Histidine-rich glycoprotein

Histidine-rich glycoprotein (HRG) is a glycoprotein that in humans is encoded by the HRG gene.[3][4] The HRG protein is produced in the liver, and it could also be synthesized by monocytes, macrophages, and megakaryocytes.[5] 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.[6]

HRG
Identifiers
AliasesHRG, HPRG, HRGP, THPH11, histidine rich glycoprotein
External IDsOMIM: 142640 HomoloGene: 133557 GeneCards: HRG
Orthologs
SpeciesHumanMouse
Entrez

3273

n/a

Ensembl

ENSG00000113905

n/a

UniProt

P04196

n/a

RefSeq (mRNA)

NM_000412

n/a

RefSeq (protein)

NP_000403

n/a

Location (UCSC)Chr 3: 186.66 – 186.68 Mbn/a
PubMed search[2]n/a
Wikidata
View/Edit Human

Structure

Gene

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.[7]

Protein

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.[8] 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.[9][10][11] The high concentration of both histidine and proline residues has resulted in HRG also being termed 'histidine–proline-rich glycoprotein' (HPRG).[12] Human HRG is also composed of approximately 14% carbohydrate attached to six predicted N-linked glycosylation sites.[8]

Function

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.[13] 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,[6][14] 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.[15] Mutations in this gene lead to thrombophilia due to abnormal histidine-rich glycoprotein levels.[4]

Clinical significance

The implications of HRG in cancer have been described as "multi-faceted".[16] 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.[16] Furthermore, the absence of the protein is associated with thrombophilia.[16] HRG has also been shown to inhibit the M2-like phenotype of tumor-associated macrophages.[17]

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.[16][18]

Interactions

This protein is known to interact with:

References
  1. GRCh38: Ensembl release 89: ENSG00000113905 - Ensembl, May 2017
  2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. 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 328603. PMID 1678514.
  4. "Entrez Gene: HRG histidine-rich glycoprotein".
  5. Wakabayashi S (2013). New insights into the functions of histidine-rich glycoprotein. pp. 467–93. doi:10.1016/B978-0-12-407696-9.00009-9. ISBN 9780124076969. PMID 23809442. {{cite book}}: |journal= ignored (help)
  6. 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. S2CID 37799666.
  7. 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. doi:10.1055/s-0038-1649971. PMID 8772226.
  8. 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.
  9. 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. doi:10.1515/bchm2.1972.353.2.1125. PMID 4116336.
  10. 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. doi:10.1016/S0021-9258(19)70451-7. PMID 6448849.
  11. 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. doi:10.1093/oxfordjournals.jbchem.a135385. PMID 4086476.
  12. 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.
  13. 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.
  14. 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 198540. PMID 11134179.
  15. 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. S2CID 23525811.
  16. 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.
  17. 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.
  18. 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. PMC 4140258. PMID 24825900.
  19. 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 424965. PMID 6690483.
  20. Morgan WT (August 1978). "Human serum histidine-rich glycoprotein. I. Interactions with heme, metal ions and organic ligands". Biochimica et Biophysica Acta (BBA) - Protein Structure. 535 (2): 319–33. doi:10.1016/0005-2795(78)90098-3. PMID 678554.
  21. 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.
  22. 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.
  23. 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.
  24. 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
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