ID IL6RA_RAT Reviewed; 462 AA.
AC P22273;
DT 01-AUG-1991, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-1995, sequence version 2.
DT 27-MAR-2024, entry version 168.
DE RecName: Full=Interleukin-6 receptor subunit alpha {ECO:0000305};
DE Short=IL-6 receptor subunit alpha;
DE Short=IL-6R subunit alpha;
DE Short=IL-6R-alpha;
DE Short=IL-6RA;
DE AltName: Full=IL-6R 1;
DE AltName: CD_antigen=CD126;
DE Contains:
DE RecName: Full=Soluble interleukin-6 receptor subunit alpha {ECO:0000305};
DE Short=sIL6R {ECO:0000305};
DE Flags: Precursor;
GN Name=Il6r {ECO:0000312|RGD:2902}; Synonyms=Il6ra;
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].
RC STRAIN=Fischer 344; TISSUE=Liver;
RX PubMed=2174054; DOI=10.1016/s0021-9258(17)45451-2;
RA Baumann M., Baumann H., Fey G.H.;
RT "Molecular cloning, characterization and functional expression of the rat
RT liver interleukin 6 receptor.";
RL J. Biol. Chem. 265:19853-19862(1990).
RN [2]
RP IDENTIFICATION OF PROBABLE FRAMESHIFT IN 227-261.
RA Gibson T.;
RL Unpublished observations (FEB-1995).
CC -!- FUNCTION: Part of the receptor for interleukin 6. Binds to IL6 with low
CC affinity, but does not transduce a signal. Signal activation
CC necessitate an association with IL6ST. Activation leads to the
CC regulation of the immune response, acute-phase reactions and
CC hematopoiesis. The interaction with membrane-bound IL6R and IL6ST
CC stimulates 'classic signaling', the restricted expression of the IL6R
CC limits classic IL6 signaling to only a few tissues such as the liver
CC and some cells of the immune system. Whereas the binding of IL6 and
CC soluble IL6R to IL6ST stimulates 'trans-signaling'. Alternatively,
CC 'cluster signaling' occurs when membrane-bound IL6:IL6R complexes on
CC transmitter cells activate IL6ST receptors on neighboring receiver
CC cells. {ECO:0000250|UniProtKB:P22272}.
CC -!- FUNCTION: [Interleukin-6 receptor subunit alpha]: Signaling via the
CC membrane-bound IL6R is mostly regenerative and anti-inflammatory.
CC Drives naive CD4(+) T cells to the Th17 lineage, through 'cluster
CC signaling' by dendritic cells. {ECO:0000250|UniProtKB:P22272}.
CC -!- FUNCTION: [Soluble interleukin-6 receptor subunit alpha]: Soluble form
CC of IL6 receptor (sIL6R) that acts as an agonist of IL6 activity (By
CC similarity). The IL6:sIL6R complex (hyper-IL6) binds to IL6ST/gp130 on
CC cell surfaces and induces signaling also on cells that do not express
CC membrane-bound IL6R in a process called IL6 'trans-signaling'. sIL6R is
CC causative for the pro-inflammatory properties of IL6 and an important
CC player in the development of chronic inflammatory diseases. In complex
CC with IL6, is required for induction of VEGF production (By similarity).
CC Plays a protective role during liver injury, being required for
CC maintenance of tissue regeneration. 'Trans-signaling' in central
CC nervous system regulates energy and glucose homeostasis (By
CC similarity). {ECO:0000250|UniProtKB:P08887,
CC ECO:0000250|UniProtKB:P22272}.
CC -!- ACTIVITY REGULATION: Classic and trans-signaling are both inhibited by
CC tocilizumab, a humanized monoclonal antibody that blocks interleukin
CC IL6R signaling. {ECO:0000250|UniProtKB:P08887}.
CC -!- SUBUNIT: Component of a hexamer of two molecules each of IL6, IL6R and
CC IL6ST; first binds to IL6 to associate with the signaling subunit
CC IL6ST. Interacts (via N-terminal ectodomain) with SORL1; this
CC interaction may affect IL6-binding to IL6R, hence decrease IL6
CC 'classic-signaling'. {ECO:0000250|UniProtKB:P22272}.
CC -!- SUBUNIT: [Soluble interleukin-6 receptor subunit alpha]: Also interacts
CC with SORL1; this interaction leads to soluble IL6R internalization. May
CC form a trimeric complex with the soluble SORL1 ectodomain and
CC circulating IL6 receptor; this interaction might stabilize circulating
CC IL6, hence promote IL6 'trans-signaling'.
CC {ECO:0000250|UniProtKB:P08887}.
CC -!- SUBCELLULAR LOCATION: [Interleukin-6 receptor subunit alpha]: Cell
CC membrane {ECO:0000250|UniProtKB:P22272}; Single-pass type I membrane
CC protein {ECO:0000255}.
CC -!- SUBCELLULAR LOCATION: [Soluble interleukin-6 receptor subunit alpha]:
CC Secreted {ECO:0000250|UniProtKB:P22272}.
CC -!- DOMAIN: The two fibronectin type-III-like domains contained in the C-
CC terminal part form together a cytokine-binding domain.
CC -!- DOMAIN: The WSXWS motif appears to be necessary for proper protein
CC folding and thereby efficient intracellular transport and cell-surface
CC receptor binding.
CC -!- PTM: A short soluble form is also released from the membrane by
CC proteolysis. The sIL6R is formed by limited proteolysis of membrane-
CC bound receptors, a process referred to as ectodomain shedding. mIL6R is
CC cleaved by the proteases ADAM10 and ADAM17.
CC {ECO:0000250|UniProtKB:P22272}.
CC -!- PTM: Glycosylated. Glycosylation is dispensable for transport,
CC signaling, and cell-surface turnover. Glycosylation at Asn-55 is a
CC protease-regulatory exosite. Glycosylation is required for ADAM17-
CC mediated proteolysis. {ECO:0000250|UniProtKB:P08887}.
CC -!- SIMILARITY: Belongs to the type I cytokine receptor family. Type 3
CC subfamily. {ECO:0000305}.
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DR EMBL; M58587; AAA41431.1; -; mRNA.
DR PIR; A37986; A37986.
DR STRING; 10116.ENSRNOP00000028234; -.
DR BindingDB; P22273; -.
DR ChEMBL; CHEMBL4289; -.
DR GlyCosmos; P22273; 5 sites, No reported glycans.
DR GlyGen; P22273; 5 sites.
DR PhosphoSitePlus; P22273; -.
DR PaxDb; 10116-ENSRNOP00000028234; -.
DR UCSC; RGD:2902; rat.
DR AGR; RGD:2902; -.
DR RGD; 2902; Il6r.
DR eggNOG; ENOG502RY0M; Eukaryota.
DR InParanoid; P22273; -.
DR PhylomeDB; P22273; -.
DR Reactome; R-RNO-1059683; Interleukin-6 signaling.
DR Reactome; R-RNO-110056; MAPK3 (ERK1) activation.
DR Reactome; R-RNO-112411; MAPK1 (ERK2) activation.
DR PRO; PR:P22273; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0016324; C:apical plasma membrane; ISO:RGD.
DR GO; GO:0070110; C:ciliary neurotrophic factor receptor complex; ISO:RGD.
DR GO; GO:0009897; C:external side of plasma membrane; IBA:GO_Central.
DR GO; GO:0005576; C:extracellular region; ISO:RGD.
DR GO; GO:0005615; C:extracellular space; IDA:RGD.
DR GO; GO:0005896; C:interleukin-6 receptor complex; ISS:UniProtKB.
DR GO; GO:0032809; C:neuronal cell body membrane; IDA:RGD.
DR GO; GO:0043235; C:receptor complex; IBA:GO_Central.
DR GO; GO:0070119; F:ciliary neurotrophic factor binding; ISO:RGD.
DR GO; GO:0004896; F:cytokine receptor activity; ISO:RGD.
DR GO; GO:0019899; F:enzyme binding; ISO:RGD.
DR GO; GO:0019970; F:interleukin-11 binding; IBA:GO_Central.
DR GO; GO:0004921; F:interleukin-11 receptor activity; IBA:GO_Central.
DR GO; GO:0019981; F:interleukin-6 binding; ISO:RGD.
DR GO; GO:0004915; F:interleukin-6 receptor activity; ISS:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; ISO:RGD.
DR GO; GO:0070120; P:ciliary neurotrophic factor-mediated signaling pathway; ISO:RGD.
DR GO; GO:0019221; P:cytokine-mediated signaling pathway; ISO:RGD.
DR GO; GO:0048589; P:developmental growth; IMP:RGD.
DR GO; GO:0031018; P:endocrine pancreas development; ISO:RGD.
DR GO; GO:0070102; P:interleukin-6-mediated signaling pathway; ISS:UniProtKB.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; IMP:RGD.
DR GO; GO:0032722; P:positive regulation of chemokine production; ISO:RGD.
DR GO; GO:0072126; P:positive regulation of glomerular mesangial cell proliferation; ISO:RGD.
DR GO; GO:0032755; P:positive regulation of interleukin-6 production; ISO:RGD.
DR GO; GO:0050731; P:positive regulation of peptidyl-tyrosine phosphorylation; ISO:RGD.
DR GO; GO:0048661; P:positive regulation of smooth muscle cell proliferation; ISO:RGD.
DR GO; GO:0042531; P:positive regulation of tyrosine phosphorylation of STAT protein; ISO:RGD.
DR GO; GO:0051591; P:response to cAMP; IEP:RGD.
DR GO; GO:0034097; P:response to cytokine; ISO:RGD.
DR GO; GO:0045471; P:response to ethanol; IEP:RGD.
DR GO; GO:0010332; P:response to gamma radiation; IEP:RGD.
DR GO; GO:0051384; P:response to glucocorticoid; IEP:RGD.
DR GO; GO:0032496; P:response to lipopolysaccharide; IEP:RGD.
DR GO; GO:0043434; P:response to peptide hormone; IEP:RGD.
DR GO; GO:0072540; P:T-helper 17 cell lineage commitment; ISS:UniProtKB.
DR GO; GO:0010573; P:vascular endothelial growth factor production; ISS:UniProtKB.
DR CDD; cd00063; FN3; 1.
DR Gene3D; 2.60.40.10; Immunoglobulins; 3.
DR InterPro; IPR003961; FN3_dom.
DR InterPro; IPR036116; FN3_sf.
DR InterPro; IPR003530; Hematopoietin_rcpt_L_F3_CS.
DR InterPro; IPR007110; Ig-like_dom.
DR InterPro; IPR036179; Ig-like_dom_sf.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR003599; Ig_sub.
DR InterPro; IPR003598; Ig_sub2.
DR InterPro; IPR013151; Immunoglobulin.
DR InterPro; IPR015321; TypeI_recpt_CBD.
DR PANTHER; PTHR23036; CYTOKINE RECEPTOR; 1.
DR PANTHER; PTHR23036:SF98; INTERLEUKIN-6 RECEPTOR SUBUNIT ALPHA; 1.
DR Pfam; PF00047; ig; 1.
DR Pfam; PF09240; IL6Ra-bind; 1.
DR SMART; SM00409; IG; 1.
DR SMART; SM00408; IGc2; 1.
DR SUPFAM; SSF49265; Fibronectin type III; 2.
DR SUPFAM; SSF48726; Immunoglobulin; 1.
DR PROSITE; PS50853; FN3; 1.
DR PROSITE; PS01354; HEMATOPO_REC_L_F3; 1.
DR PROSITE; PS50835; IG_LIKE; 1.
PE 2: Evidence at transcript level;
KW Cell membrane; Disulfide bond; Glycoprotein; Immunoglobulin domain;
KW Membrane; Receptor; Reference proteome; Secreted; Signal; Transmembrane;
KW Transmembrane helix.
FT SIGNAL 1..19
FT CHAIN 20..462
FT /note="Interleukin-6 receptor subunit alpha"
FT /id="PRO_0000010898"
FT CHAIN 20..354
FT /note="Soluble interleukin-6 receptor subunit alpha"
FT /evidence="ECO:0000250|UniProtKB:P08887"
FT /id="PRO_0000450733"
FT TOPO_DOM 20..364
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 365..385
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 386..462
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 20..108
FT /note="Ig-like C2-type"
FT DOMAIN 215..313
FT /note="Fibronectin type-III"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316"
FT REGION 420..462
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 300..304
FT /note="WSXWS motif"
FT COMPBIAS 422..455
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 354..355
FT /note="Cleavage; by ADAM10 and ADAM17"
FT /evidence="ECO:0000250|UniProtKB:P08887"
FT CARBOHYD 32
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 55
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000250|UniProtKB:P08887"
FT CARBOHYD 85
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 150
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 218
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000250|UniProtKB:P08887"
FT DISULFID 25..190
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114"
FT DISULFID 47..92
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114"
FT DISULFID 117..128
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114"
FT DISULFID 162..173
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114"
FT CONFLICT 227..261
FT /note="XPRWLKVSWQDPESWDPSYYLLQFELRYRPVWSKX -> SLVGSKSVGKTLS
FT PGTQVTTCCNSSFDTDLYGQRT (in Ref. 1; AAA41431)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 462 AA; 50401 MW; A4D6064CEDC0537D CRC64;
MLAVGCTLLV ALLAAPAVAL VLGSCRALEV ANGTVTSLPG ATVTLICPGK EAAGNATIHW
VYSGSQSREW TTTGNTLVLR AVQVNDTGHY LCFLDDHLVG TVPLLVDVPP EEPKLSCFRK
NPLVNAFCEW HPSSTPSPTT KAVMFAKKIN TTNGKSDFQV PCQYSQQLKS FSCEVEILEG
DKVYHIVSLC VANSVGSRSS HNVVFQSLKM VQPDPPANLV VSAIPGXPRW LKVSWQDPES
WDPSYYLLQF ELRYRPVWSK XFTVWPLQVA QHQCVIHDAL RGVKHVVQVR GKEEFDIGQW
SKWSPEVTGT PWLAEPRTTP AGIPGNPTQV SVEDYDNHED QYGSSTEATS VLAPVQGSSP
IPLPTFLVAG GSLAFGLLLC VFIILRLKKK WKSQAEKESK TTSPPPYPLG PLKPTFLLVP
LLTPSGSHNS SGTDNTGSHS CLGVRDPQCP NDNSNRDYLF PR
//