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

More general terms

• glycoprotein
• secreted protein

Database

• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=3273
• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:3273
• OMIM: https://mirror.omim.org/entry/142640
• OMIM: https://mirror.omim.org/entry/613116
• UniProt: http://www.uniprot.org/uniprot/P04196.html