HRG_RAT
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 03-AUG-2022, entry version 119.
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}.
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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 GlyGen; Q99PS8; 5 sites.
DR iPTMnet; Q99PS8; -.
DR PhosphoSitePlus; Q99PS8; -.
DR PaxDb; Q99PS8; -.
DR PRIDE; Q99PS8; -.
DR GeneID; 171016; -.
DR GeneID; 681544; -.
DR KEGG; rno:171016; -.
DR KEGG; rno:681544; -.
DR CTD; 3273; -.
DR RGD; 619808; Hrg.
DR eggNOG; ENOG502S50D; Eukaryota.
DR HOGENOM; CLU_575637_0_0_1; -.
DR InParanoid; Q99PS8; -.
DR OrthoDB; 715844at2759; -.
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; IEA:UniProtKB-KW.
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; 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; 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 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 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
