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-JAN-2014, entry version 70. 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; OC Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Sciurognathi; OC Muroidea; Muridae; Murinae; Rattus. OX NCBI_TaxID=10116; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, AND SUBCELLULAR RP 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 RT cellular 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., RA Ohashi T., 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 RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). CC -!- FUNCTION: Plasma glycoprotein that binds a number of ligands such CC as heme, heparin, heparan sulfate, thrombospondin, plasminogen, CC and divalent metal ions. Inhibits rosette formation. Acts as an CC adapter protein and implicated in regulating many processes such CC as immune complex and pathogen clearance, cell adhesion, CC angiogenesis, coagulation and fibrinolysis. Mediates clearance of CC necrotic cells through enhancing the phagocytosis of necrotic CC cells in a heparan sulfate-dependent pathway. This process can be CC regulated by the presence of certain HRG ligands such as heparin CC and zinc ions. Binds to IgG subclasses of immunoglobins containing CC kappa and lambda light chains with different affinities regulating CC their clearance and inhibiting the formation of insoluble immune CC complexes. Tethers plasminogen to the cell surface. Binds T-cells CC and alters the cell morphology. Modulates angiogenesis by blocking CC the CD6-mediated antiangiongenic effect of thrombospondins, THBS1 CC and THBS2 (By similarity). 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) CC with TMP1; the interaction partially mediates the antiangiogenic CC properties of HRG. Interacts with kappa and lambda light chains of CC IgG molecules. Interacts with ATP5A1; the interaction occurs on CC the surface of T-cells and alters their cell morphology in concert CC with CONA. Binds IgG molecules containing kappa and lambda light CC chains and inhibits the formation of insoluble immunoglobulin CC complexes. Interacts with F12; the interaction, which is enhanced CC in the presence of zinc ions and inhibited by heparin-binding to CC HRG, inhibits factor XII autoactivation and contact-initiated CC coagulation (By similarity). Interacts with PLG (via its Kringle CC domains); the interaction tethers PLG to the cell surface and CC enhances its activation. Interacts (via the HRR domain) with TPM1; CC the interaction appears to contribute to the antiangiogenic CC properties of the HRR domain. Interacts with THBS2; the CC interaction blocks the antiangiogenic effect of THBS2 with CD36 CC (By similarity). 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 CC wounds and chronic leg ulcers. 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 CC sequence. HRR binds heparan sulfate and possesses antiangiogenic, CC antibacterial and antifungal properties through binding Candida CC cells, and preferentially lysing the ergosterol-containing CC liposomes at low pH. The tandem repeats also bind divalent metal CC ions and heme (By similarity). CC -!- DOMAIN: The cystatin domains can also bind heparan sulfate. CC Binding is enhanced in the presence of zinc ions (By similarity). CC -!- PTM: N-glycosylated (By similarity). 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 CC an acidic environment. Cleavage reduces binding of HRG to heparan CC sulfate, but enhances the ability of HRG to bind and tether CC plasminogen to the cell surface. On platelet activation, releases CC a 33 kDa antiangiogenic peptide which encompasses the HRR. Also CC cleaved in the C-terminal by plasmin (By similarity). CC -!- SIMILARITY: Contains 2 cystatin domains. 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_596919.1; NM_133428.2. DR UniGene; Rn.16100; -. DR ProteinModelPortal; Q99PS8; -. DR STRING; 10116.ENSRNOP00000049290; -. DR MEROPS; I25.022; -. DR PaxDb; Q99PS8; -. DR PRIDE; Q99PS8; -. DR Ensembl; ENSRNOT00000047595; ENSRNOP00000049290; ENSRNOG00000001809. DR GeneID; 171016; -. DR KEGG; rno:171016; -. DR CTD; 3273; -. DR RGD; 619808; Hrg. DR eggNOG; NOG75740; -. DR GeneTree; ENSGT00730000111384; -. DR HOGENOM; HOG000090255; -. DR HOVERGEN; HBG004597; -. DR InParanoid; Q99PS8; -. DR OMA; PMILPSF; -. DR OrthoDB; EOG7HXCSK; -. DR NextBio; 621505; -. DR PRO; PR:Q99PS8; -. DR Genevestigator; Q99PS8; -. DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell. DR GO; GO:0004869; F:cysteine-type endopeptidase inhibitor activity; IEA:InterPro. 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:0004867; F:serine-type endopeptidase inhibitor activity; IEA:Ensembl. DR GO; GO:0008270; F:zinc ion binding; ISS:UniProtKB. DR GO; GO:0050832; P:defense response to fungus; ISS:UniProtKB. DR GO; GO:0042730; P:fibrinolysis; IEA:UniProtKB-KW. 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: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 proliferation; ISS:UniProtKB. DR GO; GO:2001027; P:negative regulation of endothelial cell chemotaxis; ISS:UniProtKB. DR GO; GO:0051918; P:negative regulation of fibrinolysis; IEA:Ensembl. 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: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 complex assembly; ISS:UniProtKB. DR InterPro; IPR000010; Prot_inh_cystat. DR SMART; SM00043; CY; 2. DR PROSITE; PS00287; CYSTATIN; FALSE_NEG. PE 2: Evidence at transcript level; KW Blood coagulation; Cleavage on pair of basic residues; KW Complete proteome; Copper; Disulfide bond; Fibrinolysis; Glycoprotein; KW Hemostasis; Heparin-binding; Metal-binding; Reference proteome; KW Repeat; Secreted; Signal; Zinc. FT SIGNAL 1 18 Potential. FT CHAIN 19 525 Histidine-rich glycoprotein. FT /FTId=PRO_0000408508. FT DOMAIN 19 122 Cystatin 1. FT DOMAIN 135 240 Cystatin 2. FT REGION 41 84 Interaction with ATP5A1 (By similarity). FT COMPBIAS 267 312 Pro-rich. FT COMPBIAS 337 497 His/Pro-rich (HRR). FT COMPBIAS 462 497 Pro-rich. FT SITE 439 440 Cleavage; by plasmin (By similarity). FT CARBOHYD 112 112 N-linked (GlcNAc...) (Potential). FT CARBOHYD 123 123 N-linked (GlcNAc...) (Potential). FT CARBOHYD 200 200 N-linked (GlcNAc...) (Potential). FT CARBOHYD 322 322 N-linked (GlcNAc...) (Potential). FT CARBOHYD 330 330 N-linked (GlcNAc...) (Potential). FT DISULFID 24 504 By similarity. FT DISULFID 78 89 By similarity. FT DISULFID 103 124 By similarity. FT DISULFID 201 414 By similarity. FT DISULFID 216 239 By similarity. FT CONFLICT 6 6 T -> A (in Ref. 1; AAG28417). FT CONFLICT 74 74 V -> I (in Ref. 1; AAG28417 and 2; FT BAB33093). FT CONFLICT 93 98 MRTSEV -> RWTSEI (in Ref. 1; AAG28417 and FT 2; BAB33093). FT CONFLICT 133 134 YI -> LS (in Ref. 1; AAG28417 and 2; FT BAB33093). FT CONFLICT 143 145 VDS -> FDF (in Ref. 1; AAG28417 and 2; FT BAB33093). FT CONFLICT 165 165 A -> E (in Ref. 1; AAG28417 and 2; FT BAB33093). FT CONFLICT 172 172 S -> L (in Ref. 1; AAG28417). FT CONFLICT 184 184 M -> G (in Ref. 1; AAG28417 and 2; FT BAB33093). FT CONFLICT 191 191 S -> N (in Ref. 1; AAG28417). FT CONFLICT 211 211 P -> L (in Ref. 1; AAG28417). FT CONFLICT 215 215 L -> F (in Ref. 1; AAG28417 and 2; FT BAB33093). FT CONFLICT 218 224 VVLTYST -> ALLSYSI (in Ref. 1; AAG28417 FT and 2; BAB33093). FT CONFLICT 237 238 LI -> VT (in Ref. 1; AAG28417 and 2; FT BAB33093). FT CONFLICT 242 242 F -> V (in Ref. 1; AAG28417 and 2; FT BAB33093). FT CONFLICT 329 329 H -> R (in Ref. 1; AAG28417). FT CONFLICT 339 348 Missing (in Ref. 1; AAG28417 and 2; FT BAB33093). FT CONFLICT 374 374 H -> R (in Ref. 1; AAG28417). FT CONFLICT 381 385 QHPHG -> HHLHR (in Ref. 2; BAB33093). FT CONFLICT 384 384 H -> R (in Ref. 1; AAG28417). FT CONFLICT 421 425 Missing (in Ref. 1; AAG28417). FT CONFLICT 429 429 R -> Q (in Ref. 1; AAG28417). FT CONFLICT 479 479 I -> S (in Ref. 2; BAB33093). FT CONFLICT 494 494 R -> Q (in Ref. 2; BAB33093). FT CONFLICT 510 510 G -> S (in Ref. 2; BAB33093). 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 //