IL6RA_HUMAN
ID IL6RA_HUMAN Reviewed; 468 AA.
AC P08887; A8KAE8; B2R6V4; Q16202; Q53EQ7; Q5FWG2; Q5VZ23;
DT 01-NOV-1988, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1988, sequence version 1.
DT 03-AUG-2022, entry version 238.
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: Full=Membrane glycoprotein 80;
DE Short=gp80;
DE AltName: CD_antigen=CD126;
DE Contains:
DE RecName: Full=Soluble interleukin-6 receptor subunit alpha {ECO:0000305};
DE Short=sIL6R {ECO:0000303|PubMed:12794819, ECO:0000303|PubMed:26876177, ECO:0000303|PubMed:28060820};
DE Flags: Precursor;
GN Name=IL6R {ECO:0000312|HGNC:HGNC:6019};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=3136546; DOI=10.1126/science.3136546;
RA Yamasaki K., Taga T., Hirata Y., Yawata H., Kawanishi Y., Seed B.,
RA Taniguchi T., Hirano T., Kishimoto T.;
RT "Cloning and expression of the human interleukin-6 (BSF-2/IFN beta 2)
RT receptor.";
RL Science 241:825-828(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA Yamasaki K., Taga T., Hirata Y., Yawata H., Kawanishi Y., Seed B.,
RA Taniguchi T., Hirano T., Kishimoto T.;
RT "Molecular structure of interleukin 6 receptor.";
RL Proc. Jpn. Acad., B, Phys. Biol. Sci. 64:209-211(1988).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=1872801; DOI=10.1042/bj2770659;
RA Schooltink H., Stoyan T., Lenz D., Schmitz H., Hirano T., Kishimoto T.,
RA Heinrich P.C., Rose-John S.;
RT "Structural and functional studies on the human hepatic interleukin-6
RT receptor. Molecular cloning and overexpression in HepG2 cells.";
RL Biochem. J. 277:659-664(1991).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND VARIANT
RP ALA-358.
RC TISSUE=Trachea;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Kidney;
RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.;
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A.,
RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C.,
RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K.,
RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W.,
RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J.,
RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J.,
RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y.,
RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J.,
RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S.,
RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K.,
RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R.,
RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M.,
RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S.,
RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J.,
RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W.,
RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S.,
RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M.,
RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H.,
RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E.,
RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G.,
RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Lymph;
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 [9]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 313-365 (ISOFORM 2).
RX PubMed=8056053; DOI=10.1002/eji.1830240837;
RA Horiuchi S., Koyanagi Y., Zhou Y., Miyamoto H., Tanaka Y., Waki M.,
RA Matsumoto A., Yamamoto M., Yamamoto N.;
RT "Soluble interleukin-6 receptors released from T cell or
RT granulocyte/macrophage cell lines and human peripheral blood mononuclear
RT cells are generated through an alternative splicing mechanism.";
RL Eur. J. Immunol. 24:1945-1948(1994).
RN [10]
RP PARTIAL PROTEIN SEQUENCE, GLYCOSYLATION AT ASN-55; ASN-93 AND ASN-221, LACK
RP OF GLYCOSYLATION AT ASN-245, AND DISULFIDE BONDS.
RX PubMed=10066782; DOI=10.1074/jbc.274.11.7207;
RA Cole A.R., Hall N.E., Treutlein H.R., Eddes J.S., Reid G.E., Moritz R.L.,
RA Simpson R.J.;
RT "Disulfide bond structure and N-glycosylation sites of the extracellular
RT domain of the human interleukin-6 receptor.";
RL J. Biol. Chem. 274:7207-7215(1999).
RN [11]
RP PROTEIN SEQUENCE OF 20-49, AND SUBCELLULAR LOCATION.
RX PubMed=2529343; DOI=10.1084/jem.170.4.1409;
RA Novick D., Engelmann H., Wallach D., Rubinstein M.;
RT "Soluble cytokine receptors are present in normal human urine.";
RL J. Exp. Med. 170:1409-1414(1989).
RN [12]
RP MUTAGENESIS.
RX PubMed=8467812; DOI=10.1002/j.1460-2075.1993.tb05815.x;
RA Yawata H., Yasukawa K., Natsuka S., Murakami M., Yamasaki K., Hibi M.,
RA Taga T., Kishimoto T.;
RT "Structure-function analysis of human IL-6 receptor: dissociation of amino
RT acid residues required for IL-6-binding and for IL-6 signal transduction
RT through gp130.";
RL EMBO J. 12:1705-1712(1993).
RN [13]
RP FUNCTION.
RX PubMed=11017875; DOI=10.1242/jcs.113.20.3593;
RA Martens A.S., Bode J.G., Heinrich P.C., Graeve L.;
RT "The cytoplasmic domain of the interleukin-6 receptor gp80 mediates its
RT basolateral sorting in polarized Madin-Darby canine kidney cells.";
RL J. Cell Sci. 113:3593-3602(2000).
RN [14]
RP FUNCTION.
RX PubMed=12794819; DOI=10.1002/art.11143;
RA Nakahara H., Song J., Sugimoto M., Hagihara K., Kishimoto T., Yoshizaki K.,
RA Nishimoto N.;
RT "Anti-interleukin-6 receptor antibody therapy reduces vascular endothelial
RT growth factor production in rheumatoid arthritis.";
RL Arthritis Rheum. 48:1521-1529(2003).
RN [15]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=16270750; DOI=10.1016/j.ejcb.2005.06.001;
RA Buk D.M., Renner O., Graeve L.;
RT "Increased association with detergent-resistant membranes/lipid rafts of
RT apically targeted mutants of the interleukin-6 receptor gp80.";
RL Eur. J. Cell Biol. 84:819-831(2005).
RN [16]
RP FUNCTION, AND ACTIVITY REGULATION.
RX PubMed=21990364; DOI=10.1074/jbc.m111.295758;
RA Garbers C., Thaiss W., Jones G.W., Waetzig G.H., Lorenzen I., Guilhot F.,
RA Lissilaa R., Ferlin W.G., Groetzinger J., Jones S.A., Rose-John S.,
RA Scheller J.;
RT "Inhibition of classic signaling is a novel function of soluble
RT glycoprotein 130 (sgp130), which is controlled by the ratio of interleukin
RT 6 and soluble interleukin 6 receptor.";
RL J. Biol. Chem. 286:42959-42970(2011).
RN [17]
RP FUNCTION, AND PROTEOLYTIC CLEAVAGE.
RX PubMed=26876177; DOI=10.1016/j.celrep.2016.01.053;
RA Lokau J., Nitz R., Agthe M., Monhasery N., Aparicio-Siegmund S.,
RA Schumacher N., Wolf J., Moeller-Hackbarth K., Waetzig G.H., Groetzinger J.,
RA Mueller-Newen G., Rose-John S., Scheller J., Garbers C.;
RT "Proteolytic Cleavage Governs Interleukin-11 Trans-signaling.";
RL Cell Rep. 14:1761-1773(2016).
RN [18]
RP FUNCTION, AND INTERACTION WITH SORL1.
RX PubMed=28265003; DOI=10.1128/mcb.00641-16;
RA Larsen J.V., Petersen C.M.;
RT "SorLA in Interleukin-6 Signaling and Turnover.";
RL Mol. Cell. Biol. 37:0-0(2017).
RN [19]
RP FUNCTION, PROTEOLYTIC CLEAVAGE, TISSUE SPECIFICITY (ISOFORM 2),
RP GLYCOSYLATION AT ASN-55; ASN-93; ASN-221; ASN-245; ASN-350 AND THR-352,
RP MUTAGENESIS OF ASN-55; THR-57; ASN-93; ASN-221; ASN-245; ASN-350; THR-352;
RP 355-PRO-VAL-356; PRO-355 AND VAL-356, CHARACTERIZATION OF VARIANT ALA-358,
RP AND SUBCELLULAR LOCATION.
RX PubMed=28060820; DOI=10.1371/journal.pbio.2000080;
RA Riethmueller S., Somasundaram P., Ehlers J.C., Hung C.W., Flynn C.M.,
RA Lokau J., Agthe M., Duesterhoeft S., Zhu Y., Groetzinger J., Lorenzen I.,
RA Koudelka T., Yamamoto K., Pickhinke U., Wichert R., Becker-Pauly C.,
RA Raedisch M., Albrecht A., Hessefort M., Stahnke D., Unverzagt C.,
RA Rose-John S., Tholey A., Garbers C.;
RT "Proteolytic Origin of the Soluble Human IL-6R In Vivo and a Decisive Role
RT of N-Glycosylation.";
RL PLoS Biol. 15:e2000080-e2000080(2017).
RN [20]
RP REVIEW ON FUNCTION.
RX PubMed=30995492; DOI=10.1016/j.immuni.2019.03.026;
RA Kang S., Tanaka T., Narazaki M., Kishimoto T.;
RT "Targeting Interleukin-6 Signaling in Clinic.";
RL Immunity 50:1007-1023(2019).
RN [21]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 20-344.
RX PubMed=12461182; DOI=10.1073/pnas.232432399;
RA Varghese J.N., Moritz R.L., Lou M.-Z., Van Donkelaar A., Ji H., Ivancic N.,
RA Branson K.M., Hall N.E., Simpson R.J.;
RT "Structure of the extracellular domains of the human interleukin-6 receptor
RT alpha-chain.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:15959-15964(2002).
RN [22] {ECO:0007744|PDB:1P9M}
RP X-RAY CRYSTALLOGRAPHY (3.65 ANGSTROMS) OF 115-315 IN COMPLEX WITH IL6 AND
RP IL6ST, AND SUBUNIT.
RX PubMed=12829785; DOI=10.1126/science.1083901;
RA Boulanger M.J., Chow D.C., Brevnova E.E., Garcia K.C.;
RT "Hexameric structure and assembly of the interleukin-6/IL-6 alpha-
RT receptor/gp130 complex.";
RL Science 300:2101-2104(2003).
RN [23]
RP POLYMORPHISM, VARIANT ALA-358, AND ASSOCIATION OF VARIANT ALA-358 WITH IL6
RP AND SOLUBLE IL6R SERUM LEVELS.
RX PubMed=17357077; DOI=10.1086/513206;
RG Health, Aging and Body Composition (Health ABC) Study;
RA Reich D., Patterson N., Ramesh V., De Jager P.L., McDonald G.J., Tandon A.,
RA Choy E., Hu D., Tamraz B., Pawlikowska L., Wassel-Fyr C., Huntsman S.,
RA Waliszewska A., Rossin E., Li R., Garcia M., Reiner A., Ferrell R.,
RA Cummings S., Kwok P.Y., Harris T., Zmuda J.M., Ziv E.;
RT "Admixture mapping of an allele affecting interleukin 6 soluble receptor
RT and interleukin 6 levels.";
RL Am. J. Hum. Genet. 80:716-726(2007).
RN [24]
RP INVOLVEMENT IN HIES5, VARIANTS HIES5 ASN-279 AND PRO-280, CHARACTERIZATION
RP OF VARIANTS HIES5 ASN-279 AND PRO-280, AND FUNCTION.
RX PubMed=31235509; DOI=10.1084/jem.20190344;
RA Spencer S., Koestel Bal S., Egner W., Lango Allen H., Raza S.I., Ma C.A.,
RA Guerel M., Zhang Y., Sun G., Sabroe R.A., Greene D., Rae W., Shahin T.,
RA Kania K., Ardy R.C., Thian M., Staples E., Pecchia-Bekkum A.,
RA Worrall W.P.M., Stephens J., Brown M., Tuna S., York M., Shackley F.,
RA Kerrin D., Sargur R., Condliffe A., Tipu H.N., Kuehn H.S., Rosenzweig S.D.,
RA Turro E., Tavare S., Thrasher A.J., Jodrell D.I., Smith K.G.C., Boztug K.,
RA Milner J.D., Thaventhiran J.E.D.;
RT "Loss of the interleukin-6 receptor causes immunodeficiency, atopy, and
RT abnormal inflammatory responses.";
RL J. Exp. Med. 216:1986-1998(2019).
CC -!- FUNCTION: Part of the receptor for interleukin 6. Binds to IL6 with low
CC affinity, but does not transduce a signal (PubMed:28265003). Signal
CC activation necessitate an association with IL6ST. Activation leads to
CC the regulation of the immune response, acute-phase reactions and
CC hematopoiesis (PubMed:30995492, PubMed:31235509). The interaction with
CC membrane-bound IL6R and IL6ST stimulates 'classic signaling', the
CC restricted expression of the IL6R limits classic IL6 signaling to only
CC a few tissues such as the liver and some cells of the immune system.
CC Whereas the binding of IL6 and soluble IL6R to IL6ST stimulates 'trans-
CC signaling'. Alternatively, 'cluster signaling' occurs when membrane-
CC bound IL6:IL6R complexes on transmitter cells activate IL6ST receptors
CC on neighboring receiver cells (Probable). {ECO:0000269|PubMed:28265003,
CC ECO:0000269|PubMed:31235509, ECO:0000305|PubMed:30995492}.
CC -!- FUNCTION: [Isoform 1]: Signaling via the membrane-bound IL6R is mostly
CC regenerative and anti-inflammatory (Probable). Drives naive CD4(+) T
CC cells to the Th17 lineage, through 'cluster signaling' by dendritic
CC cells (By similarity). {ECO:0000250|UniProtKB:P22272,
CC ECO:0000305|PubMed:30995492}.
CC -!- FUNCTION: [Isoform 2]: Soluble form of IL6 receptor (sIL6R) that acts
CC as an agonist of IL6 activity (PubMed:21990364). The IL6:sIL6R complex
CC (hyper-IL6) binds to IL6ST/gp130 on cell surfaces and induces signaling
CC also on cells that do not express membrane-bound IL6R in a process
CC called IL6 'trans-signaling'. sIL6R is causative for the pro-
CC inflammatory properties of IL6 and an important player in the
CC development of chronic inflammatory diseases (PubMed:21990364). In
CC complex with IL6, is required for induction of VEGF production
CC (PubMed:12794819). Plays a protective role during liver injury, being
CC required for maintenance of tissue regeneration (By similarity).
CC 'Trans-signaling' in central nervous system regulates energy and
CC glucose homeostasis (By similarity). {ECO:0000250|UniProtKB:P22272,
CC ECO:0000269|PubMed:12794819, ECO:0000269|PubMed:21990364}.
CC -!- FUNCTION: [Soluble interleukin-6 receptor subunit alpha]: Soluble form
CC of IL6 receptor (sIL6R) that acts as an agonist of IL6 activity
CC (PubMed:21990364). The IL6:sIL6R complex (hyper-IL6) binds to
CC IL6ST/gp130 on cell surfaces and induces signaling also on cells that
CC do not express membrane-bound IL6R in a process called IL6 'trans-
CC signaling'. sIL6R is causative for the pro-inflammatory properties of
CC IL6 and an important player in the development of chronic inflammatory
CC diseases (PubMed:21990364). In complex with IL6, is required for
CC induction of VEGF production (PubMed:12794819). Plays a protective role
CC during liver injury, being required for maintenance of tissue
CC regeneration (By similarity). 'Trans-signaling' in central nervous
CC system regulates energy and glucose homeostasis (By similarity).
CC {ECO:0000250|UniProtKB:P22272, ECO:0000269|PubMed:12794819,
CC ECO:0000269|PubMed:21990364}.
CC -!- ACTIVITY REGULATION: Classic and trans-signaling are both inhibited by
CC tocilizumab, a humanized monoclonal antibody that blocks interleukin
CC IL6R signaling. {ECO:0000269|PubMed:21990364}.
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 IL6ST
CC (PubMed:12829785, PubMed:28265003). Interacts (via N-terminal
CC ectodomain) with SORL1; this interaction may affect IL6-binding to
CC IL6R, hence decrease IL6 'classic-signaling' (PubMed:28265003).
CC {ECO:0000269|PubMed:12829785, ECO:0000269|PubMed:28265003}.
CC -!- SUBUNIT: [Isoform 2]: Also interacts with SORL1; this interaction leads
CC to soluble IL6R internalization. May form a trimeric complex with the
CC soluble SORL1 ectodomain and circulating IL6 receptor; this interaction
CC might stabilize circulating IL6, hence promote IL6 'trans-signaling,.
CC {ECO:0000269|PubMed:28265003}.
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:0000269|PubMed:28265003}.
CC -!- INTERACTION:
CC P08887; P05231: IL6; NbExp=7; IntAct=EBI-299383, EBI-720533;
CC P08887; Q96EQ0: SGTB; NbExp=3; IntAct=EBI-299383, EBI-744081;
CC P08887; Q92673: SORL1; NbExp=7; IntAct=EBI-299383, EBI-1171329;
CC P08887; Q2HRC7: K2; Xeno; NbExp=3; IntAct=EBI-299383, EBI-9007403;
CC P08887-2; O00233: PSMD9; NbExp=3; IntAct=EBI-16630231, EBI-750973;
CC -!- SUBCELLULAR LOCATION: [Isoform 1]: Cell membrane
CC {ECO:0000250|UniProtKB:P22272}; Single-pass type I membrane protein
CC {ECO:0000255}.
CC -!- SUBCELLULAR LOCATION: [Isoform 2]: Secreted
CC {ECO:0000269|PubMed:28060820}.
CC -!- SUBCELLULAR LOCATION: [Soluble interleukin-6 receptor subunit alpha]:
CC Secreted {ECO:0000269|PubMed:28060820}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=Long, mIL6R {ECO:0000303|PubMed:26876177};
CC IsoId=P08887-1; Sequence=Displayed;
CC Name=2; Synonyms=Short, sIL6R {ECO:0000303|PubMed:21990364};
CC IsoId=P08887-2; Sequence=VSP_001682, VSP_001683;
CC -!- TISSUE SPECIFICITY: [Isoform 2]: Expressed in peripheral blood
CC mononuclear cells and weakly found in urine and serum. 1%-20% of the
CC total sIL6R in plasma is generated by alternative splicing
CC (PubMed:28060820). {ECO:0000269|PubMed:28060820}.
CC -!- DOMAIN: The two fibronectin type-III-like domains, contained in the N-
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 released from the membrane by proteolysis
CC (PubMed:26876177). The sIL6R is formed mostly by limited proteolysis of
CC membrane-bound receptors, a process referred to as ectodomain shedding,
CC but is also directly secreted from the cells after alternative mRNA
CC splicing (PubMed:26876177, PubMed:28060820). mIL6R is cleaved by the
CC proteases ADAM10 and ADAM17 (PubMed:26876177, PubMed:28060820).
CC {ECO:0000269|PubMed:26876177, ECO:0000269|PubMed:28060820}.
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:0000269|PubMed:28060820}.
CC -!- POLYMORPHISM: Genetic variations in IL6R determine soluble IL6R serum
CC levels [MIM:614689]. {ECO:0000269|PubMed:17357077}.
CC -!- POLYMORPHISM: Genetic variations in IL6R define the IL6 serum level
CC quantitative trait locus [MIM:614752]. {ECO:0000269|PubMed:17357077}.
CC -!- DISEASE: Hyper-IgE recurrent infection syndrome 5, autosomal recessive
CC (HIES5) [MIM:618944]: An immunologic disorder characterized by
CC recurrent sinopulmonary and deep skin infections, mostly caused by
CC bacteria, including H. influenza and Staphylococcus aureus. Additional
CC features include asthma, atopic dermatitis, and impaired inflammatory
CC responses during infection. Disease onset is in early infancy.
CC {ECO:0000269|PubMed:31235509}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the type I cytokine receptor family. Type 3
CC subfamily. {ECO:0000305}.
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DR EMBL; X12830; CAA31312.1; -; mRNA.
DR EMBL; X58298; CAA41231.1; -; mRNA.
DR EMBL; AK293013; BAF85702.1; -; mRNA.
DR EMBL; AK312730; BAG35601.1; -; mRNA.
DR EMBL; AK223582; BAD97302.1; -; mRNA.
DR EMBL; AL162591; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471121; EAW53200.1; -; Genomic_DNA.
DR EMBL; BC089410; AAH89410.1; -; mRNA.
DR EMBL; S72848; AAC60635.1; -; mRNA.
DR CCDS; CCDS1067.1; -. [P08887-1]
DR CCDS; CCDS1068.1; -. [P08887-2]
DR PIR; A41242; A41242.
DR RefSeq; NP_000556.1; NM_000565.3. [P08887-1]
DR RefSeq; NP_001193795.1; NM_001206866.1.
DR RefSeq; NP_852004.1; NM_181359.2. [P08887-2]
DR PDB; 1N26; X-ray; 2.40 A; A=20-344.
DR PDB; 1P9M; X-ray; 3.65 A; C=115-315.
DR PDB; 2ARW; NMR; -; A=212-336.
DR PDB; 5FUC; X-ray; 2.70 A; C/D=111-322.
DR PDB; 7DC8; X-ray; 2.76 A; C/F=111-320.
DR PDBsum; 1N26; -.
DR PDBsum; 1P9M; -.
DR PDBsum; 2ARW; -.
DR PDBsum; 5FUC; -.
DR PDBsum; 7DC8; -.
DR AlphaFoldDB; P08887; -.
DR BMRB; P08887; -.
DR SASBDB; P08887; -.
DR SMR; P08887; -.
DR BioGRID; 109784; 25.
DR DIP; DIP-162N; -.
DR ELM; P08887; -.
DR IntAct; P08887; 18.
DR MINT; P08887; -.
DR STRING; 9606.ENSP00000357470; -.
DR ChEMBL; CHEMBL2364155; -.
DR DrugBank; DB11767; Sarilumab.
DR DrugBank; DB15762; Satralizumab.
DR DrugBank; DB06273; Tocilizumab.
DR DrugCentral; P08887; -.
DR GuidetoPHARMACOLOGY; 1708; -.
DR GlyGen; P08887; 9 sites, 3 O-linked glycans (3 sites).
DR iPTMnet; P08887; -.
DR PhosphoSitePlus; P08887; -.
DR BioMuta; IL6R; -.
DR DMDM; 124343; -.
DR jPOST; P08887; -.
DR MassIVE; P08887; -.
DR MaxQB; P08887; -.
DR PaxDb; P08887; -.
DR PeptideAtlas; P08887; -.
DR PRIDE; P08887; -.
DR ProteomicsDB; 52171; -. [P08887-1]
DR ProteomicsDB; 52172; -. [P08887-2]
DR ABCD; P08887; 138 sequenced antibodies.
DR Antibodypedia; 20397; 961 antibodies from 42 providers.
DR CPTC; P08887; 1 antibody.
DR DNASU; 3570; -.
DR Ensembl; ENST00000344086.8; ENSP00000340589.4; ENSG00000160712.13. [P08887-2]
DR Ensembl; ENST00000368485.8; ENSP00000357470.3; ENSG00000160712.13. [P08887-1]
DR GeneID; 3570; -.
DR KEGG; hsa:3570; -.
DR MANE-Select; ENST00000368485.8; ENSP00000357470.3; NM_000565.4; NP_000556.1.
DR UCSC; uc001fez.2; human. [P08887-1]
DR CTD; 3570; -.
DR DisGeNET; 3570; -.
DR GeneCards; IL6R; -.
DR HGNC; HGNC:6019; IL6R.
DR HPA; ENSG00000160712; Tissue enhanced (liver, skeletal muscle).
DR MalaCards; IL6R; -.
DR MIM; 147880; gene.
DR MIM; 614689; phenotype.
DR MIM; 614752; phenotype.
DR MIM; 618944; phenotype.
DR neXtProt; NX_P08887; -.
DR OpenTargets; ENSG00000160712; -.
DR PharmGKB; PA29835; -.
DR VEuPathDB; HostDB:ENSG00000160712; -.
DR eggNOG; ENOG502RY0M; Eukaryota.
DR GeneTree; ENSGT00940000161919; -.
DR HOGENOM; CLU_051451_0_0_1; -.
DR InParanoid; P08887; -.
DR OrthoDB; 783799at2759; -.
DR PhylomeDB; P08887; -.
DR TreeFam; TF331210; -.
DR PathwayCommons; P08887; -.
DR Reactome; R-HSA-1059683; Interleukin-6 signaling.
DR Reactome; R-HSA-110056; MAPK3 (ERK1) activation.
DR Reactome; R-HSA-112411; MAPK1 (ERK2) activation.
DR Reactome; R-HSA-6785807; Interleukin-4 and Interleukin-13 signaling.
DR Reactome; R-HSA-9616222; Transcriptional regulation of granulopoiesis.
DR Reactome; R-HSA-9679191; Potential therapeutics for SARS.
DR SignaLink; P08887; -.
DR SIGNOR; P08887; -.
DR BioGRID-ORCS; 3570; 14 hits in 1078 CRISPR screens.
DR ChiTaRS; IL6R; human.
DR EvolutionaryTrace; P08887; -.
DR GeneWiki; Interleukin-6_receptor; -.
DR GenomeRNAi; 3570; -.
DR Pharos; P08887; Tclin.
DR PRO; PR:P08887; -.
DR Proteomes; UP000005640; Chromosome 1.
DR RNAct; P08887; protein.
DR Bgee; ENSG00000160712; Expressed in blood and 191 other tissues.
DR ExpressionAtlas; P08887; baseline and differential.
DR Genevisible; P08887; HS.
DR GO; GO:0016324; C:apical plasma membrane; IDA:BHF-UCL.
DR GO; GO:0070110; C:ciliary neurotrophic factor receptor complex; IDA:BHF-UCL.
DR GO; GO:0009897; C:external side of plasma membrane; IBA:GO_Central.
DR GO; GO:0005576; C:extracellular region; IDA:UniProtKB.
DR GO; GO:0005615; C:extracellular space; IDA:BHF-UCL.
DR GO; GO:0005896; C:interleukin-6 receptor complex; IDA:BHF-UCL.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0043235; C:receptor complex; IBA:GO_Central.
DR GO; GO:0070119; F:ciliary neurotrophic factor binding; IPI:BHF-UCL.
DR GO; GO:0019955; F:cytokine binding; IBA:GO_Central.
DR GO; GO:0004896; F:cytokine receptor activity; IBA:GO_Central.
DR GO; GO:0019899; F:enzyme binding; IPI:UniProtKB.
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; IPI:BHF-UCL.
DR GO; GO:0004915; F:interleukin-6 receptor activity; IEA:Ensembl.
DR GO; GO:0042803; F:protein homodimerization activity; IPI:BHF-UCL.
DR GO; GO:0006953; P:acute-phase response; TAS:BHF-UCL.
DR GO; GO:0070120; P:ciliary neurotrophic factor-mediated signaling pathway; IMP:BHF-UCL.
DR GO; GO:0019221; P:cytokine-mediated signaling pathway; IDA:BHF-UCL.
DR GO; GO:0050829; P:defense response to Gram-negative bacterium; TAS:BHF-UCL.
DR GO; GO:0050830; P:defense response to Gram-positive bacterium; NAS:BHF-UCL.
DR GO; GO:0031018; P:endocrine pancreas development; IMP:BHF-UCL.
DR GO; GO:0097191; P:extrinsic apoptotic signaling pathway; TAS:BHF-UCL.
DR GO; GO:0002384; P:hepatic immune response; TAS:BHF-UCL.
DR GO; GO:0070102; P:interleukin-6-mediated signaling pathway; IDA:ARUK-UCL.
DR GO; GO:0002548; P:monocyte chemotaxis; IC:BHF-UCL.
DR GO; GO:0032966; P:negative regulation of collagen biosynthetic process; IDA:BHF-UCL.
DR GO; GO:0032717; P:negative regulation of interleukin-8 production; NAS:BHF-UCL.
DR GO; GO:0002446; P:neutrophil mediated immunity; TAS:BHF-UCL.
DR GO; GO:0010536; P:positive regulation of activation of Janus kinase activity; IDA:BHF-UCL.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; IDA:BHF-UCL.
DR GO; GO:0032722; P:positive regulation of chemokine production; IDA:BHF-UCL.
DR GO; GO:0072126; P:positive regulation of glomerular mesangial cell proliferation; IMP:ARUK-UCL.
DR GO; GO:0032755; P:positive regulation of interleukin-6 production; IDA:BHF-UCL.
DR GO; GO:0002690; P:positive regulation of leukocyte chemotaxis; TAS:BHF-UCL.
DR GO; GO:0043410; P:positive regulation of MAPK cascade; IDA:BHF-UCL.
DR GO; GO:0045669; P:positive regulation of osteoblast differentiation; TAS:BHF-UCL.
DR GO; GO:0050731; P:positive regulation of peptidyl-tyrosine phosphorylation; IDA:BHF-UCL.
DR GO; GO:1901731; P:positive regulation of platelet aggregation; IDA:ARUK-UCL.
DR GO; GO:0048661; P:positive regulation of smooth muscle cell proliferation; IDA:BHF-UCL.
DR GO; GO:0042531; P:positive regulation of tyrosine phosphorylation of STAT protein; IMP:BHF-UCL.
DR GO; GO:0034097; P:response to cytokine; IDA:BHF-UCL.
DR GO; GO:0072540; P:T-helper 17 cell lineage commitment; IEA:Ensembl.
DR GO; GO:0010573; P:vascular endothelial growth factor production; IDA:UniProtKB.
DR CDD; cd00063; FN3; 1.
DR Gene3D; 2.60.40.10; -; 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 Pfam; PF00047; ig; 1.
DR Pfam; PF09240; IL6Ra-bind; 1.
DR SMART; SM00060; FN3; 1.
DR SMART; SM00409; IG; 1.
DR SMART; SM00408; IGc2; 1.
DR SUPFAM; SSF48726; SSF48726; 1.
DR SUPFAM; SSF49265; SSF49265; 2.
DR PROSITE; PS50853; FN3; 2.
DR PROSITE; PS01354; HEMATOPO_REC_L_F3; 1.
DR PROSITE; PS50835; IG_LIKE; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell membrane;
KW Direct protein sequencing; Disulfide bond; Glycoprotein;
KW Immunoglobulin domain; Membrane; Receptor; Reference proteome; Repeat;
KW Secreted; Signal; Transmembrane; Transmembrane helix.
FT SIGNAL 1..19
FT /evidence="ECO:0000269|PubMed:2529343"
FT CHAIN 20..468
FT /note="Interleukin-6 receptor subunit alpha"
FT /id="PRO_0000010895"
FT CHAIN 20..355
FT /note="Soluble interleukin-6 receptor subunit alpha"
FT /id="PRO_0000450730"
FT TOPO_DOM 20..365
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 366..386
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 387..468
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 26..112
FT /note="Ig-like C2-type"
FT DOMAIN 113..217
FT /note="Fibronectin type-III 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316"
FT DOMAIN 218..316
FT /note="Fibronectin type-III 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316"
FT REGION 303..328
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 421..468
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 303..307
FT /note="WSXWS motif"
FT COMPBIAS 311..328
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 245
FT /note="Not glycosylated"
FT /evidence="ECO:0000269|PubMed:10066782"
FT SITE 355..356
FT /note="Cleavage; by ADAM10 and ADAM17"
FT /evidence="ECO:0000269|PubMed:28060820"
FT CARBOHYD 55
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:10066782,
FT ECO:0000269|PubMed:28060820"
FT CARBOHYD 93
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:10066782,
FT ECO:0000269|PubMed:28060820"
FT CARBOHYD 221
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:10066782,
FT ECO:0000269|PubMed:28060820"
FT CARBOHYD 245
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:28060820"
FT CARBOHYD 350
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:28060820"
FT CARBOHYD 352
FT /note="O-linked (GlcNAc) threonine"
FT /evidence="ECO:0000269|PubMed:28060820"
FT DISULFID 25..193
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114,
FT ECO:0000269|PubMed:10066782"
FT DISULFID 47..96
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114,
FT ECO:0000269|PubMed:10066782"
FT DISULFID 121..132
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114,
FT ECO:0000269|PubMed:10066782"
FT DISULFID 165..176
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114,
FT ECO:0000269|PubMed:10066782"
FT VAR_SEQ 356..365
FT /note="VQDSSSVPLP -> GSRRRGSCGL (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039,
FT ECO:0000303|PubMed:15489334, ECO:0000303|PubMed:8056053"
FT /id="VSP_001682"
FT VAR_SEQ 366..468
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039,
FT ECO:0000303|PubMed:15489334, ECO:0000303|PubMed:8056053"
FT /id="VSP_001683"
FT VARIANT 279
FT /note="I -> N (in HIES5; decreased STAT1 and STAT3
FT phosphorylation)"
FT /evidence="ECO:0000269|PubMed:31235509"
FT /id="VAR_084713"
FT VARIANT 280
FT /note="H -> P (in HIES5; unknown pathological significance;
FT no effect on STAT1 and STAT3 phosphorylation)"
FT /evidence="ECO:0000269|PubMed:31235509"
FT /id="VAR_084714"
FT VARIANT 358
FT /note="D -> A (significantly associated with circulating
FT levels of IL6 and soluble IL6R; increases cleavage by
FT ADAM17; dbSNP:rs2228145)"
FT /evidence="ECO:0000269|PubMed:14702039,
FT ECO:0000269|PubMed:17357077, ECO:0000269|PubMed:28060820"
FT /id="VAR_021995"
FT VARIANT 385
FT /note="V -> I (in dbSNP:rs2228146)"
FT /id="VAR_049166"
FT MUTAGEN 55
FT /note="N->A: Strongly induces cleavage and sIL6R levels. No
FT effect on IL6R signaling; when associated with A-93, A-221,
FT A-245 and A-350. Loss of cleavage by ADAM17; when
FT associated with A-93, A-221, A-245 and A-350."
FT /evidence="ECO:0000269|PubMed:28060820"
FT MUTAGEN 57
FT /note="T->A: Strongly induces cleavage and sIL6R levels."
FT /evidence="ECO:0000269|PubMed:28060820"
FT MUTAGEN 93
FT /note="N->A: No effect on cleavage or sIL6R levels. No
FT effect on IL6R signaling; when associated with A-55, A-221,
FT A-245 and A-350. Loss of cleavage by ADAM17; when
FT associated with A-55, A-221, A-245 and A-350."
FT /evidence="ECO:0000269|PubMed:28060820"
FT MUTAGEN 121
FT /note="C->S: Complete loss of ligand-binding."
FT /evidence="ECO:0000269|PubMed:8467812"
FT MUTAGEN 122
FT /note="F->A: No change of ligand-binding and IL6
FT signaling."
FT /evidence="ECO:0000269|PubMed:8467812"
FT MUTAGEN 132
FT /note="C->A: Complete loss of ligand-binding."
FT /evidence="ECO:0000269|PubMed:8467812"
FT MUTAGEN 134
FT /note="W->L: Complete loss of ligand-binding."
FT /evidence="ECO:0000269|PubMed:8467812"
FT MUTAGEN 140
FT /note="P->G: No change of ligand-binding and IL6
FT signaling."
FT /evidence="ECO:0000269|PubMed:8467812"
FT MUTAGEN 153
FT /note="F->L: No change of ligand-binding and IL6
FT signaling."
FT /evidence="ECO:0000269|PubMed:8467812"
FT MUTAGEN 165
FT /note="C->L: Complete loss of ligand-binding."
FT /evidence="ECO:0000269|PubMed:8467812"
FT MUTAGEN 174
FT /note="F->L: No change of ligand-binding and IL6
FT signaling."
FT /evidence="ECO:0000269|PubMed:8467812"
FT MUTAGEN 176
FT /note="C->A: Complete loss of ligand-binding."
FT /evidence="ECO:0000269|PubMed:8467812"
FT MUTAGEN 184
FT /note="D->T: 30% decrease of ligand-binding and IL6
FT signaling."
FT /evidence="ECO:0000269|PubMed:8467812"
FT MUTAGEN 190
FT /note="V->G: 80% decrease of ligand-binding and no IL6
FT signaling."
FT /evidence="ECO:0000269|PubMed:8467812"
FT MUTAGEN 193
FT /note="C->D: Complete loss of ligand-binding."
FT /evidence="ECO:0000269|PubMed:8467812"
FT MUTAGEN 211
FT /note="C->A: No change of ligand-binding and IL6
FT signaling."
FT /evidence="ECO:0000269|PubMed:8467812"
FT MUTAGEN 217
FT /note="D->V: Complete loss of ligand-binding."
FT /evidence="ECO:0000269|PubMed:8467812"
FT MUTAGEN 221
FT /note="N->A: No effect on cleavage or sIL6R levels. No
FT effect on IL6R signaling; when associated with A-55, A-93,
FT A-245 and A-350. Loss of cleavage by ADAM17; when
FT associated with A-55, A-93, A-245 and A-350."
FT /evidence="ECO:0000269|PubMed:28060820"
FT MUTAGEN 232
FT /note="R->S: 30% decrease of ligand-binding and IL6
FT signaling."
FT /evidence="ECO:0000269|PubMed:8467812"
FT MUTAGEN 233
FT /note="W->Q: 30% decrease of ligand-binding and increase of
FT IL6 signaling."
FT /evidence="ECO:0000269|PubMed:8467812"
FT MUTAGEN 245
FT /note="N->A: Slightly induces cleavage and sIL6R levels.No
FT effect on IL6R signaling; when associated with A-55, A-93,
FT A-221 and A-350. Loss of cleavage by ADAM17; when
FT associated with A-55, A-93, A-221 and A-350."
FT /evidence="ECO:0000269|PubMed:28060820"
FT MUTAGEN 254
FT /note="E->A: 50% decrease of ligand-binding and IL6
FT signaling."
FT /evidence="ECO:0000269|PubMed:8467812"
FT MUTAGEN 277
FT /note="C->D: 30% increase of ligand-binding and 100%
FT increase in IL6 signaling."
FT /evidence="ECO:0000269|PubMed:8467812"
FT MUTAGEN 278
FT /note="V->N: 50% Decrease of ligand-binding and 50%
FT increase in IL6 signaling."
FT /evidence="ECO:0000269|PubMed:8467812"
FT MUTAGEN 279
FT /note="I->D: Complete loss of ligand-binding."
FT /evidence="ECO:0000269|PubMed:8467812"
FT MUTAGEN 280
FT /note="H->I: No change of ligand-binding and no IL6
FT signaling."
FT /evidence="ECO:0000269|PubMed:8467812"
FT MUTAGEN 281
FT /note="D->G: 70% decrease of ligand-binding and no IL6
FT signaling."
FT /evidence="ECO:0000269|PubMed:8467812"
FT MUTAGEN 285
FT /note="G->D: 80% decrease of ligand-binding and no IL6
FT signaling."
FT /evidence="ECO:0000269|PubMed:8467812"
FT MUTAGEN 291
FT /note="Q->K: Complete loss of ligand-binding."
FT /evidence="ECO:0000269|PubMed:8467812"
FT MUTAGEN 293
FT /note="R->G: Complete loss of ligand-binding."
FT /evidence="ECO:0000269|PubMed:8467812"
FT MUTAGEN 350
FT /note="N->A: No effect on IL6R signaling; when associated
FT with A-55, A-93, A-221 and A-245. Loss of cleavage by
FT ADAM17; when associated with A-55, A-93, A-221 and A-245."
FT /evidence="ECO:0000269|PubMed:28060820"
FT MUTAGEN 352
FT /note="T->A: No effect on IL6R signaling."
FT /evidence="ECO:0000269|PubMed:28060820"
FT MUTAGEN 355..356
FT /note="PV->IE: Abolishes cleavage by ADAM17."
FT /evidence="ECO:0000269|PubMed:28060820"
FT MUTAGEN 355
FT /note="P->I,D: Reduces cleavage by ADAM17."
FT /evidence="ECO:0000269|PubMed:28060820"
FT MUTAGEN 356
FT /note="V->E,G: Abolishes cleavage by ADAM17."
FT /evidence="ECO:0000269|PubMed:28060820"
FT CONFLICT 210
FT /note="G -> D (in Ref. 5; BAD97302)"
FT /evidence="ECO:0000305"
FT STRAND 34..37
FT /evidence="ECO:0007829|PDB:1N26"
FT STRAND 43..46
FT /evidence="ECO:0007829|PDB:1N26"
FT STRAND 56..63
FT /evidence="ECO:0007829|PDB:1N26"
FT STRAND 65..68
FT /evidence="ECO:0007829|PDB:1N26"
FT STRAND 72..83
FT /evidence="ECO:0007829|PDB:1N26"
FT HELIX 88..90
FT /evidence="ECO:0007829|PDB:1N26"
FT STRAND 92..101
FT /evidence="ECO:0007829|PDB:1N26"
FT STRAND 105..110
FT /evidence="ECO:0007829|PDB:1N26"
FT STRAND 120..125
FT /evidence="ECO:0007829|PDB:1N26"
FT STRAND 130..134
FT /evidence="ECO:0007829|PDB:1N26"
FT STRAND 145..157
FT /evidence="ECO:0007829|PDB:1N26"
FT STRAND 159..168
FT /evidence="ECO:0007829|PDB:1N26"
FT TURN 169..172
FT /evidence="ECO:0007829|PDB:1N26"
FT STRAND 173..178
FT /evidence="ECO:0007829|PDB:1N26"
FT STRAND 187..196
FT /evidence="ECO:0007829|PDB:1N26"
FT STRAND 199..202
FT /evidence="ECO:0007829|PDB:1N26"
FT STRAND 206..209
FT /evidence="ECO:0007829|PDB:1N26"
FT TURN 210..212
FT /evidence="ECO:0007829|PDB:1N26"
FT STRAND 220..226
FT /evidence="ECO:0007829|PDB:1N26"
FT STRAND 234..239
FT /evidence="ECO:0007829|PDB:1N26"
FT STRAND 247..249
FT /evidence="ECO:0007829|PDB:1N26"
FT STRAND 251..259
FT /evidence="ECO:0007829|PDB:1N26"
FT STRAND 266..269
FT /evidence="ECO:0007829|PDB:1N26"
FT HELIX 271..273
FT /evidence="ECO:0007829|PDB:1N26"
FT STRAND 275..281
FT /evidence="ECO:0007829|PDB:1N26"
FT STRAND 288..296
FT /evidence="ECO:0007829|PDB:1N26"
FT TURN 297..299
FT /evidence="ECO:0007829|PDB:1N26"
FT STRAND 310..312
FT /evidence="ECO:0007829|PDB:1N26"
SQ SEQUENCE 468 AA; 51548 MW; 62AA239FA14F1B8B CRC64;
MLAVGCALLA ALLAAPGAAL APRRCPAQEV ARGVLTSLPG DSVTLTCPGV EPEDNATVHW
VLRKPAAGSH PSRWAGMGRR LLLRSVQLHD SGNYSCYRAG RPAGTVHLLV DVPPEEPQLS
CFRKSPLSNV VCEWGPRSTP SLTTKAVLLV RKFQNSPAED FQEPCQYSQE SQKFSCQLAV
PEGDSSFYIV SMCVASSVGS KFSKTQTFQG CGILQPDPPA NITVTAVARN PRWLSVTWQD
PHSWNSSFYR LRFELRYRAE RSKTFTTWMV KDLQHHCVIH DAWSGLRHVV QLRAQEEFGQ
GEWSEWSPEA MGTPWTESRS PPAENEVSTP MQALTTNKDD DNILFRDSAN ATSLPVQDSS
SVPLPTFLVA GGSLAFGTLL CIAIVLRFKK TWKLRALKEG KTSMHPPYSL GQLVPERPRP
TPVLVPLISP PVSPSSLGSD NTSSHNRPDA RDPRSPYDIS NTDYFFPR
