histidine-rich glycoprotein; histidine-proline-rich glycoprotein; HPRG (HRG)

Function: - plasma glycoprotein that binds a number of ligands such as heme, heparin, heparan sulfate, thrombospondin, plasminogen, & divalent metal ions - inhibits rosette formation - acts as an adapter protein - implicated in regulating many processes such - as immune complex & pathogen clearance - cell adhesion - angiogenesis - coagulation - fibrinolysis - mediates clearance of necrotic cells through enhancing phagocytosis of necrotic cells (heparan sulfate-dependent) - may be regulated by heparin & Zn⁺² - binds to IgG subclasses of immunoglobins containing kappa light chains & lambda light chains with different affinities regulating their clearance - inhibits formation of insoluble immune complexes - tethers plasminogen to the cell surface - binds T-cells & alters the cell morphology - modulates angiogenesis by blocking the CD6-mediated antiangiongenic effect of thrombospondins, THBS1 & THBS2 - proteolytic cleavage produces several HRG fragments which are mostly disulfide-linked &, thus, not released - cleavage by plasmin is inhibited in the presence of heparin, Zn⁺² or in an acidic environment - cleavage reduces binding of HRG to heparan sulfate - cleavage enhances the ability of HRG to bind & tether plasminogen to the cell surface - on platelet activation, releases a 33 kD antiangiogenic peptide which encompasses the HRR domain - also cleaved in the C-terminal by plasmin - 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 (putative) - 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 & enhances its activation - interacts with HPSE - the interaction is enhanced at acidic pH, partially inhibits binding of HPSE to cell surface receptors & modulates its enzymatic activity - interacts (via the HRR domain) with TMP1 - the interaction partially mediates the antiangiogenic properties of HRG - interacts with kappa & lambda light chains of IgG - interacts with ATP5A1 - the interaction occurs on the surface of T-cells & alters their cell morphology in concert with CONA - binds IgG molecules containing kappa light chains & lambda light chains & inhibits the formation of insoluble immunoglobulin complexes - interacts with F12 - interaction is enhanced in the presence of Zn+ - interaction is inhibited by heparin-binding to HRG - inhibits factor XII autoactivation & contact-initiated coagulation Structure: - N-glycosylated - 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 & possesses antiangiogenic, antibacterial & antifungal properties through binding Candida & preferentially lysing the ergosterol-containing liposomes at low pH - the tandem repeats also bind divalent metal ions & heme - contains 2 cystatin domains - the cystatin domains can also bind heparan sulfate - binding is enhanced in the presence of Zn⁺² Compartment: secreted Expression: - expressed by the liver & secreted into plasma Pathology: - defects in HRG are the cause of - thrombophilia due to histidine-rich glycoprotein deficiency

General

glycoprotein secreted protein

Properties

SIZE: entity length = 525 aa MW = 60 kD COMPARTMENT: extracellular compartment MOTIF: signal sequence {1-18} Cystatin 1 {19-136} MOTIF: cysteine residue {C24} MODIFICATION: cysteine residue {C504} ATP5A1 interaction {41-84} N-glycosylation site {N63} cysteine residue {C78} MODIFICATION: cysteine residue {C89} cysteine residue {C89} MODIFICATION: cysteine residue {C78} cysteine residue {C105} MODIFICATION: cysteine residue {C126} N-glycosylation site {N125} cysteine residue {C126} MODIFICATION: cysteine residue {C105} Cystatin 2 {137-254} MOTIF: cysteine residue {C203} MODIFICATION: cysteine residue {C417} cysteine residue {C218} MODIFICATION: cysteine residue {C241} cysteine residue {C241} MODIFICATION: cysteine residue {C218} proline-rich region SITE: 276-321 MOTIF: proline residue (SEVERAL) N-glycosylation site {N344} N-glycosylation site {N345} proline-rich region SITE: 350-497 MOTIF: proline residue (SEVERAL) cysteine residue {C417} MODIFICATION: cysteine residue {C203} proteolytic site {439-440} cysteine residue {C504} MODIFICATION: cysteine residue {C24}

Database Correlations

OMIM correlations MORBIDMAP 142640 UniProt P04196 Pfam PF00031 Entrez Gene 3273 Kegg hsa:3273

References

UniProt :accession P04196