HRG_HUMAN
ID HRG_HUMAN Reviewed; 525 AA.
AC P04196; B9EK35; D3DNU7;
DT 20-MAR-1987, integrated into UniProtKB/Swiss-Prot.
DT 20-MAR-1987, sequence version 1.
DT 03-AUG-2022, entry version 211.
DE RecName: Full=Histidine-rich glycoprotein;
DE AltName: Full=Histidine-proline-rich glycoprotein;
DE Short=HPRG;
DE Flags: Precursor;
GN Name=HRG;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Liver;
RX PubMed=3011081; DOI=10.1021/bi00356a055;
RA Koide T., Foster D.C., Yoshitake S., Davie E.W.;
RT "Amino acid sequence of human histidine-rich glycoprotein derived from the
RT nucleotide sequence of its cDNA.";
RL Biochemistry 25:2220-2225(1986).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Wakabayashi S., Takahashi K., Tokunaga F., Koide T.;
RL Submitted (JUL-1997) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Testis;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 214-247.
RX PubMed=8188234; DOI=10.1006/geno.1994.1046;
RA Hennis B.C., Frants R.R., Bakker E., Vossen R.H., van der Poort E.W.,
RA Blonden L.A., Cox S., Khan P.M., Spurr N.K., Kluft C.;
RT "Evidence for the absence of intron H of the histidine-rich glycoprotein
RT (HRG) gene: genetic mapping and in situ localization of HRG to chromosome
RT 3q28-q29.";
RL Genomics 19:195-197(1994).
RN [6]
RP PROTEIN SEQUENCE OF 19-27.
RC TISSUE=Plasma;
RX PubMed=1459097; DOI=10.1002/elps.11501301150;
RA Hughes G.J., Frutiger S., Paquet N., Ravier F., Pasquali C., Sanchez J.-C.,
RA James R., Tissot J.-D., Bjellqvist B., Hochstrasser D.F.;
RT "Plasma protein map: an update by microsequencing.";
RL Electrophoresis 13:707-714(1992).
RN [7]
RP HEME- AND METAL-BINDING.
RX PubMed=678554; DOI=10.1016/0005-2795(78)90098-3;
RA Morgan W.T.;
RT "Human serum histidine-rich glycoprotein. I. Interactions with heme, metal
RT ions and organic ligands.";
RL Biochim. Biophys. Acta 535:319-333(1978).
RN [8]
RP INTERACTION WITH IMMUNOGLOBULIN G SUBCLASSES.
RX PubMed=10514432; DOI=10.1074/jbc.274.42.29633;
RA Gorgani N.N., Parish C.R., Altin J.G.;
RT "Differential binding of histidine-rich glycoprotein (HRG) to human IgG
RT subclasses and IgG molecules containing kappa and lambda light chains.";
RL J. Biol. Chem. 274:29633-29640(1999).
RN [9]
RP INTERACTION WITH THBS1, AND FUNCTION.
RX PubMed=11134179; DOI=10.1172/jci9061;
RA Simantov R., Febbraio M., Crombie R., Asch A.S., Nachman R.L.,
RA Silverstein R.L.;
RT "Histidine-rich glycoprotein inhibits the antiangiogenic effect of
RT thrombospondin-1.";
RL J. Clin. Invest. 107:45-52(2001).
RN [10]
RP FUNCTION OF HIS/PRO-RICH DOMAIN.
RX PubMed=12235005;
RA Juarez J.C., Guan X., Shipulina N.V., Plunkett M.L., Parry G.C., Shaw D.E.,
RA Zhang J.C., Rabbani S.A., McCrae K.R., Mazar A.P., Morgan W.T., Donate F.;
RT "Histidine-proline-rich glycoprotein has potent antiangiogenic activity
RT mediated through the histidine-proline-rich domain.";
RL Cancer Res. 62:5344-5350(2002).
RN [11]
RP FUNCTION AS A NEGATIVE REGULATOR OF ANGIOGENESIS, PROTEOLYTIC PROCESSING,
RP AND TISSUE SPECIFICITY.
RX PubMed=14744774; DOI=10.1158/0008-5472.can-03-1941;
RA Olsson A.K., Larsson H., Dixelius J., Johansson I., Lee C., Oellig C.,
RA Bjork I., Claesson-Welsh L.;
RT "A fragment of histidine-rich glycoprotein is a potent inhibitor of tumor
RT vascularization.";
RL Cancer Res. 64:599-605(2004).
RN [12]
RP FUNCTION OF THE HIS/PRO-RICH REGION, AND INTERACTION WITH TPM1.
RX PubMed=15313924; DOI=10.1158/0008-5472.can-04-0440;
RA Donate F., Juarez J.C., Guan X., Shipulina N.V., Plunkett M.L.,
RA Tel-Tsur Z., Shaw D.E., Morgan W.T., Mazar A.P.;
RT "Peptides derived from the histidine-proline domain of the histidine-
RT proline-rich glycoprotein bind to tropomyosin and have antiangiogenic and
RT antitumor activities.";
RL Cancer Res. 64:5812-5817(2004).
RN [13]
RP HEPARAN SULFATE-BINDING, AND METAL-BINDING.
RX PubMed=15138272; DOI=10.1074/jbc.m401996200;
RA Jones A.L., Hulett M.D., Parish C.R.;
RT "Histidine-rich glycoprotein binds to cell-surface heparan sulfate via its
RT N-terminal domain following Zn2+ chelation.";
RL J. Biol. Chem. 279:30114-30122(2004).
RN [14]
RP INTERACTION WITH PLG, AND FUNCTION.
RX PubMed=15220341; DOI=10.1074/jbc.m406027200;
RA Jones A.L., Hulett M.D., Altin J.G., Hogg P., Parish C.R.;
RT "Plasminogen is tethered with high affinity to the cell surface by the
RT plasma protein, histidine-rich glycoprotein.";
RL J. Biol. Chem. 279:38267-38276(2004).
RN [15]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-63; ASN-125 AND ASN-344.
RC TISSUE=Plasma;
RX PubMed=16335952; DOI=10.1021/pr0502065;
RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E., Moore R.J.,
RA Smith R.D.;
RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction,
RT hydrazide chemistry, and mass spectrometry.";
RL J. Proteome Res. 4:2070-2080(2005).
RN [16]
RP FUNCTION OF THE HIS/PRO-RICH REGION AS A NEGATIVE REGULATOR OF
RP ANGIOGENESIS.
RX PubMed=16489009; DOI=10.1158/0008-5472.can-05-2217;
RA Dixelius J., Olsson A.K., Thulin A., Lee C., Johansson I.,
RA Claesson-Welsh L.;
RT "Minimal active domain and mechanism of action of the angiogenesis
RT inhibitor histidine-rich glycoprotein.";
RL Cancer Res. 66:2089-2097(2006).
RN [17]
RP FUNCTION OF THE HIS/PRO-RICH REGION AS A NEGATIVE REGULATOR OF
RP ANGIOGENESIS, COFACTOR, ZINC-BINDING, AND HEPARIN- AND HEPARAN
RP SULFATE-BINDING.
RX PubMed=16436387; DOI=10.1074/jbc.m508483200;
RA Vanwildemeersch M., Olsson A.K., Gottfridsson E., Claesson-Welsh L.,
RA Lindahl U., Spillmann D.;
RT "The anti-angiogenic His/Pro-rich fragment of histidine-rich glycoprotein
RT binds to endothelial cell heparan sulfate in a Zn2+-dependent manner.";
RL J. Biol. Chem. 281:10298-10304(2006).
RN [18]
RP PROTEOLYTIC PROCESSING, HEPARAN SULFATE-BINDING, INTERACTION WITH PLG, AND
RP FUNCTION.
RX PubMed=19712047; DOI=10.1042/bj20090794;
RA Poon I.K., Olsson A.K., Hulett M.D., Parish C.R.;
RT "Regulation of histidine-rich glycoprotein (HRG) function via plasmin-
RT mediated proteolytic cleavage.";
RL Biochem. J. 424:27-37(2009).
RN [19]
RP INTERACTION WITH ATP5F1A, FUNCTION, GLYCOSYLATION AT ASN-63, AND
RP IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=19285951; DOI=10.1016/j.bbamem.2009.03.005;
RA Ohta T., Ikemoto Y., Usami A., Koide T., Wakabayashi S.;
RT "High affinity interaction between histidine-rich glycoprotein and the cell
RT surface type ATP synthase on T-cells.";
RL Biochim. Biophys. Acta 1788:1099-1107(2009).
RN [20]
RP FUNCTION.
RX PubMed=19535045; DOI=10.1016/j.cellimm.2009.05.001;
RA Ohta T., Ikemoto Y., Saeki K., Koide T., Wakabayashi S.;
RT "Histidine-rich glycoprotein and concanavalin A synergistically stimulate
RT the phosphatidylinositol 3-kinase-independent signaling pathway in
RT leukocytes leading to increased cell adhesion and changes in cell
RT morphology.";
RL Cell. Immunol. 259:5-12(2009).
RN [21]
RP METAL-BINDING.
RX PubMed=19786305; DOI=10.1016/j.jinorgbio.2009.09.002;
RA Jancso A., Kolozsi A., Gyurcsik B., Nagy N.V., Gajda T.;
RT "Probing the Cu(2+) and Zn(2+) binding affinity of histidine-rich
RT glycoprotein.";
RL J. Inorg. Biochem. 103:1634-1643(2009).
RN [22]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-125.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of multiple
RT enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [23]
RP FUNCTION, PROTEOLYTIC PROCESSING, IDENTIFICATION BY MASS SPECTROMETRY, AND
RP TISSUE SPECIFICITY.
RX PubMed=19903770; DOI=10.1158/1541-7786.mcr-09-0094;
RA Thulin A., Ringvall M., Dimberg A., Karehed K., Vaisanen T., Vaisanen M.R.,
RA Hamad O., Wang J., Bjerkvig R., Nilsson B., Pihlajaniemi T., Akerud H.,
RA Pietras K., Jahnen-Dechent W., Siegbahn A., Olsson A.K.;
RT "Activated platelets provide a functional microenvironment for the
RT antiangiogenic fragment of histidine-rich glycoprotein.";
RL Mol. Cancer Res. 7:1792-1802(2009).
RN [24]
RP INTERACTION WITH HPSE.
RX PubMed=20561914; DOI=10.1016/j.biocel.2010.05.008;
RA Poon I.K., Yee D.Y., Jones A.L., Wood R.J., Davis D.S., Freeman C.,
RA Parish C.R., Hulett M.D.;
RT "Histidine-rich glycoprotein binds heparanase and regulates its enzymatic
RT activity and cell surface interactions.";
RL Int. J. Biochem. Cell Biol. 42:1507-1516(2010).
RN [25]
RP FUNCTION, AND HEPARIN- AND HEPARAN SULFATE-BINDING.
RX PubMed=20573803; DOI=10.1189/jlb.0210087;
RA Poon I.K., Parish C.R., Hulett M.D.;
RT "Histidine-rich glycoprotein functions cooperatively with cell surface
RT heparan sulfate on phagocytes to promote necrotic cell uptake.";
RL J. Leukoc. Biol. 88:559-569(2010).
RN [26]
RP INTERACTION WITH F12, IDENTIFICATION BY MASS SPECTROMETRY, AND FUNCTION.
RX PubMed=21304106; DOI=10.1182/blood-2010-07-290551;
RA Macquarrie J.L., Stafford A.R., Yau J.W., Leslie B.A., Vu T.T.,
RA Fredenburgh J.C., Weitz J.I.;
RT "Histidine-rich glycoprotein binds factor XIIa with high affinity and
RT inhibits contact-initiated coagulation.";
RL Blood 117:4134-4141(2011).
RN [27]
RP FUNCTION AS A TUMOR SUPPRESSOR, SUBCELLULAR LOCATION, AND TISSUE
RP SPECIFICITY.
RX PubMed=21215706; DOI=10.1016/j.ccr.2010.11.009;
RA Rolny C., Mazzone M., Tugues S., Laoui D., Johansson I., Coulon C.,
RA Squadrito M.L., Segura I., Li X., Knevels E., Costa S., Vinckier S.,
RA Dresselaer T., Akerud P., De Mol M., Salomaki H., Phillipson M., Wyns S.,
RA Larsson E., Buysschaert I., Botling J., Himmelreich U.,
RA Van Ginderachter J.A., De Palma M., Dewerchin M., Claesson-Welsh L.,
RA Carmeliet P.;
RT "HRG inhibits tumor growth and metastasis by inducing macrophage
RT polarization and vessel normalization through downregulation of PlGF.";
RL Cancer Cell 19:31-44(2011).
RN [28]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [29]
RP VARIANT THPH11 GLU-103, AND CHARACTERIZATION OF VARIANT THPH11 GLU-103.
RX PubMed=9414276;
RA Shigekiyo T., Yoshida H., Matsumoto K., Azuma H., Wakabayashi S., Saito S.,
RA Fujikawa K., Koide T.;
RT "HRG Tokushima: molecular and cellular characterization of histidine-rich
RT glycoprotein (HRG) deficiency.";
RL Blood 91:128-133(1998).
RN [30]
RP VARIANT THPH11 ARG-241, AND CHARACTERIZATION OF VARIANT THPH11 ARG-241.
RX PubMed=11057869;
RA Shigekiyo T., Yoshida H., Kanagawa Y., Satoh K., Wakabayashi S.,
RA Matsumoto T., Koide T.;
RT "Histidine-rich glycoprotein (HRG) Tokushima 2: novel HRG deficiency,
RT molecular and cellular characterization.";
RL Thromb. Haemost. 84:675-679(2000).
CC -!- FUNCTION: Plasma glycoprotein that binds a number of ligands such as
CC heme, heparin, heparan sulfate, thrombospondin, plasminogen, and
CC divalent metal ions. Binds heparin and heparin/glycosaminoglycans in a
CC zinc-dependent manner. Binds heparan sulfate on the surface of liver,
CC lung, kidney and heart endothelial cells. Binds to N-sulfated
CC polysaccharide chains on the surface of liver endothelial cells.
CC Inhibits rosette formation. Acts as an adapter protein and is
CC implicated in regulating many processes such as immune complex and
CC pathogen clearance, cell chemotaxis, cell adhesion, angiogenesis,
CC coagulation and fibrinolysis. Mediates clearance of necrotic cells
CC through enhancing the phagocytosis of necrotic cells in a heparan
CC sulfate-dependent pathway. This process can be regulated by the
CC presence of certain HRG ligands such as heparin and zinc ions. Binds to
CC IgG subclasses of immunoglobins containing kappa and lambda light
CC chains with different affinities regulating their clearance and
CC inhibiting the formation of insoluble immune complexes. Tethers
CC plasminogen to the cell surface. Binds T-cells and alters the cell
CC morphology. Modulates angiogenesis by blocking the CD6-mediated
CC antiangiongenic effect of thrombospondins, THBS1 and THBS2. Acts as a
CC regulator of the vascular endothelial growth factor (VEGF) signaling
CC pathway; inhibits endothelial cell motility by reducing VEGF-induced
CC complex formation between PXN/paxillin and ILK/integrin-linked protein
CC kinase and by promoting inhibition of VEGF-induced tyrosine
CC phosphorylation of focal adhesion kinases and alpha-actinins in
CC endothelial cells. Also plays a role in the regulation of tumor
CC angiogenesis and tumor immune surveillance. Normalizes tumor vessels
CC and promotes antitumor immunity by polarizing tumor-associated
CC macrophages, leading to decreased tumor growth and metastasis.
CC {ECO:0000269|PubMed:11134179, ECO:0000269|PubMed:12235005,
CC ECO:0000269|PubMed:14744774, ECO:0000269|PubMed:15220341,
CC ECO:0000269|PubMed:15313924, ECO:0000269|PubMed:16436387,
CC ECO:0000269|PubMed:16489009, ECO:0000269|PubMed:19285951,
CC ECO:0000269|PubMed:19535045, ECO:0000269|PubMed:19712047,
CC ECO:0000269|PubMed:19903770, ECO:0000269|PubMed:20573803,
CC ECO:0000269|PubMed:21215706, ECO:0000269|PubMed:21304106}.
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000269|PubMed:16436387};
CC -!- SUBUNIT: Interacts (via the HRR domain) with TPM1; the interaction
CC appears to contribute to the antiangiogenic properties of the HRR
CC domain. Interacts with THBS2; the interaction blocks the antiangiogenic
CC effect of THBS2 with CD36 (By similarity). Interacts with THBS1 (via
CC the TSP type I repeats); the interaction blocks the antiangiogenic
CC effect of THBS1 with CD3. Interacts with PLG (via its Kringle domains);
CC the interaction tethers PLG to the cell surface and enhances its
CC activation. Interacts with HPSE; the interaction is enhanced at acidic
CC pH, partially inhibits binding of HPSE to cell surface receptors and
CC modulates its enzymatic activity. Interacts (via the HRR domain) with
CC TMP1; the interaction partially mediates the antiangiogenic properties
CC of HRG. Interacts with kappa and lambda light chains of IgG molecules.
CC Interacts with ATP5F1A; the interaction occurs on the surface of T-
CC cells and alters their cell morphology in concert with CONA. Binds IgG
CC molecules containing kappa and lambda light chains and inhibits the
CC formation of insoluble immunoglobulin complexes. Interacts with F12;
CC the interaction, which is enhanced in the presence of zinc ions and
CC inhibited by heparin-binding to HRG, inhibits factor XII autoactivation
CC and contact-initiated coagulation. {ECO:0000250,
CC ECO:0000269|PubMed:10514432, ECO:0000269|PubMed:11134179,
CC ECO:0000269|PubMed:15220341, ECO:0000269|PubMed:15313924,
CC ECO:0000269|PubMed:19285951, ECO:0000269|PubMed:19712047,
CC ECO:0000269|PubMed:20561914, ECO:0000269|PubMed:21304106}.
CC -!- INTERACTION:
CC P04196; A8MQ03: CYSRT1; NbExp=3; IntAct=EBI-3915012, EBI-3867333;
CC P04196; Q96PM5: RCHY1; NbExp=3; IntAct=EBI-3915012, EBI-947779;
CC P04196; O76081-6: RGS20; NbExp=3; IntAct=EBI-3915012, EBI-10178530;
CC P04196; Q99XU0: SPy_2034; Xeno; NbExp=4; IntAct=EBI-3915012, EBI-8852705;
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:21215706}.
CC -!- TISSUE SPECIFICITY: Expressed in macrophages and in malignant cells.
CC Expressed by the liver and secreted in plasma (at protein level).
CC {ECO:0000269|PubMed:14744774, ECO:0000269|PubMed:19903770,
CC ECO:0000269|PubMed:21215706}.
CC -!- DOMAIN: The His/Pro-rich (HRR) region contains approximately 12 tandem
CC internal repeats of the 5-residue G[H/P][H/P]PH consensus sequence. HRR
CC binds heparan sulfate and possesses antiangiogenic, antibacterial and
CC antifungal properties through binding Candida cells, and preferentially
CC lysing the ergosterol-containing liposomes at low pH. The tandem
CC repeats also bind divalent metal ions and heme.
CC -!- DOMAIN: The cystatin domains can also bind heparan sulfate. Binding is
CC enhanced in the presence of zinc ions.
CC -!- PTM: Proteolytic cleavage produces several HRG fragments which are
CC mostly disulfide-linked and, therefore, not released. Cleavage by
CC plasmin is inhibited in the presence of heparin, zinc ions or in an
CC acidic environment. Cleavage reduces binding of HRG to heparan sulfate,
CC but enhances the ability of HRG to bind and tether plasminogen to the
CC cell surface. On platelet activation, releases a 33 kDa antiangiogenic
CC peptide which encompasses the HRR. Also cleaved in the C-terminal by
CC plasmin. {ECO:0000269|PubMed:14744774, ECO:0000269|PubMed:19712047,
CC ECO:0000269|PubMed:19903770}.
CC -!- PTM: N-glycosylated. {ECO:0000269|PubMed:16335952,
CC ECO:0000269|PubMed:19159218, ECO:0000269|PubMed:19285951}.
CC -!- DISEASE: Thrombophilia due to histidine-rich glycoprotein deficiency
CC (THPH11) [MIM:613116]: A hemostatic disorder characterized by a
CC tendency to thrombosis. {ECO:0000269|PubMed:11057869,
CC ECO:0000269|PubMed:9414276}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; M13149; AAA52694.1; -; mRNA.
DR EMBL; AB005803; BAA21613.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW78183.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW78184.1; -; Genomic_DNA.
DR EMBL; BC069574; AAH69574.1; -; mRNA.
DR EMBL; BC150591; AAI50592.1; -; mRNA.
DR EMBL; Z17218; CAA78925.1; -; Genomic_DNA.
DR CCDS; CCDS3280.1; -.
DR PIR; A01287; KGHUGH.
DR RefSeq; NP_000403.1; NM_000412.4.
DR AlphaFoldDB; P04196; -.
DR SMR; P04196; -.
DR BioGRID; 109509; 56.
DR DIP; DIP-47264N; -.
DR IntAct; P04196; 18.
DR MINT; P04196; -.
DR STRING; 9606.ENSP00000232003; -.
DR DrugBank; DB14533; Zinc chloride.
DR DrugBank; DB14548; Zinc sulfate, unspecified form.
DR MEROPS; I25.022; -.
DR MEROPS; I25.025; -.
DR GlyConnect; 805; 26 N-Linked glycans (3 sites).
DR GlyGen; P04196; 7 sites, 43 N-linked glycans (4 sites), 3 O-linked glycans (3 sites).
DR iPTMnet; P04196; -.
DR PhosphoSitePlus; P04196; -.
DR BioMuta; HRG; -.
DR DMDM; 123523; -.
DR SWISS-2DPAGE; P04196; -.
DR jPOST; P04196; -.
DR MassIVE; P04196; -.
DR PaxDb; P04196; -.
DR PeptideAtlas; P04196; -.
DR PRIDE; P04196; -.
DR ProteomicsDB; 51675; -.
DR Antibodypedia; 33854; 340 antibodies from 31 providers.
DR DNASU; 3273; -.
DR Ensembl; ENST00000232003.5; ENSP00000232003.4; ENSG00000113905.5.
DR GeneID; 3273; -.
DR KEGG; hsa:3273; -.
DR MANE-Select; ENST00000232003.5; ENSP00000232003.4; NM_000412.5; NP_000403.1.
DR UCSC; uc003fqq.5; human.
DR CTD; 3273; -.
DR DisGeNET; 3273; -.
DR GeneCards; HRG; -.
DR HGNC; HGNC:5181; HRG.
DR HPA; ENSG00000113905; Tissue enriched (liver).
DR MalaCards; HRG; -.
DR MIM; 142640; gene.
DR MIM; 613116; phenotype.
DR neXtProt; NX_P04196; -.
DR OpenTargets; ENSG00000113905; -.
DR Orphanet; 217467; Hereditary thrombophilia due to congenital histidine-rich (poly-L) glycoprotein deficiency.
DR PharmGKB; PA29455; -.
DR VEuPathDB; HostDB:ENSG00000113905; -.
DR eggNOG; ENOG502S50D; Eukaryota.
DR GeneTree; ENSGT00950000182930; -.
DR HOGENOM; CLU_575637_0_0_1; -.
DR InParanoid; P04196; -.
DR OMA; QESDCSV; -.
DR OrthoDB; 715844at2759; -.
DR PhylomeDB; P04196; -.
DR TreeFam; TF333729; -.
DR PathwayCommons; P04196; -.
DR Reactome; R-HSA-114608; Platelet degranulation.
DR Reactome; R-HSA-75205; Dissolution of Fibrin Clot.
DR SignaLink; P04196; -.
DR BioGRID-ORCS; 3273; 6 hits in 1065 CRISPR screens.
DR ChiTaRS; HRG; human.
DR GeneWiki; HRG_(gene); -.
DR GenomeRNAi; 3273; -.
DR Pharos; P04196; Tbio.
DR PRO; PR:P04196; -.
DR Proteomes; UP000005640; Chromosome 3.
DR RNAct; P04196; protein.
DR Bgee; ENSG00000113905; Expressed in liver and 119 other tissues.
DR Genevisible; P04196; HS.
DR GO; GO:0072562; C:blood microparticle; HDA:UniProtKB.
DR GO; GO:0009986; C:cell surface; IDA:UniProtKB.
DR GO; GO:0062023; C:collagen-containing extracellular matrix; HDA:BHF-UCL.
DR GO; GO:0036019; C:endolysosome; IBA:GO_Central.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0005576; C:extracellular region; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0031093; C:platelet alpha granule lumen; TAS:Reactome.
DR GO; GO:0004869; F:cysteine-type endopeptidase inhibitor activity; IEA:InterPro.
DR GO; GO:0004866; F:endopeptidase inhibitor activity; IBA:GO_Central.
DR GO; GO:0020037; F:heme binding; IDA:UniProtKB.
DR GO; GO:0043395; F:heparan sulfate proteoglycan binding; IDA:UniProtKB.
DR GO; GO:0008201; F:heparin binding; IDA:UniProtKB.
DR GO; GO:0019865; F:immunoglobulin binding; IDA:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IDA:UniProtKB.
DR GO; GO:0004867; F:serine-type endopeptidase inhibitor activity; IBA:GO_Central.
DR GO; GO:0005102; F:signaling receptor binding; IDA:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB.
DR GO; GO:0001525; P:angiogenesis; IEA:UniProtKB-KW.
DR GO; GO:0061844; P:antimicrobial humoral immune response mediated by antimicrobial peptide; IDA:UniProtKB.
DR GO; GO:0006935; P:chemotaxis; IEA:UniProtKB-KW.
DR GO; GO:0051838; P:cytolysis by host of symbiont cells; IDA:UniProtKB.
DR GO; GO:0050832; P:defense response to fungus; IDA:UniProtKB.
DR GO; GO:0042730; P:fibrinolysis; IEA:UniProtKB-KW.
DR GO; GO:0015886; P:heme transport; IBA:GO_Central.
DR GO; GO:0016525; P:negative regulation of angiogenesis; IDA:UniProtKB.
DR GO; GO:0043537; P:negative regulation of blood vessel endothelial cell migration; ISS:UniProtKB.
DR GO; GO:0007162; P:negative regulation of cell adhesion; IDA:UniProtKB.
DR GO; GO:0033629; P:negative regulation of cell adhesion mediated by integrin; IDA:UniProtKB.
DR GO; GO:0030308; P:negative regulation of cell growth; IDA:UniProtKB.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; IDA:UniProtKB.
DR GO; GO:0010951; P:negative regulation of endopeptidase activity; IBA:GO_Central.
DR GO; GO:2001027; P:negative regulation of endothelial cell chemotaxis; IDA:UniProtKB.
DR GO; GO:0051918; P:negative regulation of fibrinolysis; IBA:GO_Central.
DR GO; GO:0010593; P:negative regulation of lamellipodium assembly; IDA:UniProtKB.
DR GO; GO:1900747; P:negative regulation of vascular endothelial growth factor signaling pathway; IDA:UniProtKB.
DR GO; GO:0030168; P:platelet activation; IDA:UniProtKB.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IDA:UniProtKB.
DR GO; GO:2000504; P:positive regulation of blood vessel remodeling; IDA:UniProtKB.
DR GO; GO:0051894; P:positive regulation of focal adhesion assembly; IDA:UniProtKB.
DR GO; GO:0002839; P:positive regulation of immune response to tumor cell; IDA:UniProtKB.
DR GO; GO:0032956; P:regulation of actin cytoskeleton organization; IDA:UniProtKB.
DR GO; GO:0030193; P:regulation of blood coagulation; IDA:UniProtKB.
DR GO; GO:0010468; P:regulation of gene expression; IDA:UniProtKB.
DR GO; GO:0050730; P:regulation of peptidyl-tyrosine phosphorylation; IDA:UniProtKB.
DR GO; GO:0010543; P:regulation of platelet activation; ISS:UniProtKB.
DR GO; GO:0043254; P:regulation of protein-containing complex assembly; IDA:UniProtKB.
DR CDD; cd00042; CY; 1.
DR InterPro; IPR000010; Cystatin_dom.
DR InterPro; IPR046350; Cystatin_sf.
DR Pfam; PF00031; Cystatin; 1.
DR SMART; SM00043; CY; 2.
DR SUPFAM; SSF54403; SSF54403; 2.
PE 1: Evidence at protein level;
KW Angiogenesis; Blood coagulation; Chemotaxis;
KW Cleavage on pair of basic residues; Copper; Direct protein sequencing;
KW Disease variant; Disulfide bond; Fibrinolysis; Glycoprotein; Hemostasis;
KW Heparin-binding; Metal-binding; Reference proteome; Repeat; Secreted;
KW Signal; Thrombophilia; Zinc.
FT SIGNAL 1..18
FT /evidence="ECO:0000269|PubMed:1459097"
FT CHAIN 19..525
FT /note="Histidine-rich glycoprotein"
FT /id="PRO_0000006709"
FT DOMAIN 19..136
FT /note="Cystatin 1"
FT DOMAIN 137..254
FT /note="Cystatin 2"
FT REGION 41..84
FT /note="Interaction with ATP5F1A"
FT /evidence="ECO:0000269|PubMed:19285951"
FT REGION 252..407
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 348..382
FT /note="Necessary for endothelial cell focal adhesions and
FT anti-angiogenic activities"
FT COMPBIAS 292..309
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 324..344
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 355..405
FT /note="Basic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 439..440
FT /note="Cleavage; by plasmin"
FT /evidence="ECO:0000250"
FT CARBOHYD 63
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:16335952,
FT ECO:0000269|PubMed:19285951"
FT CARBOHYD 125
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:16335952,
FT ECO:0000269|PubMed:19159218"
FT CARBOHYD 344
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:16335952"
FT CARBOHYD 345
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 24..504
FT /evidence="ECO:0000250"
FT DISULFID 78..89
FT /evidence="ECO:0000250"
FT DISULFID 105..126
FT /evidence="ECO:0000250"
FT DISULFID 203..417
FT /evidence="ECO:0000250"
FT DISULFID 218..241
FT /evidence="ECO:0000250"
FT VARIANT 79
FT /note="S -> L (in dbSNP:rs4516605)"
FT /id="VAR_048856"
FT VARIANT 103
FT /note="G -> E (in THPH11; HRG Tokushima 1; results in
FT increased intracellular degradation and reduced protein
FT secretion; dbSNP:rs121918122)"
FT /evidence="ECO:0000269|PubMed:9414276"
FT /id="VAR_063000"
FT VARIANT 118
FT /note="D -> G (in dbSNP:rs3733008)"
FT /id="VAR_020488"
FT VARIANT 180
FT /note="I -> T (in dbSNP:rs10770)"
FT /id="VAR_022080"
FT VARIANT 204
FT /note="P -> S (in dbSNP:rs9898)"
FT /id="VAR_014528"
FT VARIANT 241
FT /note="C -> R (in THPH11; HRG Tokushima 2; results in
FT increased intracellular degradation and reduced protein
FT secretion; dbSNP:rs2276804)"
FT /evidence="ECO:0000269|PubMed:11057869"
FT /id="VAR_063001"
FT VARIANT 340
FT /note="H -> R (in dbSNP:rs2228243)"
FT /id="VAR_020489"
FT VARIANT 436
FT /note="G -> R (in dbSNP:rs2229331)"
FT /id="VAR_024427"
FT VARIANT 448
FT /note="R -> C (in dbSNP:rs1042445)"
FT /id="VAR_024428"
FT VARIANT 493
FT /note="N -> I (in dbSNP:rs1042464)"
FT /id="VAR_024429"
SQ SEQUENCE 525 AA; 59578 MW; A2B124D6CE93114F CRC64;
MKALIAALLL ITLQYSCAVS PTDCSAVEPE AEKALDLINK RRRDGYLFQL LRIADAHLDR
VENTTVYYLV LDVQESDCSV LSRKYWNDCE PPDSRRPSEI VIGQCKVIAT RHSHESQDLR
VIDFNCTTSS VSSALANTKD SPVLIDFFED TERYRKQANK ALEKYKEEND DFASFRVDRI
ERVARVRGGE GTGYFVDFSV RNCPRHHFPR HPNVFGFCRA DLFYDVEALD LESPKNLVIN
CEVFDPQEHE NINGVPPHLG HPFHWGGHER SSTTKPPFKP HGSRDHHHPH KPHEHGPPPP
PDERDHSHGP PLPQGPPPLL PMSCSSCQHA TFGTNGAQRH SHNNNSSDLH PHKHHSHEQH
PHGHHPHAHH PHEHDTHRQH PHGHHPHGHH PHGHHPHGHH PHGHHPHCHD FQDYGPCDPP
PHNQGHCCHG HGPPPGHLRR RGPGKGPRPF HCRQIGSVYR LPPLRKGEVL PLPEANFPSF
PLPHHKHPLK PDNQPFPQSV SESCPGKFKS GFPQVSMFFT HTFPK
