Histidine-rich glycoprotein

Details

Name
Histidine-rich glycoprotein
Synonyms
  • Histidine-proline-rich glycoprotein
  • HPRG
Gene Name
HRG
Organism
Humans
Amino acid sequence
>lcl|BSEQ0052383|Histidine-rich glycoprotein
MKALIAALLLITLQYSCAVSPTDCSAVEPEAEKALDLINKRRRDGYLFQLLRIADAHLDR
VENTTVYYLVLDVQESDCSVLSRKYWNDCEPPDSRRPSEIVIGQCKVIATRHSHESQDLR
VIDFNCTTSSVSSALANTKDSPVLIDFFEDTERYRKQANKALEKYKEENDDFASFRVDRI
ERVARVRGGEGTGYFVDFSVRNCPRHHFPRHPNVFGFCRADLFYDVEALDLESPKNLVIN
CEVFDPQEHENINGVPPHLGHPFHWGGHERSSTTKPPFKPHGSRDHHHPHKPHEHGPPPP
PDERDHSHGPPLPQGPPPLLPMSCSSCQHATFGTNGAQRHSHNNNSSDLHPHKHHSHEQH
PHGHHPHAHHPHEHDTHRQHPHGHHPHGHHPHGHHPHGHHPHGHHPHCHDFQDYGPCDPP
PHNQGHCCHGHGPPPGHLRRRGPGKGPRPFHCRQIGSVYRLPPLRKGEVLPLPEANFPSF
PLPHHKHPLKPDNQPFPQSVSESCPGKFKSGFPQVSMFFTHTFPK
Number of residues
525
Molecular Weight
59578.04
Theoretical pI
Not Available
GO Classification
Functions
cysteine-type endopeptidase inhibitor activity / endopeptidase inhibitor activity / heme binding / heparan sulfate proteoglycan binding / heparin binding / immunoglobulin binding / metal ion binding / serine-type endopeptidase inhibitor activity / signaling receptor binding / zinc ion binding
Processes
angiogenesis / antimicrobial humoral immune response mediated by antimicrobial peptide / chemotaxis / cytolysis by host of symbiont cells / defense response to fungus / fibrinolysis / heme transport / negative regulation of angiogenesis / negative regulation of blood vessel endothelial cell migration / negative regulation of cell adhesion / negative regulation of cell adhesion mediated by integrin / negative regulation of cell growth / negative regulation of cell population proliferation / negative regulation of endopeptidase activity / negative regulation of endothelial cell chemotaxis / negative regulation of fibrinolysis / negative regulation of lamellipodium assembly / negative regulation of vascular endothelial growth factor signaling pathway / platelet activation / platelet degranulation / positive regulation of apoptotic process / positive regulation of blood vessel remodeling / positive regulation of focal adhesion assembly / positive regulation of immune response to tumor cell / regulation of actin cytoskeleton organization / regulation of blood coagulation / regulation of gene expression / regulation of peptidyl-tyrosine phosphorylation / regulation of platelet activation / regulation of protein-containing complex assembly
Components
blood microparticle / cell surface / collagen-containing extracellular matrix / endolysosome / extracellular exosome / extracellular region / plasma membrane / platelet alpha granule lumen
General Function
Plasma glycoprotein that binds a number of ligands such as heme, heparin, heparan sulfate, thrombospondin, plasminogen, and divalent metal ions. Binds heparin and heparin/glycosaminoglycans in a zinc-dependent manner. Binds heparan sulfate on the surface of liver, lung, kidney and heart endothelial cells. Binds to N-sulfated polysaccharide chains on the surface of liver endothelial cells. Inhibits rosette formation. Acts as an adapter protein and is implicated in regulating many processes such as immune complex and pathogen clearance, cell chemotaxis, cell adhesion, angiogenesis, coagulation and fibrinolysis. Mediates clearance of necrotic cells through enhancing the phagocytosis of necrotic cells in a heparan sulfate-dependent pathway. This process can be regulated by the presence of certain HRG ligands such as heparin and zinc ions. Binds to IgG subclasses of immunoglobins containing kappa and lambda light chains with different affinities regulating their clearance and inhibiting the formation of insoluble immune complexes. Tethers plasminogen to the cell surface. Binds T-cells and alters the cell morphology. Modulates angiogenesis by blocking the CD6-mediated antiangiongenic effect of thrombospondins, THBS1 and THBS2. Acts as a regulator of the vascular endothelial growth factor (VEGF) signaling pathway; inhibits endothelial cell motility by reducing VEGF-induced complex formation between PXN/paxillin and ILK/integrin-linked protein kinase and by promoting inhibition of VEGF-induced tyrosine phosphorylation of focal adhesion kinases and alpha-actinins in endothelial cells. Also plays a role in the regulation of tumor angiogenesis and tumor immune surveillance. Normalizes tumor vessels and promotes antitumor immunity by polarizing tumor-associated macrophages, leading to decreased tumor growth and metastasis.
Specific Function
Cysteine-type endopeptidase inhibitor activity
Pfam Domain Function
Transmembrane Regions
Not Available
Cellular Location
Secreted
Gene sequence
>lcl|BSEQ0052384|Histidine-rich glycoprotein (HRG)
ATGAAGGCACTCATTGCAGCACTGCTTTTGATCACATTGCAGTATTCGTGTGCCGTGAGT
CCCACTGACTGCAGTGCTGTTGAGCCGGAGGCTGAGAAAGCTCTAGACCTGATCAATAAA
AGGCGACGGGATGGCTACCTTTTCCAATTGCTGCGGATTGCTGATGCCCACTTGGACAGA
GTGGAAAATACAACTGTATATTACTTAGTCTTAGATGTGCAAGAATCGGACTGTTCGGTC
CTATCCAGGAAATACTGGAATGACTGTGAGCCACCTGATTCCAGACGTCCATCTGAAATA
GTGATCGGACAATGTAAGGTAATAGCTACAAGACATTCCCATGAATCTCAGGACCTCAGA
GTGATTGACTTTAACTGCACCACAAGTTCTGTCTCTTCAGCACTGGCCAATACCAAAGAT
AGTCCGGTCCTCATAGATTTCTTTGAGGATACTGAGCGCTACAGAAAACAAGCCAACAAA
GCCCTTGAGAAGTACAAAGAGGAGAATGATGACTTTGCCTCTTTCAGAGTGGACCGAATC
GAGAGAGTTGCAAGAGTGAGAGGAGGGGAAGGAACTGGTTACTTCGTGGACTTCTCTGTG
CGGAACTGCCCCAGACACCATTTCCCCAGACACCCCAATGTCTTTGGATTCTGCAGAGCA
GATTTGTTCTATGATGTAGAAGCCTTGGACTTGGAAAGCCCGAAAAACCTTGTCATAAAC
TGTGAAGTCTTCGACCCTCAGGAACATGAGAACATCAATGGTGTACCGCCTCATTTGGGA
CATCCCTTCCACTGGGGTGGGCATGAGCGTTCTTCTACCACCAAGCCTCCATTCAAGCCC
CATGGATCTAGAGATCATCATCATCCCCACAAGCCACACGAACATGGACCCCCACCTCCT
CCAGATGAAAGAGATCACTCACATGGACCCCCACTTCCACAAGGCCCTCCTCCACTATTG
CCCATGTCCTGCTCAAGTTGTCAACATGCCACTTTTGGCACAAATGGGGCCCAAAGACAT
TCTCATAATAATAATTCCAGTGACCTCCATCCCCATAAGCATCATTCCCATGAACAGCAT
CCCCACGGACACCATCCCCATGCACACCATCCTCATGAACATGATACCCATAGACAGCAT
CCCCATGGACACCACCCCCATGGACACCATCCTCATGGACACCACCCCCATGGACACCAT
CCCCATGGACACCATCCCCACTGCCATGATTTCCAAGACTATGGACCTTGTGACCCACCA
CCCCATAACCAAGGTCACTGTTGCCATGGCCACGGCCCACCACCTGGGCACTTAAGAAGG
CGAGGCCCAGGTAAAGGACCCCGTCCCTTCCATTGCAGACAAATTGGATCTGTGTACCGA
CTCCCTCCTCTAAGAAAAGGTGAGGTGCTGCCACTTCCTGAGGCCAATTTTCCCAGCTTC
CCATTGCCGCACCACAAACATCCTCTAAAGCCAGACAATCAGCCCTTTCCTCAATCAGTC
TCTGAATCATGTCCAGGGAAGTTCAAGAGTGGGTTTCCACAAGTTTCCATGTTTTTTACA
CATACATTTCCAAAATAA
Chromosome Location
3
Locus
3q27.3
External Identifiers
ResourceLink
UniProtKB IDP04196
UniProtKB Entry NameHRG_HUMAN
HGNC IDHGNC:5181
General References
  1. 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. 1986 Apr 22;25(8):2220-5. doi: 10.1021/bi00356a055. [Article]
  2. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. [Article]
  3. 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. 1994 Jan 1;19(1):195-7. doi: 10.1006/geno.1994.1046. [Article]
  4. 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. 1992 Sep-Oct;13(9-10):707-14. doi: 10.1002/elps.11501301150. [Article]
  5. Morgan WT: Human serum histidine-rich glycoprotein. I. Interactions with heme, metal ions and organic ligands. Biochim Biophys Acta. 1978 Aug 21;535(2):319-33. doi: 10.1016/0005-2795(78)90098-3. [Article]
  6. 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. J Biol Chem. 1999 Oct 15;274(42):29633-40. doi: 10.1074/jbc.274.42.29633. [Article]
  7. Simantov R, Febbraio M, Crombie R, Asch AS, Nachman RL, Silverstein RL: Histidine-rich glycoprotein inhibits the antiangiogenic effect of thrombospondin-1. J Clin Invest. 2001 Jan;107(1):45-52. [Article]
  8. Juarez JC, Guan X, Shipulina NV, Plunkett ML, Parry GC, Shaw DE, Zhang JC, Rabbani SA, McCrae KR, Mazar AP, Morgan WT, Donate F: Histidine-proline-rich glycoprotein has potent antiangiogenic activity mediated through the histidine-proline-rich domain. Cancer Res. 2002 Sep 15;62(18):5344-50. [Article]
  9. Olsson AK, Larsson H, Dixelius J, Johansson I, Lee C, Oellig C, Bjork I, Claesson-Welsh L: A fragment of histidine-rich glycoprotein is a potent inhibitor of tumor vascularization. Cancer Res. 2004 Jan 15;64(2):599-605. doi: 10.1158/0008-5472.can-03-1941. [Article]
  10. Donate F, Juarez JC, Guan X, Shipulina NV, Plunkett ML, Tel-Tsur Z, Shaw DE, Morgan WT, Mazar AP: Peptides derived from the histidine-proline domain of the histidine-proline-rich glycoprotein bind to tropomyosin and have antiangiogenic and antitumor activities. Cancer Res. 2004 Aug 15;64(16):5812-7. doi: 10.1158/0008-5472.CAN-04-0440. [Article]
  11. Jones AL, Hulett MD, Parish CR: Histidine-rich glycoprotein binds to cell-surface heparan sulfate via its N-terminal domain following Zn2+ chelation. J Biol Chem. 2004 Jul 16;279(29):30114-22. doi: 10.1074/jbc.M401996200. Epub 2004 May 11. [Article]
  12. 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. J Biol Chem. 2004 Sep 10;279(37):38267-76. doi: 10.1074/jbc.M406027200. Epub 2004 Jun 25. [Article]
  13. Liu T, Qian WJ, Gritsenko MA, Camp DG 2nd, Monroe ME, Moore RJ, Smith RD: Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry. J Proteome Res. 2005 Nov-Dec;4(6):2070-80. [Article]
  14. Dixelius J, Olsson AK, Thulin A, Lee C, Johansson I, Claesson-Welsh L: Minimal active domain and mechanism of action of the angiogenesis inhibitor histidine-rich glycoprotein. Cancer Res. 2006 Feb 15;66(4):2089-97. [Article]
  15. Vanwildemeersch M, Olsson AK, 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 Apr 14;281(15):10298-304. doi: 10.1074/jbc.M508483200. Epub 2006 Jan 25. [Article]
  16. Poon IK, Olsson AK, Hulett MD, Parish CR: Regulation of histidine-rich glycoprotein (HRG) function via plasmin-mediated proteolytic cleavage. Biochem J. 2009 Oct 23;424(1):27-37. doi: 10.1042/BJ20090794. [Article]
  17. 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 May;1788(5):1099-107. doi: 10.1016/j.bbamem.2009.03.005. Epub 2009 Mar 12. [Article]
  18. 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. doi: 10.1016/j.cellimm.2009.05.001. Epub 2009 May 13. [Article]
  19. Jancso A, Kolozsi A, Gyurcsik B, Nagy NV, Gajda T: Probing the Cu(2+) and Zn(2+) binding affinity of histidine-rich glycoprotein. J Inorg Biochem. 2009 Dec;103(12):1634-43. doi: 10.1016/j.jinorgbio.2009.09.002. Epub 2009 Sep 6. [Article]
  20. Chen R, Jiang X, Sun D, Han G, Wang F, Ye M, Wang L, Zou H: Glycoproteomics analysis of human liver tissue by combination of multiple enzyme digestion and hydrazide chemistry. J Proteome Res. 2009 Feb;8(2):651-61. doi: 10.1021/pr8008012. [Article]
  21. Thulin A, Ringvall M, Dimberg A, Karehed K, Vaisanen T, Vaisanen MR, Hamad O, Wang J, Bjerkvig R, Nilsson B, Pihlajaniemi T, Akerud H, Pietras K, Jahnen-Dechent W, Siegbahn A, Olsson AK: Activated platelets provide a functional microenvironment for the antiangiogenic fragment of histidine-rich glycoprotein. Mol Cancer Res. 2009 Nov;7(11):1792-802. doi: 10.1158/1541-7786.MCR-09-0094. Epub 2009 Nov 10. [Article]
  22. Poon IK, Yee DY, Jones AL, Wood RJ, Davis DS, Freeman C, Parish CR, Hulett MD: Histidine-rich glycoprotein binds heparanase and regulates its enzymatic activity and cell surface interactions. Int J Biochem Cell Biol. 2010 Sep;42(9):1507-16. doi: 10.1016/j.biocel.2010.05.008. Epub 2010 May 31. [Article]
  23. Poon IK, Parish CR, Hulett MD: Histidine-rich glycoprotein functions cooperatively with cell surface heparan sulfate on phagocytes to promote necrotic cell uptake. J Leukoc Biol. 2010 Sep;88(3):559-69. doi: 10.1189/jlb.0210087. Epub 2010 Jun 23. [Article]
  24. MacQuarrie JL, Stafford AR, Yau JW, Leslie BA, Vu TT, Fredenburgh JC, Weitz JI: Histidine-rich glycoprotein binds factor XIIa with high affinity and inhibits contact-initiated coagulation. Blood. 2011 Apr 14;117(15):4134-41. doi: 10.1182/blood-2010-07-290551. Epub 2011 Feb 8. [Article]
  25. 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, Akerud P, De Mol M, Salomaki 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. 2011 Jan 18;19(1):31-44. doi: 10.1016/j.ccr.2010.11.009. Epub 2011 Jan 6. [Article]
  26. Bian Y, Song C, Cheng K, Dong M, Wang F, Huang J, Sun D, Wang L, Ye M, Zou H: An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome. J Proteomics. 2014 Jan 16;96:253-62. doi: 10.1016/j.jprot.2013.11.014. Epub 2013 Nov 22. [Article]
  27. 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. 1998 Jan 1;91(1):128-33. [Article]
  28. Shigekiyo T, Yoshida H, Kanagawa Y, Satoh K, Wakabayashi S, Matsumoto T, Koide T: Histidine-rich glycoprotein (HRG) Tokushima 2: novel HRG deficiency, molecular and cellular characterization. Thromb Haemost. 2000 Oct;84(4):675-9. [Article]

Drug Relations

Drug Relations
DrugBank IDNameDrug groupPharmacological action?ActionsDetails
DB14533Zinc chlorideapproved, investigationalunknowncofactorDetails
DB14548Zinc sulfate, unspecified formapproved, experimentalunknowncofactorDetails