemblClinVar.1
Natural variantiVAR_063001241C → R in THPH11; HRG Tokushima 2; results in increased intracellular degradation and reduced protein secretion. 1 PublicationCorresponds to variant dbSNP:rs2276804Ensembl.1

Keywords - Diseasei

Disease mutation, Thrombophilia

Organism-specific databases

DisGeNETi3273
MalaCardsiHRG
MIMi613116 phenotype
OpenTargetsiENSG00000113905
Orphaneti217467 Hereditary thrombophilia due to congenital histidine-rich (poly-L) glycoprotein deficiency
PharmGKBiPA29455

Polymorphism and mutation databases

BioMutaiHRG
DMDMi123523

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 181 PublicationAdd BLAST18
ChainiPRO_000000670919 – 525Histidine-rich glycoproteinAdd BLAST507

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi24 ↔ 504By similarity
Glycosylationi63N-linked (GlcNAc...) asparagine2 Publications1
Disulfide bondi78 ↔ 89By similarity
Disulfide bondi105 ↔ 126By similarity
Glycosylationi125N-linked (GlcNAc...) asparagine2 Publications1
Disulfide bondi203 ↔ 417By similarity
Disulfide bondi218 ↔ 241By similarity
Glycosylationi344N-linked (GlcNAc...) asparagine1 Publication1
Glycosylationi345N-linked (GlcNAc...) asparagineSequence analysis1

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.3 Publications
N-glycosylated.3 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei439 – 440Cleavage; by plasminBy similarity2

Keywords - PTMi

Cleavage on pair of basic residues, Disulfide bond, Glycoprotein

Proteomic databases

PaxDbiP04196
PeptideAtlasiP04196
PRIDEiP04196
ProteomicsDBi51675

2D gel databases

SWISS-2DPAGEiP04196

PTM databases

GlyConnecti805
iPTMnetiP04196
PhosphoSitePlusiP04196

Expressioni

Tissue specificityi

Expressed in macrophages and in malignant cells. Expressed by the liver and secreted in plasma (at protein level).3 Publications

Gene expression databases

BgeeiENSG00000113905 Expressed in 84 organ(s), highest expression level in liver
CleanExiHS_HRG
GenevisibleiP04196 HS

Organism-specific databases

HPAiHPA050269
HPA054598

Interactioni

Subunit structurei

Interacts (via the HRR domain) with TPM1; the interaction appears to contribute to the antiangiogenic properties of the HRR domain. Interacts with THBS2; the interaction blocks the antiangiogenic effect of THBS2 with CD36 (By similarity). Interacts with THBS1 (via the TSP type I repeats); the interaction blocks the antiangiogenic effect of THBS1 with CD3. Interacts with PLG (via its Kringle domains); the interaction tethers PLG to the cell surface and enhances its activation. 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 ATP5F1A; 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 similarity8 Publications

Binary interactionsi

GO - Molecular functioni

Protein-protein interaction databases

BioGridi109509, 30 interactors
DIPiDIP-47264N
IntActiP04196, 14 interactors
MINTiP04196
STRINGi9606.ENSP00000232003

Structurei

3D structure databases

ProteinModelPortaliP04196
SMRiP04196
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini19 – 136Cystatin 1Add BLAST118
Domaini137 – 254Cystatin 2Add BLAST118

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni41 – 84Interaction with ATP5F1A1 PublicationAdd BLAST44
Regioni348 – 382Necessary for endothelial cell focal adhesions and anti-angiogenic activitiesAdd BLAST35

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi276 – 321Pro-richAdd BLAST46
Compositional biasi350 – 497His/Pro-rich (HRR)Add BLAST148

Domaini

The His/Pro-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.

Keywords - Domaini

Repeat, Signal

Phylogenomic databases

eggNOGiENOG410IVJP Eukaryota
ENOG41117FH LUCA
GeneTreeiENSGT00730000111384
HOGENOMiHOG000090255
HOVERGENiHBG004597
InParanoidiP04196
OMAiIQPFPQS
OrthoDBiEOG091G06A6
PhylomeDBiP04196
TreeFamiTF333729

Family and domain databases

CDDicd00042 CY, 1 hit
InterProiView protein in InterPro
IPR000010 Cystatin_dom
PfamiView protein in Pfam
PF00031 Cystatin, 1 hit
SMARTiView protein in SMART
SM00043 CY, 2 hits

Sequencei

Sequence statusi: Complete.

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

P04196-1 [UniParc]FASTAAdd to basket
« Hide
        10         20         30         40         50
MKALIAALLL ITLQYSCAVS PTDCSAVEPE AEKALDLINK RRRDGYLFQL
60 70 80 90 100
LRIADAHLDR VENTTVYYLV LDVQESDCSV LSRKYWNDCE PPDSRRPSEI
110 120 130 140 150
VIGQCKVIAT RHSHESQDLR VIDFNCTTSS VSSALANTKD SPVLIDFFED
160 170 180 190 200
TERYRKQANK ALEKYKEEND DFASFRVDRI ERVARVRGGE GTGYFVDFSV
210 220 230 240 250
RNCPRHHFPR HPNVFGFCRA DLFYDVEALD LESPKNLVIN CEVFDPQEHE
260 270 280 290 300
NINGVPPHLG HPFHWGGHER SSTTKPPFKP HGSRDHHHPH KPHEHGPPPP
310 320 330 340 350
PDERDHSHGP PLPQGPPPLL PMSCSSCQHA TFGTNGAQRH SHNNNSSDLH
360 370 380 390 400
PHKHHSHEQH PHGHHPHAHH PHEHDTHRQH PHGHHPHGHH PHGHHPHGHH
410 420 430 440 450
PHGHHPHCHD FQDYGPCDPP PHNQGHCCHG HGPPPGHLRR RGPGKGPRPF
460 470 480 490 500
HCRQIGSVYR LPPLRKGEVL PLPEANFPSF PLPHHKHPLK PDNQPFPQSV
510 520
SESCPGKFKS GFPQVSMFFT HTFPK
Length:525
Mass (Da):59,578
Last modified:March 20, 1987 - v1
Checksum:iA2B124D6CE93114F
GO

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_04885679S → L. Corresponds to variant dbSNP:rs4516605Ensembl.1
Natural variantiVAR_063000103G → E in THPH11; HRG Tokushima 1; results in increased intracellular degradation and reduced protein secretion. 1 PublicationCorresponds to variant dbSNP:rs121918122EnsemblClinVar.1
Natural variantiVAR_020488118D → G. Corresponds to variant dbSNP:rs3733008Ensembl.1
Natural variantiVAR_022080180I → T. Corresponds to variant dbSNP:rs10770Ensembl.1
Natural variantiVAR_014528204P → S. Corresponds to variant dbSNP:rs9898Ensembl.1
Natural variantiVAR_063001241C → R in THPH11; HRG Tokushima 2; results in increased intracellular degradation and reduced protein secretion. 1 PublicationCorresponds to variant dbSNP:rs2276804Ensembl.1
Natural variantiVAR_020489340H → R. Corresponds to variant dbSNP:rs2228243Ensembl.1
Natural variantiVAR_024427436G → R. Corresponds to variant dbSNP:rs2229331Ensembl.1
Natural variantiVAR_024428448R → C. Corresponds to variant dbSNP:rs1042445Ensembl.1
Natural variantiVAR_024429493N → I. Corresponds to variant dbSNP:rs1042464Ensembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M13149 mRNA Translation: AAA52694.1
AB005803 Genomic DNA Translation: BAA21613.1
CH471052 Genomic DNA Translation: EAW78183.1
CH471052 Genomic DNA Translation: EAW78184.1
BC069574 mRNA Translation: AAH69574.1
BC150591 mRNA Translation: AAI50592.1
Z17218 Genomic DNA Translation: CAA78925.1
CCDSiCCDS3280.1
PIRiA01287 KGHUGH
RefSeqiNP_000403.1, NM_000412.4
UniGeneiHs.1498

Genome annotation databases

EnsembliENST00000232003; ENSP00000232003; ENSG00000113905
GeneIDi3273
KEGGihsa:3273
UCSCiuc003fqq.5 human

Keywords - Coding sequence diversityi

Polymorphism

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M13149 mRNA Translation: AAA52694.1
AB005803 Genomic DNA Translation: BAA21613.1
CH471052 Genomic DNA Translation: EAW78183.1
CH471052 Genomic DNA Translation: EAW78184.1
BC069574 mRNA Translation: AAH69574.1
BC150591 mRNA Translation: AAI50592.1
Z17218 Genomic DNA Translation: CAA78925.1
CCDSiCCDS3280.1
PIRiA01287 KGHUGH
RefSeqiNP_000403.1, NM_000412.4
UniGeneiHs.1498

3D structure databases

ProteinModelPortaliP04196
SMRiP04196
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi109509, 30 interactors
DIPiDIP-47264N
IntActiP04196, 14 interactors
MINTiP04196
STRINGi9606.ENSP00000232003

Protein family/group databases

MEROPSiI25.022

PTM databases

GlyConnecti805
iPTMnetiP04196
PhosphoSitePlusiP04196

Polymorphism and mutation databases

BioMutaiHRG
DMDMi123523

2D gel databases

SWISS-2DPAGEiP04196

Proteomic databases

PaxDbiP04196
PeptideAtlasiP04196
PRIDEiP04196
ProteomicsDBi51675

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000232003; ENSP00000232003; ENSG00000113905
GeneIDi3273
KEGGihsa:3273
UCSCiuc003fqq.5 human

Organism-specific databases

CTDi3273
DisGeNETi3273
EuPathDBiHostDB:ENSG00000113905.4
GeneCardsiHRG
HGNCiHGNC:5181 HRG
HPAiHPA050269
HPA054598
MalaCardsiHRG
MIMi142640 gene
613116 phenotype
neXtProtiNX_P04196
OpenTargetsiENSG00000113905
Orphaneti217467 Hereditary thrombophilia due to congenital histidine-rich (poly-L) glycoprotein deficiency
PharmGKBiPA29455
GenAtlasiSearch...

Phylogenomic databases

eggNOGiENOG410IVJP Eukaryota
ENOG41117FH LUCA
GeneTreeiENSGT00730000111384
HOGENOMiHOG000090255
HOVERGENiHBG004597
InParanoidiP04196
OMAiIQPFPQS
OrthoDBiEOG091G06A6
PhylomeDBiP04196
TreeFamiTF333729

Enzyme and pathway databases

ReactomeiR-HSA-114608 Platelet degranulation
R-HSA-75205 Dissolution of Fibrin Clot

Miscellaneous databases

ChiTaRSiHRG human
GeneWikiiHRG_(gene)
GenomeRNAii3273
PROiPR:P04196
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000113905 Expressed in 84 organ(s), highest expression level in liver
CleanExiHS_HRG
GenevisibleiP04196 HS

Family and domain databases

CDDicd00042 CY, 1 hit
InterProiView protein in InterPro
IPR000010 Cystatin_dom
PfamiView protein in Pfam
PF00031 Cystatin, 1 hit
SMARTiView protein in SMART
SM00043 CY, 2 hits
ProtoNetiSearch...

Entry informationi

Entry nameiHRG_HUMAN
AccessioniPrimary (citable) accession number: P04196
Secondary accession number(s): B9EK35, D3DNU7
Entry historyiIntegrated into UniProtKB/Swiss-Prot: March 20, 1987
Last sequence update: March 20, 1987
Last modified: November 7, 2018
This is version 189 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. Human chromosome 3
    Human chromosome 3: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
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