Histidine-rich glycoprotein explained

Histidine-rich glycoprotein (HRG) is a glycoprotein that in humans is encoded by the HRG gene.^{[1] [2]} The HRG protein is produced in the liver, and it could also be synthesized by monocytes, macrophages, and megakaryocytes.^[3] 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.

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.^[4]

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.^[5] 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.^{[6] [7] [8]} The high concentration of both histidine and proline residues has resulted in HRG also being termed 'histidine–proline-rich glycoprotein' (HPRG).^[9] Human HRG is also composed of approximately 14% carbohydrate attached to six predicted N-linked glycosylation sites.^[5]

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.^[10] 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,^{[11] [12]} 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.^[13] Mutations in this gene lead to thrombophilia due to abnormal histidine-rich glycoprotein levels.^[2]

Clinical significance

The implications of HRG in cancer have been described as "multi-faceted".^[14] 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.^[14] Furthermore, the absence of the protein is associated with thrombophilia.^[14] HRG has also been shown to inhibit the M2-like phenotype of tumor-associated macrophages.^[15]

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.^{[14] [16]}

Interactions

This protein is known to interact with:

• Thrombospondin^[17]
• Haem^[18]
• Zn^{2+[18] [19]}
• Heparin ^[20]
• Plasminogen ^[21]
• IgG^[22]

Further reading

• Hughes GJ, Frutiger S, Paquet N, Ravier F, Pasquali C, Sanchez JC, James R, Tissot JD, Bjellqvist B, Hochstrasser DF . Plasma protein map: an update by microsequencing . Electrophoresis . 13 . 9–10 . 707–14 . 1993 . 1459097 . 10.1002/elps.11501301150 . 21810746 .
• Hutchens TW, Yip TT, Morgan WT . Identification of histidine-rich glycoprotein in human colostrum and milk . Pediatric Research . 31 . 3 . 239–46 . March 1992 . 1561009 . 10.1203/00006450-199203000-00009 . free .
• van den Berg EA, le Clercq E, Kluft C, Koide T, van der Zee A, Oldenburg M, Wijnen JT, Meera Khan P . Assignment of the human gene for histidine-rich glycoprotein to chromosome 3 . Genomics . 7 . 2 . 276–9 . June 1990 . 2347592 . 10.1016/0888-7543(90)90551-5 .
• Shatsky M, Saigo K, Burdach S, Leung LL, Levitt LJ . 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 . May 1989 . 10.1016/S0021-9258(18)83177-5 . 2524479 . free .
• Saigo K, Shatsky M, Levitt LJ, Leung LK . Interaction of histidine-rich glycoprotein with human T lymphocytes . The Journal of Biological Chemistry . 264 . 14 . 8249–53 . May 1989 . 10.1016/S0021-9258(18)83176-3 . 2566603 . free .
• Koide T, Foster D, Yoshitake S, Davie EW . Amino acid sequence of human histidine-rich glycoprotein derived from the nucleotide sequence of its cDNA . Biochemistry . 25 . 8 . 2220–5 . April 1986 . 3011081 . 10.1021/bi00356a055 .
• Hajjar DP, Boyd DB, Harpel PC, Nachman RL . Histidine-rich glycoprotein inhibits the antiproliferative effect of heparin on smooth muscle cells . The Journal of Experimental Medicine . 165 . 3 . 908–13 . March 1987 . 3819648 . 2188292 . 10.1084/jem.165.3.908 .
• Leung LL . Interaction of histidine-rich glycoprotein with fibrinogen and fibrin . The Journal of Clinical Investigation . 77 . 4 . 1305–11 . April 1986 . 3958188 . 424483 . 10.1172/JCI112435 .
• Heimburger N, Haupt H, Kranz T, Baudner S . [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 . July 1972 . 4116337 . 10.1515/bchm2.1972.353.2.1133.
• Silverstein RL, Leung LL, Harpel PC, Nachman RL . Complex formation of platelet thrombospondin with plasminogen. Modulation of activation by tissue activator . The Journal of Clinical Investigation . 74 . 5 . 1625–33 . November 1984 . 6438154 . 425339 . 10.1172/JCI111578 .
• Hennis BC, Frants RR, Bakker E, Vossen RH, van der Poort EW, Blonden LA, Cox S, Khan PM, Spurr NK, Kluft C . 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 . January 1994 . 8188234 . 10.1006/geno.1994.1046 .
• Sørensen CB, Krogh-Pedersen H, Petersen TE . Determination of the disulphide bridge arrangement of bovine histidine-rich glycoprotein . FEBS Letters . 328 . 3 . 285–90 . August 1993 . 8348977 . 10.1016/0014-5793(93)80945-Q . 11051275 .
• Leung L . Histidine-rich glycoprotein: an abundant plasma protein in search of a function . The Journal of Laboratory and Clinical Medicine . 121 . 5 . 630–1 . May 1993 . 8478589 .
• Angles-Cano E, Gris JC, Loyau S, Schved JF . 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 . May 1993 . 8478593 .
• Gorgani NN, Parish CR, Easterbrook Smith SB, Altin JG . Histidine-rich glycoprotein binds to human IgG and C1q and inhibits the formation of insoluble immune complexes . Biochemistry . 36 . 22 . 6653–62 . June 1997 . 9184145 . 10.1021/bi962573n .
• Schinke T, Koide T, Jahnen-Dechent W . Human histidine-rich glycoprotein expressed in SF9 insect cells inhibits apatite formation . FEBS Letters . 412 . 3 . 559–62 . August 1997 . 9276466 . 10.1016/S0014-5793(97)00827-2 . 46534395 . free .
• Shigekiyo T, Yoshida H, Matsumoto K, Azuma H, Wakabayashi S, Saito S, Fujikawa K, Koide T . HRG Tokushima: molecular and cellular characterization of histidine-rich glycoprotein (HRG) deficiency . Blood . 91 . 1 . 128–33 . January 1998 . 9414276 . 10.1182/blood.V91.1.128. free .
• Wakabayashi S, Takahashi K, Koide T . 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 . March 1999 . 10050040 . 10.1093/oxfordjournals.jbchem.a022316 .
• Gorgani NN, Altin JG, Parish CR . Histidine-rich glycoprotein regulates the binding of monomeric IgG and immune complexes to monocytes . International Immunology . 11 . 8 . 1275–82 . August 1999 . 10421785 . 10.1093/intimm/11.8.1275 . free .

Notes and References

1. Hennis BC, Kluft C . KpnI RFLP in the human histidine-rich glycoprotein gene . Nucleic Acids Research . 19 . 15 . 4311 . August 1991 . 1678514 . 328603 . 10.1093/nar/19.15.4311-a .
2. Web site: Entrez Gene: HRG histidine-rich glycoprotein.
3. Book: Wakabayashi S . New insights into the functions of histidine-rich glycoprotein . International Review of Cell and Molecular Biology . 304 . 467–93 . 2013 . 23809442 . 10.1016/B978-0-12-407696-9.00009-9 . 9780124076969 .
4. Hennis BC, van Boheemen PA, Wakabayashi S, Koide T, Hoffmann JJ, Kievit P, Dooijewaard G, Jansen JG, Kluft C . 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 . December 1995 . 8772226 . 10.1055/s-0038-1649971 . 44971634 .
5. Koide T, Foster D, Yoshitake S, Davie EW . Amino acid sequence of human histidine-rich glycoprotein derived from the nucleotide sequence of its cDNA . Biochemistry . 25 . 8 . 2220–5 . April 1986 . 3011081 . 10.1021/bi00356a055.
6. Haupt H, Heimburger N . [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 . July 1972 . 4116336 . 10.1515/bchm2.1972.353.2.1125 .
7. Lijnen HR, Hoylaerts M, Collen D . 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 . November 1980 . 10.1016/S0021-9258(19)70451-7 . 6448849 . free .
8. Koide T, Odani S, Ono T . Human histidine-rich glycoprotein: simultaneous purification with antithrombin III and characterization of its gross structure . Journal of Biochemistry . 98 . 5 . 1191–200 . November 1985 . 4086476 . 10.1093/oxfordjournals.jbchem.a135385 .
9. Borza DB, Tatum FM, Morgan WT . Domain structure and conformation of histidine-proline-rich glycoprotein . Biochemistry . 35 . 6 . 1925–34 . February 1996 . 8639676 . 10.1021/bi952061t .
10. Poon IK, Patel KK, Davis DS, Parish CR, Hulett MD . Histidine-rich glycoprotein: the Swiss Army knife of mammalian plasma . Blood . 117 . 7 . 2093–101 . February 2011 . 20971949 . 10.1182/blood-2010-09-303842 . free .
11. Blank M, Shoenfeld Y . Histidine-rich glycoprotein modulation of immune/autoimmune, vascular, and coagulation systems . Clinical Reviews in Allergy & Immunology . 34 . 3 . 307–12 . June 2008 . 18219588 . 10.1007/s12016-007-8058-6 . 37799666 .
12. Simantov R, Febbraio M, Crombie R, Asch AS, Nachman RL, Silverstein RL . Histidine-rich glycoprotein inhibits the antiangiogenic effect of thrombospondin-1 . The Journal of Clinical Investigation . 107 . 1 . 45–52 . January 2001 . 11134179 . 10.1172/JCI9061 . 198540.
13. Jones AL, Hulett MD, Parish CR . 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 . April 2005 . 15748207 . 10.1111/j.1440-1711.2005.01320.x . 23525811 . free .
14. Johnson LD, Goubran HA, Kotb RR . Histidine rich glycoprotein and cancer: a multi-faceted relationship . Anticancer Research . 34 . 2 . 593–603 . February 2014 . 24510988 .
15. 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 . HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF . Cancer Cell . 19 . 1 . 31–44 . January 2011 . 21215706 . 10.1016/j.ccr.2010.11.009 . free .
16. 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 . 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 . June 2014 . 24825900 . 10.1074/jbc.M114.565978 . 4140258. free .
17. Leung LL, Nachman RL, Harpel PC . Complex formation of platelet thrombospondin with histidine-rich glycoprotein . The Journal of Clinical Investigation . 73 . 1 . 5–12 . January 1984 . 6690483 . 10.1172/JCI111206 . 424965.
18. Morgan WT . 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 . August 1978 . 678554 . 10.1016/0005-2795(78)90098-3.
19. Morgan WT . Interactions of the histidine-rich glycoprotein of serum with metals . Biochemistry . 20 . 5 . 1054–61 . March 1981 . 7225317 . 10.1021/bi00508a002.
20. Jones AL, Hulett MD, Parish CR . 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 . July 2004 . 15138272 . 10.1074/jbc.M401996200 . free .
21. Jones AL, Hulett MD, Altin JG, Hogg P, Parish CR . 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 . September 2004 . 15220341 . 10.1074/jbc.M406027200 . free .
22. Gorgani NN, Parish CR, Altin JG . 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 . October 1999 . 10514432 . 10.1074/jbc.274.42.29633. free .