HRG_MOUSE
ID HRG_MOUSE Reviewed; 525 AA.
AC Q9ESB3; Q6YK32; Q6YKA2; Q99PS5; Q99PS6;
DT 31-MAY-2011, integrated into UniProtKB/Swiss-Prot.
DT 31-MAY-2011, sequence version 2.
DT 03-AUG-2022, entry version 116.
DE RecName: Full=Histidine-rich glycoprotein;
DE AltName: Full=Histidine-proline-rich glycoprotein;
DE Short=HPRG;
DE Flags: Precursor;
GN Name=Hrg;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY.
RC STRAIN=129;
RX PubMed=10849117; DOI=10.1046/j.1440-1711.2000.00940.x;
RA Hulett M.D., Parish C.R.;
RT "Murine histidine-rich glycoprotein: cloning, characterization and cellular
RT origin.";
RL Immunol. Cell Biol. 78:280-287(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
RC STRAIN=NIH/Ola;
RX PubMed=15499407; DOI=10.1139/g04-043;
RA Hsu S.J., Nagase H., Balmain A.;
RT "Identification of fetuin-B as a member of a cystatin-like gene family on
RT mouse chromosome 16 with tumor suppressor activity.";
RL Genome 47:931-946(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA], DISRUPTION PHENOTYPE, AND FUNCTION.
RC STRAIN=BALB/cJ; TISSUE=Liver;
RX PubMed=15869579; DOI=10.1111/j.1538-7836.2005.01238.x;
RA Tsuchida-Straeten N., Ensslen S., Schafer C., Woltje M., Denecke B.,
RA Moser M., Graber S., Wakabayashi S., Koide T., Jahnen-Dechent W.;
RT "Enhanced blood coagulation and fibrinolysis in mice lacking histidine-rich
RT glycoprotein (HRG).";
RL J. Thromb. Haemost. 3:865-872(2005).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=FVB/N; TISSUE=Liver;
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 INTERACTION WITH THBS2, AND FUNCTION.
RX PubMed=15748999; DOI=10.1016/j.matbio.2004.11.005;
RA Simantov R., Febbraio M., Silverstein R.L.;
RT "The antiangiogenic effect of thrombospondin-2 is mediated by CD36 and
RT modulated by histidine-rich glycoprotein.";
RL Matrix Biol. 24:27-34(2005).
RN [6]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-200.
RC STRAIN=C57BL/6J; TISSUE=Plasma;
RX PubMed=17330941; DOI=10.1021/pr0604559;
RA Bernhard O.K., Kapp E.A., Simpson R.J.;
RT "Enhanced analysis of the mouse plasma proteome using cysteine-containing
RT tryptic glycopeptides.";
RL J. Proteome Res. 6:987-995(2007).
RN [7]
RP DISRUPTION PHENOTYPE, TISSUE SPECIFICITY, AND FUNCTION.
RX PubMed=18797515; DOI=10.1371/journal.ppat.1000116;
RA Rydengard V., Shannon O., Lundqvist K., Kacprzyk L., Chalupka A.,
RA Olsson A.K., Morgelin M., Jahnen-Dechent W., Malmsten M., Schmidtchen A.;
RT "Histidine-rich glycoprotein protects from systemic Candida infection.";
RL PLoS Pathog. 4:E1000116-E1000116(2008).
RN [8]
RP DISRUPTION PHENOTYPE, AND FUNCTION.
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 [9]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brown adipose tissue, Heart, Liver, Lung, Spleen, and Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [10]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=22374984; DOI=10.1158/0008-5472.can-11-2194;
RA Tugues S., Honjo S., Konig C., Noguer O., Hedlund M., Botling J.,
RA Deschoemaeker S., Wenes M., Rolny C., Jahnen-Dechent W., Mazzone M.,
RA Claesson-Welsh L.;
RT "Genetic deficiency in plasma protein HRG enhances tumor growth and
RT metastasis by exacerbating immune escape and vessel abnormalization.";
RL Cancer Res. 72:1953-1963(2012).
RN [11]
RP DISRUPTION PHENOTYPE.
RX PubMed=21264222; DOI=10.1371/journal.pone.0014526;
RA Ringvall M., Thulin A., Zhang L., Cedervall J., Tsuchida-Straeten N.,
RA Jahnen-Dechent W., Siegbahn A., Olsson A.K.;
RT "Enhanced platelet activation mediates the accelerated angiogenic switch in
RT mice lacking histidine-rich glycoprotein.";
RL PLoS ONE 6:E14526-E14526(2011).
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. Acts as a regulator of the vascular endothelial growth
CC factor (VEGF) signaling pathway; inhibits endothelial cell motility by
CC reducing VEGF-induced complex formation between PXN/paxillin and
CC ILK/integrin-linked protein kinase and by promoting inhibition of VEGF-
CC induced tyrosine phosphorylation of focal adhesion kinases and alpha-
CC actinins in endothelial cells. Also plays a role in the regulation of
CC tumor angiogenesis and tumor immune surveillance. Normalizes tumor
CC vessels and promotes antitumor immunity by polarizing tumor-associated
CC macrophages, leading to decreased tumor growth and metastasis (By
CC similarity). Modulates angiogenesis by blocking the CD6-mediated
CC antiangiongenic effect of thrombospondins, THBS1 and THBS2.
CC {ECO:0000250, ECO:0000269|PubMed:15748999, ECO:0000269|PubMed:15869579,
CC ECO:0000269|PubMed:18797515, ECO:0000269|PubMed:19903770,
CC ECO:0000269|PubMed:22374984}.
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105; Evidence={ECO:0000250};
CC -!- SUBUNIT: Interacts with THBS1 (via the TSP type I repeats); the
CC interaction blocks the antiangiogenic effect of THBS1 with CD36.
CC Interacts with HPSE; the interaction is enhanced at acidic pH,
CC 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 (By similarity). Interacts with PLG
CC (via its Kringle domains); the interaction tethers PLG to the cell
CC surface and enhances its activation. Interacts (via the HRR domain)
CC with TPM1; the interaction appears to contribute to the antiangiogenic
CC properties of the HRR domain (By similarity). Interacts with THBS2; the
CC interaction blocks the antiangiogenic effect of THBS2 with CD36.
CC {ECO:0000250, ECO:0000269|PubMed:15748999}.
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- TISSUE SPECIFICITY: Expressed in liver, blood plasma, serum and in
CC platelets. Also present in fibrin clots, wound fluid from acute wounds
CC and chronic leg ulcers. {ECO:0000269|PubMed:10849117,
CC ECO:0000269|PubMed:18797515}.
CC -!- DOMAIN: The His-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 (By similarity). {ECO:0000250}.
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 (By similarity). {ECO:0000250}.
CC -!- PTM: N-glycosylated. {ECO:0000269|PubMed:17330941}.
CC -!- DISRUPTION PHENOTYPE: Null mice are viable and fertile, but have
CC enhanced coagulation resulting in decreased bleeding times. The
CC observed enhanced platelet activation mediates the accelerated
CC angiogenic switch. Also enhanced fibrinolysis. Animals are unprotected
CC against Candida fungal infection. Also shows larger tumor volume in
CC cancerous state, an excessive stimulation of tumor angiogenesis, a
CC suppression of tumor immune respons and an increased tumor growth and
CC metastatic spread. {ECO:0000269|PubMed:15869579,
CC ECO:0000269|PubMed:18797515, ECO:0000269|PubMed:19903770,
CC ECO:0000269|PubMed:21264222, ECO:0000269|PubMed:22374984}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAN10183.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC Sequence=AAN27996.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
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; AF194028; AAG28416.1; -; mRNA.
DR EMBL; AY135662; AAN10183.1; ALT_INIT; mRNA.
DR EMBL; AY137504; AAN27996.1; ALT_SEQ; Genomic_DNA.
DR EMBL; AB055897; BAB33094.1; -; mRNA.
DR EMBL; AB055898; BAB33095.1; -; Genomic_DNA.
DR EMBL; BC011168; AAH11168.1; -; mRNA.
DR RefSeq; NP_444406.2; NM_053176.2.
DR AlphaFoldDB; Q9ESB3; -.
DR SMR; Q9ESB3; -.
DR BioGRID; 220456; 2.
DR IntAct; Q9ESB3; 2.
DR STRING; 10090.ENSMUSP00000023590; -.
DR MEROPS; I25.022; -.
DR MEROPS; I25.025; -.
DR GlyGen; Q9ESB3; 5 sites.
DR iPTMnet; Q9ESB3; -.
DR PhosphoSitePlus; Q9ESB3; -.
DR SwissPalm; Q9ESB3; -.
DR CPTAC; non-CPTAC-3299; -.
DR CPTAC; non-CPTAC-5610; -.
DR jPOST; Q9ESB3; -.
DR MaxQB; Q9ESB3; -.
DR PaxDb; Q9ESB3; -.
DR PeptideAtlas; Q9ESB3; -.
DR PRIDE; Q9ESB3; -.
DR ProteomicsDB; 267157; -.
DR DNASU; 94175; -.
DR GeneID; 94175; -.
DR KEGG; mmu:94175; -.
DR UCSC; uc007ysw.2; mouse.
DR CTD; 3273; -.
DR MGI; MGI:2146636; Hrg.
DR eggNOG; ENOG502S50D; Eukaryota.
DR InParanoid; Q9ESB3; -.
DR OrthoDB; 715844at2759; -.
DR TreeFam; TF333729; -.
DR Reactome; R-MMU-114608; Platelet degranulation.
DR Reactome; R-MMU-75205; Dissolution of Fibrin Clot.
DR BioGRID-ORCS; 94175; 0 hits in 72 CRISPR screens.
DR ChiTaRS; Nrg1; mouse.
DR PRO; PR:Q9ESB3; -.
DR Proteomes; UP000000589; Unplaced.
DR RNAct; Q9ESB3; protein.
DR GO; GO:0009986; C:cell surface; ISO:MGI.
DR GO; GO:0062023; C:collagen-containing extracellular matrix; HDA:BHF-UCL.
DR GO; GO:0036019; C:endolysosome; IDA:MGI.
DR GO; GO:0005576; C:extracellular region; ISO:MGI.
DR GO; GO:0061474; C:phagolysosome membrane; IDA:MGI.
DR GO; GO:0031982; C:vesicle; IDA:MGI.
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; ISS:UniProtKB.
DR GO; GO:0043395; F:heparan sulfate proteoglycan binding; ISS:UniProtKB.
DR GO; GO:0008201; F:heparin binding; ISS:UniProtKB.
DR GO; GO:0019865; F:immunoglobulin binding; ISS:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; ISS:UniProtKB.
DR GO; GO:0004867; F:serine-type endopeptidase inhibitor activity; IMP:MGI.
DR GO; GO:0005102; F:signaling receptor binding; ISS:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; ISS:UniProtKB.
DR GO; GO:0001525; P:angiogenesis; IEA:UniProtKB-KW.
DR GO; GO:0061844; P:antimicrobial humoral immune response mediated by antimicrobial peptide; IMP:UniProtKB.
DR GO; GO:0006935; P:chemotaxis; IEA:UniProtKB-KW.
DR GO; GO:0051838; P:cytolysis by host of symbiont cells; ISO:MGI.
DR GO; GO:0050832; P:defense response to fungus; IMP:UniProtKB.
DR GO; GO:0042730; P:fibrinolysis; IMP:MGI.
DR GO; GO:0097037; P:heme export; IMP:MGI.
DR GO; GO:0015886; P:heme transport; IMP:MGI.
DR GO; GO:0016525; P:negative regulation of angiogenesis; IMP:UniProtKB.
DR GO; GO:0043537; P:negative regulation of blood vessel endothelial cell migration; IMP:UniProtKB.
DR GO; GO:0007162; P:negative regulation of cell adhesion; ISS:UniProtKB.
DR GO; GO:0033629; P:negative regulation of cell adhesion mediated by integrin; ISS:UniProtKB.
DR GO; GO:0030308; P:negative regulation of cell growth; IDA:UniProtKB.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; ISS: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; ISS:UniProtKB.
DR GO; GO:0051918; P:negative regulation of fibrinolysis; IMP:MGI.
DR GO; GO:0010593; P:negative regulation of lamellipodium assembly; ISS:UniProtKB.
DR GO; GO:1900747; P:negative regulation of vascular endothelial growth factor signaling pathway; ISS:UniProtKB.
DR GO; GO:0030168; P:platelet activation; ISS:UniProtKB.
DR GO; GO:0043065; P:positive regulation of apoptotic process; ISS:UniProtKB.
DR GO; GO:2000504; P:positive regulation of blood vessel remodeling; IMP:UniProtKB.
DR GO; GO:0051894; P:positive regulation of focal adhesion assembly; ISS:UniProtKB.
DR GO; GO:0002839; P:positive regulation of immune response to tumor cell; IMP:UniProtKB.
DR GO; GO:0032956; P:regulation of actin cytoskeleton organization; ISS:UniProtKB.
DR GO; GO:0030193; P:regulation of blood coagulation; IMP:UniProtKB.
DR GO; GO:0010468; P:regulation of gene expression; IMP:UniProtKB.
DR GO; GO:0050730; P:regulation of peptidyl-tyrosine phosphorylation; ISS:UniProtKB.
DR GO; GO:0010543; P:regulation of platelet activation; IMP:UniProtKB.
DR GO; GO:0043254; P:regulation of protein-containing complex assembly; ISS:UniProtKB.
DR GO; GO:0034395; P:regulation of transcription from RNA polymerase II promoter in response to iron; IDA:MGI.
DR GO; GO:0014070; P:response to organic cyclic compound; IDA:MGI.
DR InterPro; IPR000010; Cystatin_dom.
DR InterPro; IPR046350; Cystatin_sf.
DR SMART; SM00043; CY; 2.
DR SUPFAM; SSF54403; SSF54403; 1.
PE 1: Evidence at protein level;
KW Angiogenesis; Blood coagulation; Chemotaxis;
KW Cleavage on pair of basic residues; Copper; Disulfide bond; Fibrinolysis;
KW Glycoprotein; Hemostasis; Heparin-binding; Metal-binding; Phosphoprotein;
KW Reference proteome; Repeat; Secreted; Signal; Zinc.
FT SIGNAL 1..18
FT /evidence="ECO:0000250"
FT CHAIN 19..525
FT /note="Histidine-rich glycoprotein"
FT /id="PRO_0000408507"
FT DOMAIN 19..122
FT /note="Cystatin 1"
FT DOMAIN 135..240
FT /note="Cystatin 2"
FT REGION 41..84
FT /note="Interaction with ATP5F1A"
FT /evidence="ECO:0000250"
FT REGION 273..447
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 345..379
FT /note="Necessary for endothelial cell focal adhesions and
FT anti-angiogenic activities"
FT /evidence="ECO:0000250"
FT COMPBIAS 273..302
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 340..402
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 MOD_RES 438
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q99PS8"
FT CARBOHYD 112
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 123
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 200
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:17330941"
FT CARBOHYD 322
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 330
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 103..124
FT /evidence="ECO:0000250"
FT DISULFID 201..414
FT /evidence="ECO:0000250"
FT DISULFID 216..239
FT /evidence="ECO:0000250"
FT CONFLICT 6
FT /note="T -> A (in Ref. 1; AAG28416)"
FT /evidence="ECO:0000305"
FT CONFLICT 511
FT /note="E -> G (in Ref. 3; BAB33094)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 525 AA; 59163 MW; A83E93A439CFB126 CRC64;
MKVLTTALLL VTLQCSHALS PTNCDASEPL AEKVLDLINK GRRSGYVFEL LRVSDAHLDR
AGTATVYYLA LDVIESDCWV LSTKAQDDCL PSRWQSEIVI GQCKVIATRY SNESQDLSVN
GYNCTTSSVS SALRNTKDSP VLLDFFEDSE LYRKQARKAL DKYKTDNGDF ASFRVERAER
VIRARGGERT NYYVEFSMRN CSTQHFPRSP LVFGFCRALL SYSIETSDLE TPDSIDINCE
VFNIEDHKDT SDMKPHWGHE RPLCDKHLCK LSGSRDHHHT HKTDKLGCPP PPEGKDNSDR
PRLQEGALPQ LPPGYPPHSG ANRTHRPSYN HSCNEHPCHG HRPHGHHPHS HHPPGHHSHG
HHPHGHHPHS HHSHGHHPPG HHPHGHHPHG HHPHGHHPHG HHPHGHDFLD YGPCDPPSNS
QELKGQYHRG YGPPHGHSRK RGPGKGLFPF HHQQIGYVYR LPPLNIGEVL TLPEANFPSF
SLPNCNRSLQ PEIQPFPQTA SRSCPGKFES EFPQISKFFG YTPPK
