Biology:Histidine-rich glycoprotein
 Generic protein structure example |
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.[4]
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.[5]
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.[6] 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.[7][8][9] The high concentration of both histidine and proline residues has resulted in HRG also being termed 'histidine–proline-rich glycoprotein' (HPRG).[10] Human HRG is also composed of approximately 14% carbohydrate attached to six predicted N-linked glycosylation sites.[6]
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.[11] 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,[4][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:
References
- ↑ "KpnI RFLP in the human histidine-rich glycoprotein gene". Nucleic Acids Research 19 (15): 4311. August 1991. doi:10.1093/nar/19.15.4311-a. PMID 1678514.
- ↑ 2.0 2.1 "Entrez Gene: HRG histidine-rich glycoprotein". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3273.
- ↑ New insights into the functions of histidine-rich glycoprotein. 304. 2013. 467–93. doi:10.1016/B978-0-12-407696-9.00009-9. ISBN 9780124076969.
- ↑ 4.0 4.1 "Histidine-rich glycoprotein modulation of immune/autoimmune, vascular, and coagulation systems". Clinical Reviews in Allergy & Immunology 34 (3): 307–12. June 2008. doi:10.1007/s12016-007-8058-6. PMID 18219588.
- ↑ "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. doi:10.1055/s-0038-1649971. PMID 8772226.
- ↑ 6.0 6.1 "Amino acid sequence of human histidine-rich glycoprotein derived from the nucleotide sequence of its cDNA". Biochemistry 25 (8): 2220–5. April 1986. doi:10.1021/bi00356a055. PMID 3011081.
- ↑ "[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. doi:10.1515/bchm2.1972.353.2.1125. PMID 4116336.
- ↑ "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. doi:10.1016/S0021-9258(19)70451-7. PMID 6448849.
- ↑ "Human histidine-rich glycoprotein: simultaneous purification with antithrombin III and characterization of its gross structure". Journal of Biochemistry 98 (5): 1191–200. November 1985. doi:10.1093/oxfordjournals.jbchem.a135385. PMID 4086476.
- ↑ "Domain structure and conformation of histidine-proline-rich glycoprotein". Biochemistry 35 (6): 1925–34. February 1996. doi:10.1021/bi952061t. PMID 8639676.
- ↑ "Histidine-rich glycoprotein: the Swiss Army knife of mammalian plasma". Blood 117 (7): 2093–101. February 2011. doi:10.1182/blood-2010-09-303842. PMID 20971949.
- ↑ "Histidine-rich glycoprotein inhibits the antiangiogenic effect of thrombospondin-1". The Journal of Clinical Investigation 107 (1): 45–52. January 2001. doi:10.1172/JCI9061. PMID 11134179.
- ↑ "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. doi:10.1111/j.1440-1711.2005.01320.x. PMID 15748207.
- ↑ 14.0 14.1 14.2 14.3 "Histidine rich glycoprotein and cancer: a multi-faceted relationship". Anticancer Research 34 (2): 593–603. February 2014. PMID 24510988.
- ↑ "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. doi:10.1016/j.ccr.2010.11.009. PMID 21215706.
- ↑ "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. doi:10.1074/jbc.M114.565978. PMID 24825900.
- ↑ "Complex formation of platelet thrombospondin with histidine-rich glycoprotein". The Journal of Clinical Investigation 73 (1): 5–12. January 1984. doi:10.1172/JCI111206. PMID 6690483.
- ↑ 18.0 18.1 "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. doi:10.1016/0005-2795(78)90098-3. PMID 678554.
- ↑ "Interactions of the histidine-rich glycoprotein of serum with metals". Biochemistry 20 (5): 1054–61. March 1981. doi:10.1021/bi00508a002. PMID 7225317.
- ↑ "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. doi:10.1074/jbc.M401996200. PMID 15138272.
- ↑ "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. doi:10.1074/jbc.M406027200. PMID 15220341.
- ↑ "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. doi:10.1074/jbc.274.42.29633. PMID 10514432.
Further reading
- "Plasma protein map: an update by microsequencing". Electrophoresis 13 (9–10): 707–14. 1993. doi:10.1002/elps.11501301150. PMID 1459097.
- "Identification of histidine-rich glycoprotein in human colostrum and milk". Pediatric Research 31 (3): 239–46. March 1992. doi:10.1203/00006450-199203000-00009. PMID 1561009.
- "Assignment of the human gene for histidine-rich glycoprotein to chromosome 3". Genomics 7 (2): 276–9. June 1990. doi:10.1016/0888-7543(90)90551-5. PMID 2347592.
- "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. doi:10.1016/S0021-9258(18)83177-5. PMID 2524479.
- "Interaction of histidine-rich glycoprotein with human T lymphocytes". The Journal of Biological Chemistry 264 (14): 8249–53. May 1989. doi:10.1016/S0021-9258(18)83176-3. PMID 2566603.
- "Amino acid sequence of human histidine-rich glycoprotein derived from the nucleotide sequence of its cDNA". Biochemistry 25 (8): 2220–5. April 1986. doi:10.1021/bi00356a055. PMID 3011081.
- "Histidine-rich glycoprotein inhibits the antiproliferative effect of heparin on smooth muscle cells". The Journal of Experimental Medicine 165 (3): 908–13. March 1987. doi:10.1084/jem.165.3.908. PMID 3819648.
- "Interaction of histidine-rich glycoprotein with fibrinogen and fibrin". The Journal of Clinical Investigation 77 (4): 1305–11. April 1986. doi:10.1172/JCI112435. PMID 3958188.
- "[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. doi:10.1515/bchm2.1972.353.2.1133. PMID 4116337.
- "Complex formation of platelet thrombospondin with plasminogen. Modulation of activation by tissue activator". The Journal of Clinical Investigation 74 (5): 1625–33. November 1984. doi:10.1172/JCI111578. PMID 6438154.
- "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. doi:10.1006/geno.1994.1046. PMID 8188234.
- "Determination of the disulphide bridge arrangement of bovine histidine-rich glycoprotein". FEBS Letters 328 (3): 285–90. August 1993. doi:10.1016/0014-5793(93)80945-Q. PMID 8348977.
- "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. PMID 8478589.
- "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. PMID 8478593.
- "Histidine-rich glycoprotein binds to human IgG and C1q and inhibits the formation of insoluble immune complexes". Biochemistry 36 (22): 6653–62. June 1997. doi:10.1021/bi962573n. PMID 9184145.
- "Human histidine-rich glycoprotein expressed in SF9 insect cells inhibits apatite formation". FEBS Letters 412 (3): 559–62. August 1997. doi:10.1016/S0014-5793(97)00827-2. PMID 9276466.
- "HRG Tokushima: molecular and cellular characterization of histidine-rich glycoprotein (HRG) deficiency". Blood 91 (1): 128–33. January 1998. doi:10.1182/blood.V91.1.128. PMID 9414276.
- "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. doi:10.1093/oxfordjournals.jbchem.a022316. PMID 10050040.
- "Histidine-rich glycoprotein regulates the binding of monomeric IgG and immune complexes to monocytes". International Immunology 11 (8): 1275–82. August 1999. doi:10.1093/intimm/11.8.1275. PMID 10421785.
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