ID HRG_RAT Reviewed; 525 AA. AC Q99PS8; D3ZJN0; Q99PS7; Q9ESB2; DT 31-MAY-2011, integrated into UniProtKB/Swiss-Prot. DT 01-JUN-2001, sequence version 1. DT 22-FEB-2023, entry version 122. DE RecName: Full=Histidine-rich glycoprotein; DE AltName: Full=Histidine-proline-rich glycoprotein; DE Short=HPRG; DE AltName: Full=Histidine-rich glycoprotein 1; DE Short=HRG1; DE Flags: Precursor; GN Name=Hrg; Synonyms=Hrg1; OS Rattus norvegicus (Rat). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Rattus. OX NCBI_TaxID=10116; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION. RC STRAIN=Lewis; 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 [MRNA]. RC STRAIN=Sprague-Dawley; TISSUE=Liver; RA Wakabayashi S., Takahashi K., Hirokado Y., Togo Y., Izumi S., Ohashi T., RA Sato N., Hirata D., Tsuchida N., Koide T.; RT "Molecular diversity of mammalian histidine-rich glycoprotein."; RL Submitted (FEB-2001) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC 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 [4] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-145 AND SER-438, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=22673903; DOI=10.1038/ncomms1871; RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C., RA Olsen J.V.; RT "Quantitative maps of protein phosphorylation sites across 14 different rat RT organs and tissues."; RL Nat. Commun. 3:876-876(2012). CC -!- FUNCTION: Plasma glycoprotein that binds a number of ligands such as CC heme, heparin, heparan sulfate, thrombospondin, plasminogen, and CC divalent metal ions. Inhibits rosette formation. Acts as an adapter CC protein and implicated in regulating many processes such as immune CC complex and pathogen clearance, 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 (By CC similarity). {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. Interacts with THBS2; the interaction CC blocks the antiangiogenic effect of THBS2 with CD36 (By similarity). CC {ECO:0000250}. CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:10849117}. 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 -!- 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 (By similarity). CC {ECO:0000250}. 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: N-glycosylated. {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 --------------------------------------------------------------------------- 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; AF194029; AAG28417.1; -; mRNA. DR EMBL; AB055895; BAB33092.1; -; mRNA. DR EMBL; AB055896; BAB33093.1; -; mRNA. DR EMBL; BC089779; AAH89779.1; -; mRNA. DR RefSeq; NP_001316829.1; NM_001329900.1. DR RefSeq; NP_596919.1; NM_133428.2. DR AlphaFoldDB; Q99PS8; -. DR SMR; Q99PS8; -. DR IntAct; Q99PS8; 6. DR STRING; 10116.ENSRNOP00000049290; -. DR MEROPS; I25.022; -. DR MEROPS; I25.025; -. DR GlyCosmos; Q99PS8; 5 sites, No reported glycans. DR GlyGen; Q99PS8; 5 sites. DR iPTMnet; Q99PS8; -. DR PhosphoSitePlus; Q99PS8; -. DR PaxDb; Q99PS8; -. DR GeneID; 171016; -. DR GeneID; 681544; -. DR KEGG; rno:171016; -. DR KEGG; rno:681544; -. DR AGR; RGD:1594092; -. DR AGR; RGD:619808; -. DR CTD; 3273; -. DR RGD; 619808; Hrg. DR eggNOG; ENOG502S50D; Eukaryota. DR HOGENOM; CLU_575637_0_0_1; -. DR InParanoid; Q99PS8; -. DR OrthoDB; 5324439at2759; -. DR PhylomeDB; Q99PS8; -. DR TreeFam; TF333729; -. DR Reactome; R-RNO-114608; Platelet degranulation. DR Reactome; R-RNO-75205; Dissolution of Fibrin Clot. DR PRO; PR:Q99PS8; -. DR Proteomes; UP000002494; Chromosome 11. DR Bgee; ENSRNOG00000001809; Expressed in liver and 14 other tissues. DR ExpressionAtlas; Q99PS8; baseline and differential. DR Genevisible; Q99PS8; RN. DR GO; GO:0009986; C:cell surface; ISO:RGD. DR GO; GO:0036019; C:endolysosome; ISO:RGD. DR GO; GO:0005576; C:extracellular region; ISO:RGD. DR GO; GO:0061474; C:phagolysosome membrane; ISO:RGD. DR GO; GO:0031982; C:vesicle; ISO:RGD. 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; ISO:RGD. DR GO; GO:0005102; F:signaling receptor binding; ISS:UniProtKB. DR GO; GO:0008270; F:zinc ion binding; ISS:UniProtKB. DR GO; GO:0061844; P:antimicrobial humoral immune response mediated by antimicrobial peptide; ISO:RGD. DR GO; GO:0051838; P:cytolysis by host of symbiont cells; ISO:RGD. DR GO; GO:0050832; P:defense response to fungus; ISS:UniProtKB. DR GO; GO:0042730; P:fibrinolysis; ISO:RGD. DR GO; GO:0097037; P:heme export; ISO:RGD. DR GO; GO:0015886; P:heme transport; ISO:RGD. DR GO; GO:0016525; P:negative regulation of angiogenesis; ISS: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; 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; ISS:UniProtKB. DR GO; GO:0008285; P:negative regulation of cell population proliferation; ISS:UniProtKB. DR GO; GO:0010951; P:negative regulation of endopeptidase activity; ISO:RGD. DR GO; GO:2001027; P:negative regulation of endothelial cell chemotaxis; ISS:UniProtKB. DR GO; GO:0051918; P:negative regulation of fibrinolysis; ISO:RGD. 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; ISS: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; ISS:UniProtKB. DR GO; GO:0032956; P:regulation of actin cytoskeleton organization; ISS:UniProtKB. DR GO; GO:0030193; P:regulation of blood coagulation; ISS:UniProtKB. DR GO; GO:0010468; P:regulation of gene expression; ISS:UniProtKB. DR GO; GO:0050730; P:regulation of peptidyl-tyrosine phosphorylation; ISS:UniProtKB. DR GO; GO:0010543; P:regulation of platelet activation; ISS: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; ISO:RGD. DR GO; GO:0014070; P:response to organic cyclic compound; ISO:RGD. DR CDD; cd00042; CY; 1. DR Gene3D; 3.10.450.10; -; 2. DR InterPro; IPR000010; Cystatin_dom. DR InterPro; IPR046350; Cystatin_sf. DR PANTHER; PTHR13814; FETUIN; 1. DR PANTHER; PTHR13814:SF3; HISTIDINE-RICH GLYCOPROTEIN; 1. DR SMART; SM00043; CY; 2. DR SUPFAM; SSF54403; Cystatin/monellin; 1. PE 1: Evidence at protein level; KW Blood coagulation; Cleavage on pair of basic residues; Copper; KW Disulfide bond; Fibrinolysis; Glycoprotein; Hemostasis; Heparin-binding; KW Metal-binding; Phosphoprotein; Reference proteome; Repeat; Secreted; KW Signal; Zinc. FT SIGNAL 1..18 FT /evidence="ECO:0000255" FT CHAIN 19..525 FT /note="Histidine-rich glycoprotein" FT /id="PRO_0000408508" 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 275..445 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 275..289 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 342..399 FT /note="Basic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 430..445 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 145 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:22673903" FT MOD_RES 438 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:22673903" 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:0000255" 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; AAG28417)" FT /evidence="ECO:0000305" FT CONFLICT 74 FT /note="V -> I (in Ref. 1; AAG28417 and 2; BAB33093)" FT /evidence="ECO:0000305" FT CONFLICT 93..98 FT /note="MRTSEV -> RWTSEI (in Ref. 1; AAG28417 and 2; FT BAB33093)" FT /evidence="ECO:0000305" FT CONFLICT 133..134 FT /note="YI -> LS (in Ref. 1; AAG28417 and 2; BAB33093)" FT /evidence="ECO:0000305" FT CONFLICT 143..145 FT /note="VDS -> FDF (in Ref. 1; AAG28417 and 2; BAB33093)" FT /evidence="ECO:0000305" FT CONFLICT 165 FT /note="A -> E (in Ref. 1; AAG28417 and 2; BAB33093)" FT /evidence="ECO:0000305" FT CONFLICT 172 FT /note="S -> L (in Ref. 1; AAG28417)" FT /evidence="ECO:0000305" FT CONFLICT 184 FT /note="M -> G (in Ref. 1; AAG28417 and 2; BAB33093)" FT /evidence="ECO:0000305" FT CONFLICT 191 FT /note="S -> N (in Ref. 1; AAG28417)" FT /evidence="ECO:0000305" FT CONFLICT 211 FT /note="P -> L (in Ref. 1; AAG28417)" FT /evidence="ECO:0000305" FT CONFLICT 215 FT /note="L -> F (in Ref. 1; AAG28417 and 2; BAB33093)" FT /evidence="ECO:0000305" FT CONFLICT 218..224 FT /note="VVLTYST -> ALLSYSI (in Ref. 1; AAG28417 and 2; FT BAB33093)" FT /evidence="ECO:0000305" FT CONFLICT 237..238 FT /note="LI -> VT (in Ref. 1; AAG28417 and 2; BAB33093)" FT /evidence="ECO:0000305" FT CONFLICT 242 FT /note="F -> V (in Ref. 1; AAG28417 and 2; BAB33093)" FT /evidence="ECO:0000305" FT CONFLICT 329 FT /note="H -> R (in Ref. 1; AAG28417)" FT /evidence="ECO:0000305" FT CONFLICT 339..348 FT /note="Missing (in Ref. 1; AAG28417 and 2; BAB33093)" FT /evidence="ECO:0000305" FT CONFLICT 374 FT /note="H -> R (in Ref. 1; AAG28417)" FT /evidence="ECO:0000305" FT CONFLICT 381..385 FT /note="QHPHG -> HHLHR (in Ref. 2; BAB33093)" FT /evidence="ECO:0000305" FT CONFLICT 384 FT /note="H -> R (in Ref. 1; AAG28417)" FT /evidence="ECO:0000305" FT CONFLICT 421..425 FT /note="Missing (in Ref. 1; AAG28417)" FT /evidence="ECO:0000305" FT CONFLICT 429 FT /note="R -> Q (in Ref. 1; AAG28417)" FT /evidence="ECO:0000305" FT CONFLICT 479 FT /note="I -> S (in Ref. 2; BAB33093)" FT /evidence="ECO:0000305" FT CONFLICT 494 FT /note="R -> Q (in Ref. 2; BAB33093)" FT /evidence="ECO:0000305" FT CONFLICT 510 FT /note="G -> S (in Ref. 2; BAB33093)" FT /evidence="ECO:0000305" SQ SEQUENCE 525 AA; 59049 MW; 38290A631FAC7777 CRC64; MKVLTTALLL VTLQCSHALS PTNCDASKPL AEKVLDLINK GRRSGYTFQL LRVSDAHLDR VETATIYYLV LDVVESDCWV LSTKAQDECL PAMRTSEVVI GQCKVIATRY SNESQDLSVN GYNCTMRSVS SAYINTKDSP VLVDSFEDSE PYRKLARKAL DKYKAENGDF ASFRVERAER VIRMRGGERT SYFIEFSVRN CSTQHFPRHP PVFGLCRVVL TYSTEASDLE TPEYTDLICE VFNTEDLKNR SDMKPHRGHE HPHCDKHLCK LSGPRDHHHT HKTHEIGCPP PPEGKDNSDR PPLQEGALPQ MLPGHSGPSG TNRSHRPPHN HSCNEHPCHG QHPHGHHPHG QHPHGHHPHG QHPHGHHPHG QHPHGHHPHG QHPHGHHPHG HHPHGDHPHG HHPHGHDFLD YGPCDPPSNS QELKGQYHRG HGPPHGHSRK RGPGKGLFPF HQRQIGYVYR LPPLNVGEVL TPPEANFPIF SLPNCNRPPQ PEIRPFPQTA SKSCPGKFEG KFPQVSNFFE HTPPK //