P04196 · HRG_HUMAN
- ProteinHistidine-rich glycoprotein
- GeneHRG
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids525 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
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.
Cofactor
Features
Showing features for site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Site | 439-440 | Cleavage; by plasmin | ||||
Sequence: RR |
GO annotations
Keywords
- Molecular function
- Biological process
- Ligand
Enzyme and pathway databases
Protein family/group databases
Names & Taxonomy
Protein names
- Recommended nameHistidine-rich glycoprotein
- Alternative names
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionP04196
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
Disease & Variants
Involvement in disease
Thrombophilia due to histidine-rich glycoprotein deficiency (THPH11)
- Note
- DescriptionA hemostatic disorder characterized by a tendency to thrombosis.
- See alsoMIM:613116
Natural variants in THPH11
Variant ID | Position(s) | Change | Description | |
---|---|---|---|---|
VAR_063000 | 103 | G>E | in THPH11; HRGTokushima 1; results in increased intracellular degradation and reduced protein secretion; dbSNP:rs121918122 | |
VAR_063001 | 241 | C>R | in THPH11; HRGTokushima 2; results in increased intracellular degradation and reduced protein secretion; dbSNP:rs2276804 |
Features
Showing features for natural variant.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Natural variant | VAR_048856 | 79 | in dbSNP:rs4516605 | |||
Sequence: S → L | ||||||
Natural variant | VAR_063000 | 103 | in THPH11; HRGTokushima 1; results in increased intracellular degradation and reduced protein secretion; dbSNP:rs121918122 | |||
Sequence: G → E | ||||||
Natural variant | VAR_020488 | 118 | in dbSNP:rs3733008 | |||
Sequence: D → G | ||||||
Natural variant | VAR_022080 | 180 | in dbSNP:rs10770 | |||
Sequence: I → T | ||||||
Natural variant | VAR_014528 | 204 | in dbSNP:rs9898 | |||
Sequence: P → S | ||||||
Natural variant | VAR_063001 | 241 | in THPH11; HRGTokushima 2; results in increased intracellular degradation and reduced protein secretion; dbSNP:rs2276804 | |||
Sequence: C → R | ||||||
Natural variant | VAR_020489 | 340 | in dbSNP:rs2228243 | |||
Sequence: H → R | ||||||
Natural variant | VAR_024427 | 436 | in dbSNP:rs2229331 | |||
Sequence: G → R | ||||||
Natural variant | VAR_024428 | 448 | in dbSNP:rs1042445 | |||
Sequence: R → C | ||||||
Natural variant | VAR_024429 | 493 | in dbSNP:rs1042464 | |||
Sequence: N → I |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 680 variants from UniProt as well as other sources including ClinVar and dbSNP.
Keywords
- Disease
Organism-specific databases
Miscellaneous
Chemistry
Genetic variation databases
PTM/Processing
Features
Showing features for signal, chain, disulfide bond, glycosylation.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Signal | 1-18 | |||||
Sequence: MKALIAALLLITLQYSCA | ||||||
Chain | PRO_0000006709 | 19-525 | Histidine-rich glycoprotein | |||
Sequence: VSPTDCSAVEPEAEKALDLINKRRRDGYLFQLLRIADAHLDRVENTTVYYLVLDVQESDCSVLSRKYWNDCEPPDSRRPSEIVIGQCKVIATRHSHESQDLRVIDFNCTTSSVSSALANTKDSPVLIDFFEDTERYRKQANKALEKYKEENDDFASFRVDRIERVARVRGGEGTGYFVDFSVRNCPRHHFPRHPNVFGFCRADLFYDVEALDLESPKNLVINCEVFDPQEHENINGVPPHLGHPFHWGGHERSSTTKPPFKPHGSRDHHHPHKPHEHGPPPPPDERDHSHGPPLPQGPPPLLPMSCSSCQHATFGTNGAQRHSHNNNSSDLHPHKHHSHEQHPHGHHPHAHHPHEHDTHRQHPHGHHPHGHHPHGHHPHGHHPHGHHPHCHDFQDYGPCDPPPHNQGHCCHGHGPPPGHLRRRGPGKGPRPFHCRQIGSVYRLPPLRKGEVLPLPEANFPSFPLPHHKHPLKPDNQPFPQSVSESCPGKFKSGFPQVSMFFTHTFPK | ||||||
Disulfide bond | 24↔504 | |||||
Sequence: CSAVEPEAEKALDLINKRRRDGYLFQLLRIADAHLDRVENTTVYYLVLDVQESDCSVLSRKYWNDCEPPDSRRPSEIVIGQCKVIATRHSHESQDLRVIDFNCTTSSVSSALANTKDSPVLIDFFEDTERYRKQANKALEKYKEENDDFASFRVDRIERVARVRGGEGTGYFVDFSVRNCPRHHFPRHPNVFGFCRADLFYDVEALDLESPKNLVINCEVFDPQEHENINGVPPHLGHPFHWGGHERSSTTKPPFKPHGSRDHHHPHKPHEHGPPPPPDERDHSHGPPLPQGPPPLLPMSCSSCQHATFGTNGAQRHSHNNNSSDLHPHKHHSHEQHPHGHHPHAHHPHEHDTHRQHPHGHHPHGHHPHGHHPHGHHPHGHHPHCHDFQDYGPCDPPPHNQGHCCHGHGPPPGHLRRRGPGKGPRPFHCRQIGSVYRLPPLRKGEVLPLPEANFPSFPLPHHKHPLKPDNQPFPQSVSESC | ||||||
Glycosylation | 63 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Disulfide bond | 78↔89 | |||||
Sequence: CSVLSRKYWNDC | ||||||
Disulfide bond | 105↔126 | |||||
Sequence: CKVIATRHSHESQDLRVIDFNC | ||||||
Glycosylation | 125 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Disulfide bond | 203↔417 | |||||
Sequence: CPRHHFPRHPNVFGFCRADLFYDVEALDLESPKNLVINCEVFDPQEHENINGVPPHLGHPFHWGGHERSSTTKPPFKPHGSRDHHHPHKPHEHGPPPPPDERDHSHGPPLPQGPPPLLPMSCSSCQHATFGTNGAQRHSHNNNSSDLHPHKHHSHEQHPHGHHPHAHHPHEHDTHRQHPHGHHPHGHHPHGHHPHGHHPHGHHPHCHDFQDYGPC | ||||||
Disulfide bond | 218↔241 | |||||
Sequence: CRADLFYDVEALDLESPKNLVINC | ||||||
Glycosylation | 344 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Glycosylation | 345 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N |
Post-translational modification
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.
N-glycosylated.
Keywords
- PTM
Proteomic databases
PTM databases
Interaction
Subunit
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
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
Binary interactions
Type | Entry 1 | Entry 2 | Number of experiments | Intact | |
---|---|---|---|---|---|
BINARY | P04196 | CYSRT1 A8MQ03 | 3 | EBI-3915012, EBI-3867333 | |
BINARY | P04196 | RCHY1 Q96PM5 | 3 | EBI-3915012, EBI-947779 | |
BINARY | P04196 | RGS20 O76081-6 | 3 | EBI-3915012, EBI-10178530 | |
XENO | P04196 | SPy_2034 Q99XU0 | 4 | EBI-3915012, EBI-8852705 |
Protein-protein interaction databases
Miscellaneous
Structure
Family & Domains
Features
Showing features for domain, region, compositional bias.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Domain | 19-136 | Cystatin 1 | ||||
Sequence: VSPTDCSAVEPEAEKALDLINKRRRDGYLFQLLRIADAHLDRVENTTVYYLVLDVQESDCSVLSRKYWNDCEPPDSRRPSEIVIGQCKVIATRHSHESQDLRVIDFNCTTSSVSSALA | ||||||
Region | 41-84 | Interaction with ATP5F1A | ||||
Sequence: RRRDGYLFQLLRIADAHLDRVENTTVYYLVLDVQESDCSVLSRK | ||||||
Domain | 137-254 | Cystatin 2 | ||||
Sequence: NTKDSPVLIDFFEDTERYRKQANKALEKYKEENDDFASFRVDRIERVARVRGGEGTGYFVDFSVRNCPRHHFPRHPNVFGFCRADLFYDVEALDLESPKNLVINCEVFDPQEHENING | ||||||
Region | 252-407 | Disordered | ||||
Sequence: INGVPPHLGHPFHWGGHERSSTTKPPFKPHGSRDHHHPHKPHEHGPPPPPDERDHSHGPPLPQGPPPLLPMSCSSCQHATFGTNGAQRHSHNNNSSDLHPHKHHSHEQHPHGHHPHAHHPHEHDTHRQHPHGHHPHGHHPHGHHPHGHHPHGHHPH | ||||||
Compositional bias | 292-309 | Basic and acidic residues | ||||
Sequence: PHEHGPPPPPDERDHSHG | ||||||
Compositional bias | 324-344 | Polar residues | ||||
Sequence: CSSCQHATFGTNGAQRHSHNN | ||||||
Region | 348-382 | Necessary for endothelial cell focal adhesions and anti-angiogenic activities | ||||
Sequence: DLHPHKHHSHEQHPHGHHPHAHHPHEHDTHRQHPH | ||||||
Compositional bias | 355-405 | Basic residues | ||||
Sequence: HSHEQHPHGHHPHAHHPHEHDTHRQHPHGHHPHGHHPHGHHPHGHHPHGHH |
Domain
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
- Domain
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Sequence processingThe displayed sequence is further processed into a mature form.
- Length525
- Mass (Da)59,578
- Last updated1987-03-20 v1
- ChecksumA2B124D6CE93114F
Features
Showing features for compositional bias.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Compositional bias | 292-309 | Basic and acidic residues | ||||
Sequence: PHEHGPPPPPDERDHSHG | ||||||
Compositional bias | 324-344 | Polar residues | ||||
Sequence: CSSCQHATFGTNGAQRHSHNN | ||||||
Compositional bias | 355-405 | Basic residues | ||||
Sequence: HSHEQHPHGHHPHAHHPHEHDTHRQHPHGHHPHGHHPHGHHPHGHHPHGHH |
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
M13149 EMBL· GenBank· DDBJ | AAA52694.1 EMBL· GenBank· DDBJ | mRNA | ||
AB005803 EMBL· GenBank· DDBJ | BAA21613.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
CH471052 EMBL· GenBank· DDBJ | EAW78183.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
CH471052 EMBL· GenBank· DDBJ | EAW78184.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
BC069574 EMBL· GenBank· DDBJ | AAH69574.1 EMBL· GenBank· DDBJ | mRNA | ||
BC150591 EMBL· GenBank· DDBJ | AAI50592.1 EMBL· GenBank· DDBJ | mRNA | ||
Z17218 EMBL· GenBank· DDBJ | CAA78925.1 EMBL· GenBank· DDBJ | Genomic DNA |