HRG_RABIT
ID HRG_RABIT Reviewed; 526 AA.
AC Q28640;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1997, sequence version 1.
DT 25-MAY-2022, entry version 98.
DE RecName: Full=Histidine-rich glycoprotein;
DE AltName: Full=Histidine-proline-rich glycoprotein;
DE Short=HPRG;
DE Flags: Precursor; Fragment;
GN Name=HRG;
OS Oryctolagus cuniculus (Rabbit).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Lagomorpha; Leporidae; Oryctolagus.
OX NCBI_TaxID=9986;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND PROTEIN SEQUENCE OF 9-23; 301-313 AND
RP 422-429.
RC TISSUE=Serum;
RX PubMed=8639676; DOI=10.1021/bi952061t;
RA Borza D.-B., Tatum F.M., Morgan W.T.;
RT "Domain structure and conformation of histidine-proline-rich
RT glycoprotein.";
RL Biochemistry 35:1925-1934(1996).
RN [2]
RP HEME- AND METAL-BINDING.
RX PubMed=2636901; DOI=10.1002/jmr.300020304;
RA Morgan W.T., Deaciuc V., Riehm J.P.;
RT "A heme- and metal-binding hexapeptide from the sequence of rabbit plasma
RT histidine-rich glycoprotein.";
RL J. Mol. Recognit. 2:122-126(1989).
RN [3]
RP INTERACTION WITH PLG.
RX PubMed=9102401; DOI=10.1074/jbc.272.9.5718;
RA Borza D.B., Morgan W.T.;
RT "Acceleration of plasminogen activation by tissue plasminogen activator on
RT surface-bound histidine-proline-rich glycoprotein.";
RL J. Biol. Chem. 272:5718-5726(1997).
RN [4]
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 [5]
RP INTERACTION WITH TPM1.
RX PubMed=15269838; DOI=10.1160/th04-02-0073;
RA Guan X., Juarez J.C., Qi X., Shipulina N.V., Shaw D.E., Morgan W.T.,
RA McCrae K.R., Mazar A.P., Donate F.;
RT "Histidine-proline rich glycoprotein (HPRG) binds and transduces anti-
RT angiogenic signals through cell surface tropomyosin on endothelial cells.";
RL Thromb. Haemost. 92:403-412(2004).
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. Binds T-cells
CC and alters the cell morphology Modulates angiogenesis by blocking the
CC CD6-mediated antiangiongenic effect of thrombospondins, THBS1 and THBS2
CC (By similarity). Tethers plasminogen to the cell surface. {ECO:0000250,
CC ECO:0000269|PubMed:12235005}.
CC -!- SUBUNIT: Interacts with THBS1 (via the TSP type I repeats); the
CC interaction blocks the antiangiogenic effect of THBS1 with CD36 (By
CC similarity). Interacts with THBS2; the interaction blocks the
CC antiangiogenic effect of THBS2 with CD36. Interacts with HPSE; the
CC interaction is enhanced at acidic pH, partially inhibits binding of
CC HPSE to cell surface receptors and modulates its enzymatic activity.
CC Interacts (via the HRR domain) with TMP1; the interaction partially
CC mediates the antiangiogenic properties of HRG. Interacts with kappa and
CC lambda light chains of IgG molecules. Interacts with ATP5F1A; the
CC interaction occurs on the surface of T-cells and alters their cell
CC morphology in concert with CONA. Binds IgG molecules containing kappa
CC and lambda light chains and inhibits the formation of insoluble
CC immunoglobulin complexes. Interacts with F12; the interaction, which is
CC enhanced in the presence of zinc ions and inhibited by heparin-binding
CC to 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 enhances
CC its activation. Interacts (via the HRR domain) with TPM1; the
CC interaction appears to contribute to the antiangiogenic properties of
CC the HRR domain. {ECO:0000250, ECO:0000269|PubMed:15269838,
CC ECO:0000269|PubMed:9102401}.
CC -!- SUBCELLULAR LOCATION: Secreted.
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.
CC -!- PTM: N-glycosylated. {ECO:0000250}.
CC -!- PTM: Proteolytic cleavage produces several HRG fragments which are
CC mostly disulfide-linked and, therefore, not released. On platelet
CC activation, may release a 33 kDa antiangiogenic peptide which
CC encompasses the HRR (By similarity). {ECO:0000250}.
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DR EMBL; U32189; AAC48516.1; -; mRNA.
DR PDB; 4CCV; X-ray; 1.93 A; A=131-245.
DR PDBsum; 4CCV; -.
DR AlphaFoldDB; Q28640; -.
DR SMR; Q28640; -.
DR STRING; 9986.ENSOCUP00000025254; -.
DR eggNOG; ENOG502S50D; Eukaryota.
DR InParanoid; Q28640; -.
DR Proteomes; UP000001811; Unplaced.
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:0046872; F:metal ion binding; ISS:UniProtKB.
DR GO; GO:0005102; F:signaling receptor binding; ISS:UniProtKB.
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; 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; 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:2001027; P:negative regulation of endothelial cell chemotaxis; ISS:UniProtKB.
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:0010755; P:regulation of plasminogen activation; IDA: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 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; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Blood coagulation; Copper; Direct protein sequencing;
KW Disulfide bond; Fibrinolysis; Glycoprotein; Hemostasis; Heparin-binding;
KW Reference proteome; Repeat; Secreted; Signal; Zinc.
FT SIGNAL <1..8
FT /evidence="ECO:0000255"
FT CHAIN 9..526
FT /note="Histidine-rich glycoprotein"
FT /id="PRO_0000006710"
FT DOMAIN 9..126
FT /note="Cystatin 1"
FT DOMAIN 127..243
FT /note="Cystatin 2"
FT REGION 31..74
FT /note="Interaction with ATP5F1A"
FT /evidence="ECO:0000250"
FT REGION 243..449
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 304..318
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 329..350
FT /note="Basic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 351..403
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 404..427
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 303..304
FT /note="Cleavage; by plasmin"
FT SITE 421..422
FT /note="Cleavage; by plasmin"
FT CARBOHYD 115
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 192
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 240
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 310
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 485
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 14..505
FT /evidence="ECO:0000250"
FT DISULFID 68..79
FT /evidence="ECO:0000250"
FT DISULFID 95..116
FT /evidence="ECO:0000250"
FT DISULFID 193..415
FT /evidence="ECO:0000250"
FT DISULFID 207..230
FT /evidence="ECO:0000250"
FT DISULFID 272..302
FT /evidence="ECO:0000255"
FT NON_TER 1
FT STRAND 134..137
FT /evidence="ECO:0007829|PDB:4CCV"
FT HELIX 142..144
FT /evidence="ECO:0007829|PDB:4CCV"
FT HELIX 145..157
FT /evidence="ECO:0007829|PDB:4CCV"
FT HELIX 160..162
FT /evidence="ECO:0007829|PDB:4CCV"
FT STRAND 165..177
FT /evidence="ECO:0007829|PDB:4CCV"
FT STRAND 179..192
FT /evidence="ECO:0007829|PDB:4CCV"
FT HELIX 193..196
FT /evidence="ECO:0007829|PDB:4CCV"
FT STRAND 203..214
FT /evidence="ECO:0007829|PDB:4CCV"
FT STRAND 219..221
FT /evidence="ECO:0007829|PDB:4CCV"
FT STRAND 224..234
FT /evidence="ECO:0007829|PDB:4CCV"
FT HELIX 235..237
FT /evidence="ECO:0007829|PDB:4CCV"
FT TURN 239..242
FT /evidence="ECO:0007829|PDB:4CCV"
SQ SEQUENCE 526 AA; 58877 MW; 810F23D367D93D42 CRC64;
ATLQCSWALT PTDCKTTKPL AEKALDLINK WRRDGYLFQL LRVADAHLDG AESATVYYLV
LDVKETDCSV LSRKHWEDCD PDLTKRPSLD VIGQCKVIAT RYSDEYQTLR LNDFNCTTSS
VSSALANTKD SPVLFDFIED TEPFRKSADK ALEVYKSESE AYASFRVDRV ERVTRVKGGE
RTNYYVDFSV RNCSRSHFHR HPAFGFCRAD LSFDVEASNL ENPEDVIISC EVFNFEEHGN
ISGFRPHLGK TPLGTDGSRD HHHPHKPHKF GCPPPQEGED FSEGPPLQGG TPPLSPPFRP
RCRHRPFGTN ETHRFPHHRI SVNIIHRPPP HGHHPHGPPP HGHHPHGPPP HGHPPHGPPP
RHPPHGPPPH GHPPHGPPPH GHPPHGPPPH GHPPHGPPPH GHPPHGHGFH DHGPCDPPSH
KEGPQDLHQH AMGPPPKHPG KRGPGKGHFP FHWRRIGSVY QLPPLQKGEV LPLPEANFPQ
LLLRNHTHPL KPEIQPFPQV ASERCPEEFN GEFAQLSKFF PSTFPK
