The reference OMIM entry for this protein is 142640

Histidine-rich glycoprotein; hrg
Hrgp

CLONING

Koide et al. (1986) cloned HRG from a human liver cDNA library. The deduced HRG protein contains a leader sequence of 18 amino acids and a mature protein of 507 amino acids. It is histidine and proline rich and has a molecular mass of 75 kD. More than half of the protein sequence consists of 5 different types of internal repeats. Within the last 3 internal repeats (type V), there are 12 tandem repetitions of a 5-amino acid segment with a consensus sequence of GHHPH. This 'histidine-rich region' in the C terminus shows a high degree of similarity to the histidine-rich region of high molecular weight kininogen (HMWK; see 612358); the N terminus shares sequence similarity with antithrombin III (AT3; 107300).

GENE FUNCTION

Koide et al. (1986) noted that HRG interacts with heparin, the lysine-binding site of plasminogen (173350), and thrombospondin (see 188060). Shatsky et al. (1989) found that HRGP could inhibit or delay T-cell proliferation and cytokine release by interfering with early T-cell activation events. They proposed that HRGP may function as a natural suppressive regulator of T-lymphocyte activation. Hutchens et al. (1992) noted that HRG has high capacity to bind Zn(2+) and Cu(2+), both of which are highly bioavailable in human milk. Using dot blot and SDS-PAGE immunoblot analyses, they found that HRG was present in both human colostrum and milk. Immuno- and Zn-affinity isolation and N-terminal sequence analysis confirmed the identity of the protein. Leung (1993) characterized HRG as an abundant plasma protein and noted that several biologic properties of the protein had been identified. Properties that are relevant to the hemostatic mechanism are its binding to plasminogen and to heparin. By binding to plasminogen, HRG reduces the amount of plasminogen in the circulating blood that is available for activation into plasmin and thus acts as an inhibitor of fibrinolysis. By binding to heparin, HRG reduces the amount of heparin and through this mechanism reduces the inhibition of coagulation by the heparin-antithrombin III complex. Since both effects, the inhibition of fibrinolysis and the reduction of inhibition of coagulation, work in the same direction, an excess of HRG might be expected to have a prothrombotic effect. Using fluorescence and electron microscopy, Rydengard et al. (2007) showed that HRGP exerted pH- and zinc-dependent activity against gram-positive and gram-negative bacteria. This activity required the heparin-binding and histidine-rich domains of HRGP and was blocked in the presence of heparin. A peptide consisting of the 4 consecutive GHHPH motifs in HRGP was antibacterial. Using ELISA, immunoblot analysis, bioassays, and confocal microscopy, Manderson et al. (2009) showed that HRG bound strongly to, but neither activated nor inhibited, several complement proteins and that complexes existed in human serum and in synovial fluid of rheumatoid arthritis (RA; see 180300) patients. HRG enhanced complement activation on necrotic cells. Immune complexes formed in the presence of HRG showed enhanced complement activation, while those formed in the presence of C1q (120550) had diminished activation. Manderson et al. (2009) proposed that HRG may assist in the maintenance of normal immune function by mediating clearance of necrotic material and inhibiting formation of insoluble immune complexes, allowing for better complement activation and complex clearance.

MAPPING

Using a cDNA for ... More on the omim web site

Subscribe to this protein entry history

Nov. 17, 2018: Protein entry updated
Automatic update: OMIM entry 142640 was added.

Oct. 19, 2018: Additional information
Initial protein addition to the database. This entry was referenced in Bryk and co-workers. (2017).