Semin Thromb Hemost 2011; 37(4): 389-394
DOI: 10.1055/s-0031-1276588
© Thieme Medical Publishers

Histidine-Rich Glycoprotein: A Possible Modulator of Coagulation and Fibrinolysis

Sadao Wakabayashi1 , Takehiko Koide1
  • 1Department of Life Science, Graduate School of Life Science, University of Hyogo, Harima Science Garden City, Hyogo, Japan
Further Information

Publication History

Publication Date:
30 July 2011 (online)

ABSTRACT

Histidine-rich glycoprotein (HRG) is one of the major plasma proteins and thought to function in blood coagulation, fibrinolysis, and innate immune systems. The amino acid sequence of HRG revealed a multidomain structure consisting of cystatin-like domains 1 and 2, a Pro-rich domain 1, a His-rich domain, a Pro-rich domain 2, and a C-terminal domain. Broad ligand-binding properties of HRG are involved in the multivalent functions of HRG. Among various functions of HRG, its interactions with heparin/heparan sulfate, fibrinogen, and plasminogen are thought to be intimately related to its roles in the coagulation and fibrinolytic systems. Recent studies on these topics are mainly reviewed in this article. The newly disclosed abilities of HRG in angiogenesis, its antibacterial effect, its activation of T-cell lines in cooperation with Concanavalin A, and the identification of a putative receptor for HRG on T cell lines are also described.

REFERENCES

  • 1 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 -glycoprotein (CM-protein I).  Hoppe Seylers Z Physiol Chem. 1972;  353 (7) 1133-1140
  • 2 Morgan W T. Human serum histidine-rich glycoprotein. I. Interactions with heme, metal ions and organic ligands.  Biochim Biophys Acta. 1978;  535 (2) 319-333
  • 3 Lijnen H R, 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.  J Biol Chem. 1980;  255 (21) 10214-10222
  • 4 Leung L L. Interaction of histidine-rich glycoprotein with fibrinogen and fibrin.  J Clin Invest. 1986;  77 (4) 1305-1311
  • 5 Koide T, Odani S, Ono T. The N-terminal sequence of human plasma histidine-rich glycoprotein homologous to antithrombin with high affinity for heparin.  FEBS Lett. 1982;  141 (2) 222-224
  • 6 Lijnen H R, van Hoef B, Collen D. Interaction of heparin with histidine-rich glycoprotein and with antithrombin III.  Thromb Haemost. 1983;  50 (2) 560-562
  • 7 Engesser L, Kluft C, Briët E, Brommer E J. Familial elevation of plasma histidine-rich glycoprotein in a family with thrombophilia.  Br J Haematol. 1987;  67 (3) 355-358
  • 8 Angles-Cano E, Gris J C, Loyau S, Schved J F. Familial association of high levels of histidine-rich glycoprotein and plasminogen activator inhibitor-1 with venous thromboembolism.  J Lab Clin Med. 1993;  121 (5) 646-653
  • 9 Shigekiyo T, Ohshima T, Oka H, Tomonari A, Azuma H, Saito S. Congenital histidine-rich glycoprotein deficiency.  Thromb Haemost. 1993;  70 (2) 263-265
  • 10 Souto J C, Garí M, Falkon L, Fontcuberta J. A new case of hereditary histidine-rich glycoprotein deficiency with familial thrombophilia.  Thromb Haemost. 1996;  75 (2) 374-375
  • 11 Shigekiyo T, Yoshida H, Kanagawa Y et al.. Histidine-rich glycoprotein (HRG) Tokushima 2: novel HRG deficiency, molecular and cellular characterization.  Thromb Haemost. 2000;  84 (4) 675-679
  • 12 Tsuchida-Straeten N, Ensslen S, Schäfer C et al.. Enhanced blood coagulation and fibrinolysis in mice lacking histidine-rich glycoprotein (HRG).  J Thromb Haemost. 2005;  3 (5) 865-872
  • 13 Simantov R, Febbraio M, Crombie R, Asch A S, Nachman R L, Silverstein R L. Histidine-rich glycoprotein inhibits the antiangiogenic effect of thrombospondin-1.  J Clin Invest. 2001;  107 (1) 45-52
  • 14 Rydengård V, Olsson A K, Mörgelin M, Schmidtchen A. Histidine-rich glycoprotein exerts antibacterial activity.  FEBS J. 2007;  274 (2) 377-389
  • 15 Blank M, Shoenfeld Y. Histidine-rich glycoprotein modulation of immune/autoimmune, vascular, and coagulation systems.  Clin Rev Allergy Immunol. 2008;  34 (3) 307-312
  • 16 Jones A L, Hulett M D, Parish C R. Histidine-rich glycoprotein: a novel adaptor protein in plasma that modulates the immune, vascular and coagulation systems.  Immunol Cell Biol. 2005;  83 (2) 106-118
  • 17 Koide T, Foster D, Yoshitake S, Davie E W. Amino acid sequence of human histidine-rich glycoprotein derived from the nucleotide sequence of its cDNA.  Biochemistry. 1986;  25 (8) 2220-2225
  • 18 Koide T, Odani S. Histidine-rich glycoprotein is evolutionarily related to the cystatin superfamily. Presence of two cystatin domains in the N-terminal region.  FEBS Lett. 1987;  216 (1) 17-21
  • 19 Koide T, Izumi S, Ohashi T et al.. Histidine-rich glycoproteins from human, bovine, and rat plasma: Presence of two forms in rat plasma and a remarkable diversity of primary structure among species.  Paper presented at: 13th International Congress on Fibrinolysis and Proteolysis; June 1996; Barcelona, Spain
  • 20 Wakabayashi S, Ioroi M, Maruyama K, Koide T. Amino acid sequence of chicken plasma histidine-rich glycoprotein. Paper presented at: 1st Annual Meeting of the Protein Science Society of Japan; June 2001; Osaka, Japan. 
  • 21 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.  J Biochem. 1999;  125 (3) 522-530
  • 22 Hennis B C, Frants R R, Bakker E et al.. 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. Available at: http://www.ncbi.nlm.nih.gov/genome/guide/human/ Accessed April 4, 2011
  • 23 Morgan W T, Koskelo P, Koenig H, Conway T P. Human histidine-rich glycoprotein. II. Serum levels in adults, pregnant women and neonates.  Proc Soc Exp Biol Med. 1978;  158 (4) 647-651
  • 24 Lijnen H R, Jacobs G, Collen D. Histidine-rich glycoprotein in a normal and a clinical population.  Thromb Res. 1981;  22 (4) 519-523
  • 25 Hennis B C, DeMaat M PM, Quax P HA, LeClercq E J, Kuiper J, Kluft C. Evaluation of sites of synthesis of the histidine-rich glycoprotein. In: Proceedings from the 13th Congress of the International Society on Thrombosis and Haemostasis.  Thromb Haemost. 1991;  65 884 Abstract 660
  • 26 Leung L L, Harpel P C, Nachman R L, Rabellino E M. Histidine-rich glycoprotein is present in human platelets and is released following thrombin stimulation.  Blood. 1983;  62 (5) 1016-1021
  • 27 Hutchens T W, Yip T T, Morgan W T. Identification of histidine-rich glycoprotein in human colostrum and milk.  Pediatr Res. 1992;  31 (3) 239-246
  • 28 Jespersen J, Petersen K R, Skouby S O. Effects of newer oral contraceptives on the inhibition of coagulation and fibrinolysis in relation to dosage and type of steroid.  Am J Obstet Gynecol. 1990;  163 (1 Pt 2) 396-403
  • 29 Saito H, Goodnough L T, Boyle J M, Heimburger N. Reduced histidine-rich glycoprotein levels in plasma of patients with advanced liver cirrhosis. Possible implications for enhanced fibrinolysis.  Am J Med. 1982;  73 (2) 179-182
  • 30 Saigo K, Yoshida A, Ryo R, Yamaguchi N, Leung L L. Histidine-rich glycoprotein as a negative acute phase reactant.  Am J Hematol. 1990;  34 (2) 149-150
  • 31 Kazama Y, Koide T. Modulation of protein C inhibitor activity by histidine-rich glycoprotein and platelet factor 4: role of zinc and calcium ions in the heparin-neutralizing ability of histidine-rich glycoprotein.  Thromb Haemost. 1992;  67 (1) 50-55
  • 32 Koide T, Kazama Y, Odani S et al.. Histidine-rich glycoprotein: Analyses of heparin-binding domain by limited proteolysis and by monoclonal antibodies. Proceedings from the 12th Congress of the International Society on Thrombosis and Haemostasis; Thromb Haemost 1989;62:473. Abstract 1482. 
  • 33 Jones A L, Hulett M D, Parish C R. Histidine-rich glycoprotein binds to cell-surface heparan sulfate via its N-terminal domain following Zn2+ chelation.  J Biol Chem. 2004;  279 (29) 30114-30122
  • 34 Vanwildemeersch M, Olsson A K, Gottfridsson E, Claesson-Welsh L, Lindahl U, Spillmann D. The anti-angiogenic His/Pro-rich fragment of histidine-rich glycoprotein binds to endothelial cell heparan sulfate in a Zn2+-dependent manner.  J Biol Chem. 2006;  281 (15) 10298-10304
  • 35 Koide T, Fujimoto M, Ohnishi T, Murase K. Identification of fibrinogen binding site of human histidine-rich glycoprotein (HRG).  Paper presented at: 18th International Congress on Fibrinolysis and Proteolysis; August 2006; San Diego, CA
  • 36 Koide T, Ohshima M, Takeuchi Y, Wakabayashi S. Fibrinogen interacts with histidine-rich glycoprotein (HRG) at the multiple sites.  Paper presented at: 19th International Congress on Fibrinolysis and Proteolysis; July 2008; Vienna, Austria
  • 37 Fujimoto M, Koide T. Zn2+-dependent promotion of fibrinolysis by HRG.  Paper presented at: 27th Congress of the Japanese Society on Thrombosis and Hemostasis; November 2004; Nara, Japan
  • 38 Leung L L, Nachman R L, Harpel P C. Complex formation of platelet thrombospondin with histidine-rich glycoprotein.  J Clin Invest. 1984;  73 (1) 5-12
  • 39 Lerch P G, Nydegger U E, Kuyas C, Haeberli A. Histidine-rich glycoprotein binding to activated human platelets.  Br J Haematol. 1988;  70 (2) 219-224
  • 40 Silverstein R L, Febbraio M. CD36-TSP-HRGP interactions in the regulation of angiogenesis.  Curr Pharm Des. 2007;  13 (35) 3559-3567
  • 41 Silverstein R L, Nachman R L, Leung L L, Harpel P C. Activation of immobilized plasminogen by tissue activator. Multimolecular complex formation.  J Biol Chem. 1985;  260 (18) 10346-10352
  • 42 Koide T, Kawate Y. Identification of plasminogen-binding site with which histidine-rich glycoprotein functions as an antifibrinolytic factor.  Paper presented at: 16th Congress of the International Society on Thrombosis and Haemostasis; June 1997; Florence, Italy
  • 43 Jones A L, Hulett M D, Altin J G, Hogg P, Parish C R. Plasminogen is tethered with high affinity to the cell surface by the plasma protein, histidine-rich glycoprotein.  J Biol Chem. 2004;  279 (37) 38267-38276
  • 44 Poon I K, Olsson A K, Hulett M D, Parish C R. Regulation of histidine-rich glycoprotein (HRG) function via plasmin-mediated proteolytic cleavage.  Biochem J. 2009;  424 (1) 27-37
  • 45 Thulin A, Ringvall M, Dimberg A et al.. Activated platelets provide a functional microenvironment for the antiangiogenic fragment of histidine-rich glycoprotein.  Mol Cancer Res. 2009;  7 (11) 1792-1802
  • 46 Ohta T, Ikemoto Y, Saeki K, Koide T, Wakabayashi S. Histidine-rich glycoprotein and concanavalin A synergistically stimulate the phosphatidylinositol 3-kinase-independent signaling pathway in leukocytes leading to increased cell adhesion and changes in cell morphology.  Cell Immunol. 2009;  259 (1) 5-12
  • 47 Ohta T, Ikemoto Y, Usami A, Koide T, Wakabayashi S. High affinity interaction between histidine-rich glycoprotein and the cell surface type ATP synthase on T-cells.  Biochim Biophys Acta. 2009;  1788 (5) 1099-1107

Takehiko KoideD.Sc. 

Professor, Department of Life Science, Graduate School of Life Science, University of Hyogo

Harima Science Garden City, Hyogo 678-1297, Japan

Email: koide@sci.u-hyogo.ac.jp

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