Histidine-rich glycoprotein

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Aliases HRG, HPRG, HRGP, THPH11, histidine rich glycoprotein
External IDs HomoloGene: 133557 GeneCards: HRG
RNA expression pattern
PBB GE HRG 31835 at fs.png

PBB GE HRG 206226 at fs.png
More reference expression data
Species Human Mouse
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC) Chr 3: 186.66 – 186.68 Mb n/a
PubMed search [1] n/a
View/Edit Human

Histidine-rich glycoprotein (HRG)is a glycoprotein that in humans is encoded by the HRG gene.[2][3] The HRG protein is produced in the liver, and it could also be synthesized by monocytes, macrophages, and megakaryocytes.[4] It possesses a multi-domain structure, which makes it capable of binding to numerous ligands and modulating various biological processes including immunity, vascularization and coagulation.[5]



The HRG gene lies on location of 3q27 on the chromosome 3, spans approximately 11kb, and consist of 7 exons. Two common isoforms of the HRG gene have been found in humans. These isoforms exist due to a polymorphism occurring in exon 5.[6]


HRG is a glycoprotein of 70-75kDa present at a relatively high concentration in the plasma of vertebrates. The primary structure of human HRG is predicted to be a 507 amino acid multidomain polypeptide consisting of two cystatin-like regions at the N-terminus, a histidine-rich region (HRR) flanked by proline-rich regions (PRR), and a C-terminal domain.[7] HRG has an unusually high concentration of histidine and proline residues, each constituting approximately 13% of total amino acids, concentrated within the HRR and PRR.[8][9][10] The high concentration of both histidine and proline residues has resulted in HRG also being termed 'histidine–proline-rich glycoprotein' (HPRG).[11] Human HRG is also composed of approximately 14% carbohydrate attached to six predicted N-linked glycosylation sites.[7]


This histidine-rich glycoprotein contains two cystatin-like domains and is located in plasma and platelets. It is known that HRG binds heme, dyes, and divalent metal ions and it is thought to have multiple roles in the human blood, including roles in immunity, angiogenesis and coagulation.[12] It can inhibit rosette formation and interacts with heparin, thrombospondin, and plasminogen. Two of the protein's effects, the inhibition of fibrinolysis and the reduced inhibition of coagulation, indicate a potential prothrombotic effect. HRG is also reported to be involved in clearance of apoptotic phagocytes, immune complexes, cell adhesion, migration and angiogenesis,[5][13] due to its ability to bind various ligands such as phospholipids, fibrinogen, plasminogen, heparin, heparansulfate, tropomysin, and heme, as well as the divalent metal ions zinc, copper, mercury, cadmium and nickel.[14] Mutations in this gene lead to thrombophilia due to abnormal histidine-rich glycoprotein levels.[3]

Clinical significance[edit]

The implications of HRG in cancer have been described as "multi-faceted".[15] For example, the protein appears to have both pro- and anti-angiogenic effects. In biomarker studies, the protein has been found to have potential prognostic and diagnostic value for cancer.[15] Furthermore, the absence of the protein is associated with thrombophilia.[15] HRG has also been shown to inhibit the M2-like phenotype of tumor-associated macrophages.[16]

In addition, HRG has been discovered to play a role in infection. Some studies have found HRG has the antibacterial activity against Streptococcus pyogenes and a direct interaction between a S. pyogenes virulence factor (sHIP) and the human HRG has been identified.[15][17]


This protein is known to interact with:


  1. ^ "Human PubMed Reference:". 
  2. ^ Hennis BC, Kluft C (August 1991). "KpnI RFLP in the human histidine-rich glycoprotein gene". Nucleic Acids Research. 19 (15): 4311. doi:10.1093/nar/19.15.4311-a. PMC 328603Freely accessible. PMID 1678514. 
  3. ^ a b "Entrez Gene: HRG histidine-rich glycoprotein". 
  4. ^ Wakabayashi S (2013). "New insights into the functions of histidine-rich glycoprotein". International Review of Cell and Molecular Biology. 304: 467–93. doi:10.1016/B978-0-12-407696-9.00009-9. PMID 23809442. 
  5. ^ a b Blank M, Shoenfeld Y (June 2008). "Histidine-rich glycoprotein modulation of immune/autoimmune, vascular, and coagulation systems". Clinical Reviews in Allergy & Immunology. 34 (3): 307–12. doi:10.1007/s12016-007-8058-6. PMID 18219588. 
  6. ^ Hennis BC, van Boheemen PA, Wakabayashi S, Koide T, Hoffmann JJ, Kievit P, Dooijewaard G, Jansen JG, Kluft C (December 1995). "Identification and genetic analysis of a common molecular variant of histidine-rich glycoprotein with a difference of 2kD in apparent molecular weight". Thrombosis and Haemostasis. 74 (6): 1491–6. PMID 8772226. 
  7. ^ a b Koide T, Foster D, Yoshitake S, Davie EW (April 1986). "Amino acid sequence of human histidine-rich glycoprotein derived from the nucleotide sequence of its cDNA". Biochemistry. 25 (8): 2220–5. doi:10.1021/bi00356a055. PMID 3011081. 
  8. ^ Haupt H, Heimburger N (July 1972). "[Human serum proteins with high affinity for carboxymethylcellulose. I. Isolation of lysozyme, C1q and 2 hitherto unknown -globulins]". Hoppe-Seyler's Zeitschrift Für Physiologische Chemie. 353 (7): 1125–32. PMID 4116336. 
  9. ^ Lijnen HR, Hoylaerts M, Collen D (November 1980). "Isolation and characterization of a human plasma protein with affinity for the lysine binding sites in plasminogen. Role in the regulation of fibrinolysis and identification as histidine-rich glycoprotein". The Journal of Biological Chemistry. 255 (21): 10214–22. PMID 6448849. 
  10. ^ Koide T, Odani S, Ono T (November 1985). "Human histidine-rich glycoprotein: simultaneous purification with antithrombin III and characterization of its gross structure". Journal of Biochemistry. 98 (5): 1191–200. PMID 4086476. 
  11. ^ Borza DB, Tatum FM, Morgan WT (February 1996). "Domain structure and conformation of histidine-proline-rich glycoprotein". Biochemistry. 35 (6): 1925–34. doi:10.1021/bi952061t. PMID 8639676. 
  12. ^ Poon IK, Patel KK, Davis DS, Parish CR, Hulett MD (February 2011). "Histidine-rich glycoprotein: the Swiss Army knife of mammalian plasma". Blood. 117 (7): 2093–101. doi:10.1182/blood-2010-09-303842. PMID 20971949. 
  13. ^ Simantov R, Febbraio M, Crombie R, Asch AS, Nachman RL, Silverstein RL (January 2001). "Histidine-rich glycoprotein inhibits the antiangiogenic effect of thrombospondin-1". The Journal of Clinical Investigation. 107 (1): 45–52. doi:10.1172/JCI9061. PMC 198540Freely accessible. PMID 11134179. 
  14. ^ Jones AL, Hulett MD, Parish CR (April 2005). "Histidine-rich glycoprotein: A novel adaptor protein in plasma that modulates the immune, vascular and coagulation systems". Immunology and Cell Biology. 83 (2): 106–18. doi:10.1111/j.1440-1711.2005.01320.x. PMID 15748207. 
  15. ^ a b c d Johnson LD, Goubran HA, Kotb RR (February 2014). "Histidine rich glycoprotein and cancer: a multi-faceted relationship". Anticancer Research. 34 (2): 593–603. PMID 24510988. 
  16. ^ Rolny C, Mazzone M, Tugues S, Laoui D, Johansson I, Coulon C, Squadrito ML, Segura I, Li X, Knevels E, Costa S, Vinckier S, Dresselaer T, Åkerud P, De Mol M, Salomäki H, Phillipson M, Wyns S, Larsson E, Buysschaert I, Botling J, Himmelreich U, Van Ginderachter JA, De Palma M, Dewerchin M, Claesson-Welsh L, Carmeliet P (January 2011). "HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF". Cancer Cell. 19 (1): 31–44. doi:10.1016/j.ccr.2010.11.009. PMID 21215706. 
  17. ^ Wisniewska M, Happonen L, Kahn F, Varjosalo M, Malmström L, Rosenberger G, Karlsson C, Cazzamali G, Pozdnyakova I, Frick IM, Björck L, Streicher W, Malmström J, Wikström M (June 2014). "Functional and structural properties of a novel protein and virulence factor (Protein sHIP) in Streptococcus pyogenes". The Journal of Biological Chemistry. 289 (26): 18175–88. doi:10.1074/jbc.M114.565978. PMID 24825900. 
  18. ^ Leung LL, Nachman RL, Harpel PC (January 1984). "Complex formation of platelet thrombospondin with histidine-rich glycoprotein". The Journal of Clinical Investigation. 73 (1): 5–12. doi:10.1172/JCI111206. PMC 424965Freely accessible. PMID 6690483. 
  19. ^ a b Morgan WT (August 1978). "Human serum histidine-rich glycoprotein. I. Interactions with heme, metal ions and organic ligands". Biochimica et Biophysica Acta. 535 (2): 319–33. doi:10.1016/0005-2795(78)90098-3. PMID 678554. 
  20. ^ Morgan WT (March 1981). "Interactions of the histidine-rich glycoprotein of serum with metals". Biochemistry. 20 (5): 1054–61. doi:10.1021/bi00508a002. PMID 7225317. 
  21. ^ Jones AL, Hulett MD, Parish CR (July 2004). "Histidine-rich glycoprotein binds to cell-surface heparan sulfate via its N-terminal domain following Zn2+ chelation". The Journal of Biological Chemistry. 279 (29): 30114–22. doi:10.1074/jbc.M401996200. PMID 15138272. 
  22. ^ Jones AL, Hulett MD, Altin JG, Hogg P, Parish CR (September 2004). "Plasminogen is tethered with high affinity to the cell surface by the plasma protein, histidine-rich glycoprotein". The Journal of Biological Chemistry. 279 (37): 38267–76. doi:10.1074/jbc.M406027200. PMID 15220341. 
  23. ^ Gorgani NN, Parish CR, Altin JG (October 1999). "Differential binding of histidine-rich glycoprotein (HRG) to human IgG subclasses and IgG molecules containing kappa and lambda light chains". The Journal of Biological Chemistry. 274 (42): 29633–40. doi:10.1074/jbc.274.42.29633. PMID 10514432. 

Further reading[edit]

  • Hughes GJ, Frutiger S, Paquet N, Ravier F, Pasquali C, Sanchez JC, James R, Tissot JD, Bjellqvist B, Hochstrasser DF (1993). "Plasma protein map: an update by microsequencing". Electrophoresis. 13 (9-10): 707–14. doi:10.1002/elps.11501301150. PMID 1459097. 
  • Hutchens TW, Yip TT, Morgan WT (March 1992). "Identification of histidine-rich glycoprotein in human colostrum and milk". Pediatric Research. 31 (3): 239–46. doi:10.1203/00006450-199203000-00009. PMID 1561009. 
  • van den Berg EA, le Clercq E, Kluft C, Koide T, van der Zee A, Oldenburg M, Wijnen JT, Meera Khan P (June 1990). "Assignment of the human gene for histidine-rich glycoprotein to chromosome 3". Genomics. 7 (2): 276–9. doi:10.1016/0888-7543(90)90551-5. PMID 2347592. 
  • Shatsky M, Saigo K, Burdach S, Leung LL, Levitt LJ (May 1989). "Histidine-rich glycoprotein blocks T cell rosette formation and modulates both T cell activation and immunoregulation". The Journal of Biological Chemistry. 264 (14): 8254–9. PMID 2524479. 
  • Saigo K, Shatsky M, Levitt LJ, Leung LK (May 1989). "Interaction of histidine-rich glycoprotein with human T lymphocytes". The Journal of Biological Chemistry. 264 (14): 8249–53. PMID 2566603. 
  • Koide T, Foster D, Yoshitake S, Davie EW (April 1986). "Amino acid sequence of human histidine-rich glycoprotein derived from the nucleotide sequence of its cDNA". Biochemistry. 25 (8): 2220–5. doi:10.1021/bi00356a055. PMID 3011081. 
  • Hajjar DP, Boyd DB, Harpel PC, Nachman RL (March 1987). "Histidine-rich glycoprotein inhibits the antiproliferative effect of heparin on smooth muscle cells". The Journal of Experimental Medicine. 165 (3): 908–13. doi:10.1084/jem.165.3.908. PMC 2188292Freely accessible. PMID 3819648. 
  • Leung LL (April 1986). "Interaction of histidine-rich glycoprotein with fibrinogen and fibrin". The Journal of Clinical Investigation. 77 (4): 1305–11. doi:10.1172/JCI112435. PMC 424483Freely accessible. PMID 3958188. 
  • Heimburger N, Haupt H, Kranz T, Baudner S (July 1972). "[Human serum proteins with high affinity to carboxymethylcellulose. II. Physico-chemical and immunological characterization of a histidine-rich 3,8S- 2 -glycoportein (CM-protein I)]". Hoppe-Seyler's Zeitschrift Für Physiologische Chemie. 353 (7): 1133–40. PMID 4116337. 
  • Silverstein RL, Leung LL, Harpel PC, Nachman RL (November 1984). "Complex formation of platelet thrombospondin with plasminogen. Modulation of activation by tissue activator". The Journal of Clinical Investigation. 74 (5): 1625–33. doi:10.1172/JCI111578. PMC 425339Freely accessible. PMID 6438154. 
  • Hennis BC, Frants RR, Bakker E, Vossen RH, van der Poort EW, Blonden LA, Cox S, Khan PM, Spurr NK, Kluft C (January 1994). "Evidence for the absence of intron H of the histidine-rich glycoprotein (HRG) gene: genetic mapping and in situ localization of HRG to chromosome 3q28-q29". Genomics. 19 (1): 195–7. doi:10.1006/geno.1994.1046. PMID 8188234. 
  • Sørensen CB, Krogh-Pedersen H, Petersen TE (August 1993). "Determination of the disulphide bridge arrangement of bovine histidine-rich glycoprotein". FEBS Letters. 328 (3): 285–90. doi:10.1016/0014-5793(93)80945-Q. PMID 8348977. 
  • Leung L (May 1993). "Histidine-rich glycoprotein: an abundant plasma protein in search of a function". The Journal of Laboratory and Clinical Medicine. 121 (5): 630–1. PMID 8478589. 
  • Angles-Cano E, Gris JC, Loyau S, Schved JF (May 1993). "Familial association of high levels of histidine-rich glycoprotein and plasminogen activator inhibitor-1 with venous thromboembolism". The Journal of Laboratory and Clinical Medicine. 121 (5): 646–53. PMID 8478593. 
  • Gorgani NN, Parish CR, Easterbrook Smith SB, Altin JG (June 1997). "Histidine-rich glycoprotein binds to human IgG and C1q and inhibits the formation of insoluble immune complexes". Biochemistry. 36 (22): 6653–62. doi:10.1021/bi962573n. PMID 9184145. 
  • Schinke T, Koide T, Jahnen-Dechent W (August 1997). "Human histidine-rich glycoprotein expressed in SF9 insect cells inhibits apatite formation". FEBS Letters. 412 (3): 559–62. doi:10.1016/S0014-5793(97)00827-2. PMID 9276466. 
  • Shigekiyo T, Yoshida H, Matsumoto K, Azuma H, Wakabayashi S, Saito S, Fujikawa K, Koide T (January 1998). "HRG Tokushima: molecular and cellular characterization of histidine-rich glycoprotein (HRG) deficiency". Blood. 91 (1): 128–33. PMID 9414276. 
  • Wakabayashi S, Takahashi K, Koide T (March 1999). "Structural characterization of the gene for human histidine-rich glycoprotein, reinvestigation of the 5'-terminal region of cDNA and a search for the liver specific promoter in the gene". Journal of Biochemistry. 125 (3): 522–30. doi:10.1093/oxfordjournals.jbchem.a022316. PMID 10050040. 
  • Gorgani NN, Altin JG, Parish CR (August 1999). "Histidine-rich glycoprotein regulates the binding of monomeric IgG and immune complexes to monocytes". International Immunology. 11 (8): 1275–82. doi:10.1093/intimm/11.8.1275. PMID 10421785.