ID TLR3_HUMAN Reviewed; 904 AA.
AC O15455; B2RAI7; B7Z7K0; E6Y0F0; E6Y0F1; E9PGH4; Q4VAL2; Q504W0;
DT 31-JAN-2002, integrated into UniProtKB/Swiss-Prot.
DT 01-JAN-1998, sequence version 1.
DT 27-MAR-2024, entry version 220.
DE RecName: Full=Toll-like receptor 3 {ECO:0000305};
DE AltName: CD_antigen=CD283;
DE Flags: Precursor;
GN Name=TLR3 {ECO:0000312|HGNC:HGNC:11849};
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=9435236; DOI=10.1073/pnas.95.2.588;
RA Rock F.L., Hardiman G., Timans J.C., Kastelein R.A., Bazan J.F.;
RT "A family of human receptors structurally related to Drosophila Toll.";
RL Proc. Natl. Acad. Sci. U.S.A. 95:588-593(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND TISSUE SPECIFICITY.
RC TISSUE=Neuron;
RX PubMed=17085778; DOI=10.1385/jmn:29:3:185;
RA Lafon M., Megret F., Lafage M., Prehaud C.;
RT "The innate immune facet of brain: human neurons express TLR-3 and sense
RT viral dsRNA.";
RL J. Mol. Neurosci. 29:185-194(2006).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=18810425; DOI=10.1007/s00251-008-0332-0;
RA Nakajima T., Ohtani H., Satta Y., Uno Y., Akari H., Ishida T., Kimura A.;
RT "Natural selection in the TLR-related genes in the course of primate
RT evolution.";
RL Immunogenetics 60:727-735(2008).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT PHE-412.
RA Macquin C., Bahram S.;
RT "TLR polymorphism.";
RL Submitted (JAN-2006) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND VARIANT
RP PHE-412.
RC TISSUE=Testis, and Thymus;
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 [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT 4.";
RL Nature 434:724-731(2005).
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 1).
RC TISSUE=Placenta;
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 PROTEIN SEQUENCE OF 24-38.
RX PubMed=15340161; DOI=10.1110/ps.04682504;
RA Zhang Z., Henzel W.J.;
RT "Signal peptide prediction based on analysis of experimentally verified
RT cleavage sites.";
RL Protein Sci. 13:2819-2824(2004).
RN [10]
RP FUNCTION, AND INTERACTION WITH TICAM1.
RX PubMed=12471095; DOI=10.4049/jimmunol.169.12.6668;
RA Yamamoto M., Sato S., Mori K., Hoshino K., Takeuchi O., Takeda K.,
RA Akira S.;
RT "A novel Toll/IL-1 receptor domain-containing adapter that preferentially
RT activates the IFN-beta promoter in the Toll-like receptor signaling.";
RL J. Immunol. 169:6668-6672(2002).
RN [11]
RP FUNCTION, AND INTERACTION WITH TICAM1.
RC TISSUE=Lung;
RX PubMed=12539043; DOI=10.1038/ni886;
RA Oshiumi H., Matsumoto M., Funami K., Akazawa T., Seya T.;
RT "TICAM-1, an adapter molecule that participates in Toll-like receptor 3
RT mediated interferon-beta induction.";
RL Nat. Immunol. 4:161-167(2003).
RN [12]
RP FUNCTION, SUBUNIT, AND MUTAGENESIS OF CYS-95; CYS-122; ASN-196 AND ASN-247.
RX PubMed=16144834; DOI=10.1074/jbc.m507163200;
RA de Bouteiller O., Merck E., Hasan U.A., Hubac S., Benguigui B.,
RA Trinchieri G., Bates E.E., Caux C.;
RT "Recognition of double-stranded RNA by human toll-like receptor 3 and
RT downstream receptor signaling requires multimerization and an acidic pH.";
RL J. Biol. Chem. 280:38133-38145(2005).
RN [13]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH SRC.
RX PubMed=16858407; DOI=10.1038/sj.emboj.7601222;
RA Johnsen I.B., Nguyen T.T., Ringdal M., Tryggestad A.M., Bakke O., Lien E.,
RA Espevik T., Anthonsen M.W.;
RT "Toll-like receptor 3 associates with c-Src tyrosine kinase on endosomes to
RT initiate antiviral signaling.";
RL EMBO J. 25:3335-3346(2006).
RN [14]
RP FUNCTION, AND MUTAGENESIS OF HIS-539 AND ASN-541.
RX PubMed=16720699; DOI=10.1073/pnas.0603245103;
RA Bell J.K., Askins J., Hall P.R., Davies D.R., Segal D.M.;
RT "The dsRNA binding site of human Toll-like receptor 3.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:8792-8797(2006).
RN [15]
RP PHOSPHORYLATION AT TYR-759 AND TYR-858, FUNCTION, AND MUTAGENESIS OF
RP TYR-759.
RX PubMed=17178723; DOI=10.1074/jbc.c600226200;
RA Sarkar S.N., Elco C.P., Peters K.L., Chattopadhyay S., Sen G.C.;
RT "Two tyrosine residues of Toll-like receptor 3 trigger different steps of
RT NF-kappa B activation.";
RL J. Biol. Chem. 282:3423-3427(2007).
RN [16]
RP FUNCTION, DOUBLE-STRANDED RNA-BINDING, AND HOMODIMERIZATION.
RX PubMed=18172197; DOI=10.1073/pnas.0710779105;
RA Leonard J.N., Ghirlando R., Askins J., Bell J.K., Margulies D.H.,
RA Davies D.R., Segal D.M.;
RT "The TLR3 signaling complex forms by cooperative receptor dimerization.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:258-263(2008).
RN [17]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-52 AND ASN-57.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of multiple
RT enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [18]
RP FUNCTION, PROTEOLYTIC PROCESSING, SUBCELLULAR LOCATION, AND INTERACTION
RP WITH UNC93B1.
RX PubMed=22611194; DOI=10.1073/pnas.1115091109;
RA Garcia-Cattaneo A., Gobert F.X., Muller M., Toscano F., Flores M.,
RA Lescure A., Del Nery E., Benaroch P.;
RT "Cleavage of Toll-like receptor 3 by cathepsins B and H is essential for
RT signaling.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:9053-9058(2012).
RN [19]
RP INTERACTION WITH WDFY1 AND TICAM1, SUBCELLULAR LOCATION, AND MUTAGENESIS OF
RP TYR-759 AND TYR-858.
RX PubMed=25736436; DOI=10.15252/embr.201439637;
RA Hu Y.H., Zhang Y., Jiang L.Q., Wang S., Lei C.Q., Sun M.S., Shu H.B.,
RA Liu Y.;
RT "WDFY1 mediates TLR3/4 signaling by recruiting TRIF.";
RL EMBO Rep. 16:447-455(2015).
RN [20]
RP UBIQUITINATION AT LYS-831 BY TRIM3, AND MUTAGENESIS OF LYS-831.
RX PubMed=32878999; DOI=10.1073/pnas.2002472117;
RA Li W.W., Nie Y., Yang Y., Ran Y., Luo W.W., Xiong M.G., Wang S.Y., Xu Z.S.,
RA Wang Y.Y.;
RT "Ubiquitination of TLR3 by TRIM3 signals its ESCRT-mediated trafficking to
RT the endolysosomes for innate antiviral response.";
RL Proc. Natl. Acad. Sci. U.S.A. 117:23707-23716(2020).
RN [21]
RP FUNCTION, AND UBIQUITINATION BY RNF170.
RX PubMed=31076723; DOI=10.1038/s41423-019-0236-y;
RA Song X., Liu S., Wang W., Ma Z., Cao X., Jiang M.;
RT "E3 ubiquitin ligase RNF170 inhibits innate immune responses by targeting
RT and degrading TLR3 in murine cells.";
RL Cell. Mol. Immunol. 17:865-874(2020).
RN [22]
RP UBIQUITINATION AT LYS-812, AND MUTAGENESIS OF LYS-812.
RX PubMed=37158982; DOI=10.1084/jem.20220727;
RA Lin Y.S., Chang Y.C., Chao T.L., Tsai Y.M., Jhuang S.J., Ho Y.H., Lai T.Y.,
RA Liu Y.L., Chen C.Y., Tsai C.Y., Hsueh Y.P., Chang S.Y., Chuang T.H.,
RA Lee C.Y., Hsu L.C.;
RT "The Src-ZNRF1 axis controls TLR3 trafficking and interferon responses to
RT limit lung barrier damage.";
RL J. Exp. Med. 220:0-0(2023).
RN [23]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 22-703, FUNCTION, DISULFIDE BONDS,
RP SUBUNIT, GLYCOSYLATION AT ASN-52; ASN-70; ASN-196; ASN-252; ASN-265;
RP ASN-275; ASN-291; ASN-398; ASN-413; ASN-507 AND ASN-636, AND IDENTIFICATION
RP BY MASS SPECTROMETRY.
RX PubMed=16043704; DOI=10.1073/pnas.0505077102;
RA Bell J.K., Botos I., Hall P.R., Askins J., Shiloach J., Segal D.M.,
RA Davies D.R.;
RT "The molecular structure of the Toll-like receptor 3 ligand-binding
RT domain.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:10976-10980(2005).
RN [24]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 27-700, DISULFIDE BONDS, AND
RP GLYCOSYLATION AT ASN-124; ASN-252; ASN-275; ASN-291; ASN-398; ASN-413 AND
RP ASN-507.
RX PubMed=15961631; DOI=10.1126/science.1115253;
RA Choe J., Kelker M.S., Wilson I.A.;
RT "Crystal structure of human toll-like receptor 3 (TLR3) ectodomain.";
RL Science 309:581-585(2005).
RN [25]
RP X-RAY CRYSTALLOGRAPHY (3.52 ANGSTROMS) OF 22-702 IN COMPLEX WITH ANTIBODY,
RP DISULFIDE BONDS, SUBUNIT, DS-RNA BINDING REGIONS, AND GLYCOSYLATION AT
RP ASN-52; ASN-70; ASN-124; ASN-247; ASN-252; ASN-265; ASN-275; ASN-291;
RP ASN-398; ASN-413 AND ASN-507.
RX PubMed=22579623; DOI=10.1016/j.jmb.2012.05.006;
RA Luo J., Obmolova G., Malia T.J., Wu S.J., Duffy K.E., Marion J.D.,
RA Bell J.K., Ge P., Zhou Z.H., Teplyakov A., Zhao Y., Lamb R.J., Jordan J.L.,
RA San Mateo L.R., Sweet R.W., Gilliland G.L.;
RT "Lateral clustering of TLR3:dsRNA signaling units revealed by TLR3ecd:3Fabs
RT quaternary structure.";
RL J. Mol. Biol. 421:112-124(2012).
RN [26] {ECO:0007744|PDB:7C76}
RP STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS) IN COMPLEX WITH UNC93B1,
RP AND INTERACTION WITH UNC93B1.
RX PubMed=33432245; DOI=10.1038/s41594-020-00542-w;
RA Ishida H., Asami J., Zhang Z., Nishizawa T., Shigematsu H., Ohto U.,
RA Shimizu T.;
RT "Cryo-EM structures of Toll-like receptors in complex with UNC93B1.";
RL Nat. Struct. Mol. Biol. 28:173-180(2021).
RN [27]
RP VARIANT IMD83 SER-554.
RX PubMed=17872438; DOI=10.1126/science.1139522;
RA Zhang S.-Y., Jouanguy E., Ugolini S., Smahi A., Elain G., Romero P.,
RA Segal D., Sancho-Shimizu V., Lorenzo L., Puel A., Picard C., Chapgier A.,
RA Plancoulaine S., Titeux M., Cognet C., von Bernuth H., Ku C.-L.,
RA Casrouge A., Zhang X.-X., Barreiro L., Leonard J., Hamilton C., Lebon P.,
RA Heron B., Vallee L., Quintana-Murci L., Hovnanian A., Rozenberg F.,
RA Vivier E., Geissmann F., Tardieu M., Abel L., Casanova J.-L.;
RT "TLR3 deficiency in patients with herpes simplex encephalitis.";
RL Science 317:1522-1527(2007).
RN [28]
RP VARIANT PHE-412.
RX PubMed=18753640; DOI=10.1056/nejmoa0802437;
RA Yang Z., Stratton C., Francis P.J., Kleinman M.E., Tan P.L., Gibbs D.,
RA Tong Z., Chen H., Constantine R., Yang X., Chen Y., Zeng J., Davey L.,
RA Ma X., Hau V.S., Wang C., Harmon J., Buehler J., Pearson E., Patel S.,
RA Kaminoh Y., Watkins S., Luo L., Zabriskie N.A., Bernstein P.S., Cho W.,
RA Schwager A., Hinton D.R., Klein M.L., Hamon S.C., Simmons E., Yu B.,
RA Campochiaro B., Sunness J.S., Campochiaro P., Jorde L., Parmigiani G.,
RA Zack D.J., Katsanis N., Ambati J., Zhang K.;
RT "Toll-like receptor 3 and geographic atrophy in age-related macular
RT degeneration.";
RL N. Engl. J. Med. 359:1456-1463(2008).
RN [29]
RP ERRATUM OF PUBMED:18753640.
RA Yang Z., Stratton C., Francis P.J., Kleinman M.E., Tan P.L., Gibbs D.,
RA Tong Z., Chen H., Constantine R., Yang X., Chen Y., Zeng J., Davey L.,
RA Ma X., Hau V.S., Wang C., Harmon J., Buehler J., Pearson E., Patel S.,
RA Kaminoh Y., Watkins S., Luo L., Zabriskie N.A., Bernstein P.S., Cho W.,
RA Schwager A., Hinton D.R., Klein M.L., Hamon S.C., Simmons E., Yu B.,
RA Campochiaro B., Sunness J.S., Campochiaro P., Jorde L., Parmigiani G.,
RA Zack D.J., Katsanis N., Ambati J., Zhang K.;
RL N. Engl. J. Med. 359:1859-1859(2008).
RN [30]
RP VARIANT PHE-412.
RX PubMed=22174453; DOI=10.4049/jimmunol.1102179;
RA Sironi M., Biasin M., Cagliani R., Forni D., De Luca M., Saulle I.,
RA Lo Caputo S., Mazzotta F., Macias J., Pineda J.A., Caruz A., Clerici M.;
RT "A common polymorphism in TLR3 confers natural resistance to HIV-1
RT infection.";
RL J. Immunol. 188:818-823(2012).
RN [31]
RP VARIANTS PRO-134; GLY-251; SER-554; LEU-732; 746-GLU--HIS-904 DEL;
RP 769-TRP--HIS-904 DEL; GLN-867 AND VAL-870, AND CHARACTERIZATION OF VARIANTS
RP PRO-134; GLY-251; SER-554; LEU-732; 746-GLU--HIS-904 DEL; 769-TRP--HIS-904
RP DEL; GLN-867 AND VAL-870.
RX PubMed=32972995; DOI=10.1126/science.abd4570;
RG COVID-STORM Clinicians;
RG COVID Clinicians;
RG Imagine COVID Group;
RG French COVID Cohort Study Group;
RG CoV-Contact Cohort;
RG Amsterdam UMC Covid-19 Biobank;
RG COVID Human Genetic Effort;
RG NIAID-USUHS/TAGC COVID Immunity Group;
RA Zhang Q., Bastard P., Liu Z., Le Pen J., Moncada-Velez M., Chen J.,
RA Ogishi M., Sabli I.K.D., Hodeib S., Korol C., Rosain J., Bilguvar K.,
RA Ye J., Bolze A., Bigio B., Yang R., Arias A.A., Zhou Q., Zhang Y.,
RA Onodi F., Korniotis S., Karpf L., Philippot Q., Chbihi M., Bonnet-Madin L.,
RA Dorgham K., Smith N., Schneider W.M., Razooky B.S., Hoffmann H.H.,
RA Michailidis E., Moens L., Han J.E., Lorenzo L., Bizien L., Meade P.,
RA Neehus A.L., Ugurbil A.C., Corneau A., Kerner G., Zhang P., Rapaport F.,
RA Seeleuthner Y., Manry J., Masson C., Schmitt Y., Schlueter A., Le Voyer T.,
RA Khan T., Li J., Fellay J., Roussel L., Shahrooei M., Alosaimi M.F.,
RA Mansouri D., Al-Saud H., Al-Mulla F., Almourfi F., Al-Muhsen S.Z.,
RA Alsohime F., Al Turki S., Hasanato R., van de Beek D., Biondi A.,
RA Bettini L.R., D'Angio' M., Bonfanti P., Imberti L., Sottini A., Paghera S.,
RA Quiros-Roldan E., Rossi C., Oler A.J., Tompkins M.F., Alba C.,
RA Vandernoot I., Goffard J.C., Smits G., Migeotte I., Haerynck F.,
RA Soler-Palacin P., Martin-Nalda A., Colobran R., Morange P.E., Keles S.,
RA Coelkesen F., Ozcelik T., Yasar K.K., Senoglu S., Karabela S.N.,
RA Rodriguez-Gallego C., Novelli G., Hraiech S., Tandjaoui-Lambiotte Y.,
RA Duval X., Laouenan C., Snow A.L., Dalgard C.L., Milner J.D., Vinh D.C.,
RA Mogensen T.H., Marr N., Spaan A.N., Boisson B., Boisson-Dupuis S.,
RA Bustamante J., Puel A., Ciancanelli M.J., Meyts I., Maniatis T.,
RA Soumelis V., Amara A., Nussenzweig M., Garcia-Sastre A., Krammer F.,
RA Pujol A., Duffy D., Lifton R.P., Zhang S.Y., Gorochov G., Beziat V.,
RA Jouanguy E., Sancho-Shimizu V., Rice C.M., Abel L., Notarangelo L.D.,
RA Cobat A., Su H.C., Casanova J.L.;
RT "Inborn errors of type I IFN immunity in patients with life-threatening
RT COVID-19.";
RL Science 370:0-0(2020).
CC -!- FUNCTION: Key component of innate and adaptive immunity. TLRs (Toll-
CC like receptors) control host immune response against pathogens through
CC recognition of molecular patterns specific to microorganisms. TLR3 is a
CC nucleotide-sensing TLR which is activated by double-stranded RNA, a
CC sign of viral infection. Acts via the adapter TRIF/TICAM1, leading to
CC NF-kappa-B activation, IRF3 nuclear translocation, cytokine secretion
CC and the inflammatory response. {ECO:0000269|PubMed:12471095,
CC ECO:0000269|PubMed:12539043, ECO:0000269|PubMed:16043704,
CC ECO:0000269|PubMed:16144834, ECO:0000269|PubMed:16720699,
CC ECO:0000269|PubMed:16858407, ECO:0000269|PubMed:17178723,
CC ECO:0000269|PubMed:18172197, ECO:0000269|PubMed:22611194}.
CC -!- SUBUNIT: Monomer and homodimer; dimerization is triggered by ligand-
CC binding, the signaling unit is composed of one ds-RNA of around 40 bp
CC and two TLR3 molecules, and lateral clustering of signaling units along
CC the length of the ds-RNA ligand is required for TLR3 signal
CC transduction. Interacts (via transmembrane domain) with UNC93B1; the
CC interaction is required for transport from the ER to the endosomes
CC (PubMed:33432245). Interacts with SRC; upon binding of double-stranded
CC RNA. Interacts with TICAM1 (via the TIR domain) in response to
CC poly(I:C) and this interaction is enhanced in the presence of WDFY1
CC (PubMed:25736436). The tyrosine-phosphorylated form (via TIR domain)
CC interacts with WDFY1 (via WD repeat 2) in response to poly(I:C)
CC (PubMed:25736436). {ECO:0000269|PubMed:12471095,
CC ECO:0000269|PubMed:12539043, ECO:0000269|PubMed:16043704,
CC ECO:0000269|PubMed:16144834, ECO:0000269|PubMed:16858407,
CC ECO:0000269|PubMed:22579623, ECO:0000269|PubMed:22611194,
CC ECO:0000269|PubMed:25736436, ECO:0000269|PubMed:31076723,
CC ECO:0000269|PubMed:33432245}.
CC -!- INTERACTION:
CC O15455; P27986: PIK3R1; NbExp=2; IntAct=EBI-6116630, EBI-79464;
CC O15455; O15455: TLR3; NbExp=5; IntAct=EBI-6116630, EBI-6116630;
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane; Single-pass type
CC I membrane protein. Endosome membrane. Early endosome
CC {ECO:0000269|PubMed:25736436}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=O15455-1; Sequence=Displayed;
CC Name=2;
CC IsoId=O15455-2; Sequence=VSP_054188;
CC -!- TISSUE SPECIFICITY: Expressed at high level in placenta and pancreas.
CC Also detected in CD11c+ immature dendritic cells. Only expressed in
CC dendritic cells and not in other leukocytes, including monocyte
CC precursors. TLR3 is the TLR that is expressed most strongly in the
CC brain, especially in astrocytes, glia, and neurons.
CC {ECO:0000269|PubMed:17085778}.
CC -!- DOMAIN: ds-RNA binding is mediated by LRR 1 to 3, and LRR 17 to 18.
CC -!- PTM: Heavily N-glycosylated, except on that part of the surface of the
CC ectodomain that is involved in ligand binding.
CC {ECO:0000269|PubMed:15961631, ECO:0000269|PubMed:16043704,
CC ECO:0000269|PubMed:19159218, ECO:0000269|PubMed:22579623}.
CC -!- PTM: TLR3 signaling requires a proteolytic cleavage mediated by
CC cathepsins CTSB and CTSH, the cleavage occurs between amino acids 252
CC and 346. The cleaved form of TLR3 is the predominant form found in
CC endosomes. {ECO:0000269|PubMed:22611194}.
CC -!- PTM: Ubiquitinated by TRIM3; leading to recognition and sorting of
CC polyubiquitinated TLR3 by the ESCRT complexes (PubMed:32878999).
CC Ubiquitinated by ZNRF1 via 'Lys-63'-linked ubiquitin chains; leading to
CC TLR3 lysosomal trafficking and degradation (PubMed:37158982).
CC Ubiquitinated by RNF170 at Lys-765 via 'Lys-48'-linked ubiquitin
CC chains; leading to TLR3 proteasomal degradation (PubMed:31076723).
CC {ECO:0000269|PubMed:31076723, ECO:0000269|PubMed:32878999,
CC ECO:0000269|PubMed:37158982}.
CC -!- POLYMORPHISM: The Phe-412 allele (dbSNP:rs3775291) occurs with a
CC frequency of 30% in populations with European and Asian ancestry, and
CC confers some natural resistance to HIV-1 infection.
CC -!- DISEASE: Immunodeficiency 83, susceptibility to viral infections
CC (IMD83) [MIM:613002]: An immunologic disorder characterized by
CC increased susceptibility to severe viral infections, including herpes
CC simplex virus (HSV), varicella zoster virus (VZV), influenza A virus
CC (IAV), hantavirus, and possibly respiratory syncytial virus (RSV).
CC IMD83 clinical manifestations include acute infection-induced
CC encephalitis and pneumonitis. The susceptibility to encephalitis or
CC pneumonitis appears to result from impaired TLR3-dependent interferon
CC production by nonhematopoietic cells that reside within the central
CC nervous system or lung epithelial cells. IMD83 transmission pattern is
CC consistent with autosomal dominant or autosomal recessive inheritance
CC with incomplete penetrance. {ECO:0000269|PubMed:17872438}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the Toll-like receptor family. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=TLR3base; Note=TLR3 mutation db;
CC URL="http://structure.bmc.lu.se/idbase/TLR3base/";
CC ---------------------------------------------------------------------------
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DR EMBL; U88879; AAC34134.1; -; mRNA.
DR EMBL; DQ445682; ABE01399.1; -; mRNA.
DR EMBL; AB445631; BAG55028.1; -; mRNA.
DR EMBL; DQ360814; ABC86908.1; -; Genomic_DNA.
DR EMBL; DQ360815; ABC86909.1; -; Genomic_DNA.
DR EMBL; DQ360816; ABC86910.1; -; Genomic_DNA.
DR EMBL; AK302143; BAH13636.1; -; mRNA.
DR EMBL; AK314208; BAG36884.1; -; mRNA.
DR EMBL; AC104070; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471056; EAX04628.1; -; Genomic_DNA.
DR EMBL; BC094737; AAH94737.1; -; mRNA.
DR EMBL; BC096333; AAH96333.1; -; mRNA.
DR EMBL; BC096334; AAH96334.1; -; mRNA.
DR EMBL; BC096335; AAH96335.1; -; mRNA.
DR CCDS; CCDS3846.1; -. [O15455-1]
DR RefSeq; NP_003256.1; NM_003265.2. [O15455-1]
DR RefSeq; XP_016864066.1; XM_017008577.1.
DR PDB; 1ZIW; X-ray; 2.10 A; A=27-700.
DR PDB; 2A0Z; X-ray; 2.40 A; A=22-703.
DR PDB; 2MK9; NMR; -; A/B=698-730.
DR PDB; 2MKA; NMR; -; A/B/C=698-730.
DR PDB; 3ULU; X-ray; 3.52 A; A=22-702.
DR PDB; 3ULV; X-ray; 3.52 A; A=22-702.
DR PDB; 5GS0; X-ray; 3.27 A; A/B=27-697.
DR PDB; 7C76; EM; 3.40 A; A=1-904.
DR PDB; 7WV3; EM; 2.26 A; A/B/C/D=24-904.
DR PDB; 7WV4; EM; 3.35 A; A/B/C/D=27-697.
DR PDB; 7WV5; EM; 3.10 A; A/B=27-697.
DR PDB; 7WVE; EM; 3.11 A; A/B=27-697.
DR PDB; 7WVF; EM; 3.91 A; A/B=27-697.
DR PDB; 7WVJ; EM; 3.26 A; A/B=27-697.
DR PDB; 8AR1; NMR; -; A=698-746.
DR PDBsum; 1ZIW; -.
DR PDBsum; 2A0Z; -.
DR PDBsum; 2MK9; -.
DR PDBsum; 2MKA; -.
DR PDBsum; 3ULU; -.
DR PDBsum; 3ULV; -.
DR PDBsum; 5GS0; -.
DR PDBsum; 7C76; -.
DR PDBsum; 7WV3; -.
DR PDBsum; 7WV4; -.
DR PDBsum; 7WV5; -.
DR PDBsum; 7WVE; -.
DR PDBsum; 7WVF; -.
DR PDBsum; 7WVJ; -.
DR PDBsum; 8AR1; -.
DR AlphaFoldDB; O15455; -.
DR BMRB; O15455; -.
DR EMDB; EMD-30293; -.
DR EMDB; EMD-32844; -.
DR EMDB; EMD-32845; -.
DR EMDB; EMD-32846; -.
DR EMDB; EMD-32851; -.
DR EMDB; EMD-32852; -.
DR EMDB; EMD-32853; -.
DR SMR; O15455; -.
DR BioGRID; 112953; 47.
DR DIP; DIP-29660N; -.
DR IntAct; O15455; 15.
DR MINT; O15455; -.
DR STRING; 9606.ENSP00000296795; -.
DR BindingDB; O15455; -.
DR ChEMBL; CHEMBL1075113; -.
DR TCDB; 8.A.43.1.35; the neat-domain containing methaemoglobin heme sequestration (n-mhs) family.
DR GlyCosmos; O15455; 15 sites, No reported glycans.
DR GlyGen; O15455; 17 sites, 1 O-linked glycan (1 site).
DR iPTMnet; O15455; -.
DR PhosphoSitePlus; O15455; -.
DR BioMuta; TLR3; -.
DR EPD; O15455; -.
DR jPOST; O15455; -.
DR MassIVE; O15455; -.
DR MaxQB; O15455; -.
DR PaxDb; 9606-ENSP00000296795; -.
DR PeptideAtlas; O15455; -.
DR ProteomicsDB; 20320; -.
DR ProteomicsDB; 48678; -. [O15455-1]
DR Pumba; O15455; -.
DR ABCD; O15455; 13 sequenced antibodies.
DR Antibodypedia; 17502; 1231 antibodies from 48 providers.
DR DNASU; 7098; -.
DR Ensembl; ENST00000296795.8; ENSP00000296795.3; ENSG00000164342.14. [O15455-1]
DR Ensembl; ENST00000504367.1; ENSP00000423684.1; ENSG00000164342.14. [O15455-2]
DR Ensembl; ENST00000508051.2; ENSP00000513677.1; ENSG00000164342.14. [O15455-2]
DR Ensembl; ENST00000512264.1; ENSP00000513668.1; ENSG00000164342.14. [O15455-2]
DR Ensembl; ENST00000698354.1; ENSP00000513676.1; ENSG00000164342.14. [O15455-2]
DR GeneID; 7098; -.
DR KEGG; hsa:7098; -.
DR MANE-Select; ENST00000296795.8; ENSP00000296795.3; NM_003265.3; NP_003256.1.
DR UCSC; uc003iyq.4; human. [O15455-1]
DR AGR; HGNC:11849; -.
DR CTD; 7098; -.
DR DisGeNET; 7098; -.
DR GeneCards; TLR3; -.
DR HGNC; HGNC:11849; TLR3.
DR HPA; ENSG00000164342; Low tissue specificity.
DR MalaCards; TLR3; -.
DR MIM; 603029; gene.
DR MIM; 613002; phenotype.
DR neXtProt; NX_O15455; -.
DR OpenTargets; ENSG00000164342; -.
DR Orphanet; 1930; Herpes simplex virus encephalitis.
DR PharmGKB; PA36551; -.
DR VEuPathDB; HostDB:ENSG00000164342; -.
DR eggNOG; KOG4641; Eukaryota.
DR GeneTree; ENSGT00940000159678; -.
DR HOGENOM; CLU_006000_4_1_1; -.
DR InParanoid; O15455; -.
DR OMA; PYIYFWG; -.
DR OrthoDB; 3428126at2759; -.
DR PhylomeDB; O15455; -.
DR TreeFam; TF325595; -.
DR PathwayCommons; O15455; -.
DR Reactome; R-HSA-1679131; Trafficking and processing of endosomal TLR.
DR Reactome; R-HSA-168164; Toll Like Receptor 3 (TLR3) Cascade.
DR Reactome; R-HSA-168927; TICAM1, RIP1-mediated IKK complex recruitment.
DR Reactome; R-HSA-1810476; RIP-mediated NFkB activation via ZBP1.
DR Reactome; R-HSA-5602410; TLR3 deficiency - HSE.
DR Reactome; R-HSA-5602415; UNC93B1 deficiency - HSE.
DR Reactome; R-HSA-5602566; TICAM1 deficiency - HSE.
DR Reactome; R-HSA-5602571; TRAF3 deficiency - HSE.
DR Reactome; R-HSA-9013957; TLR3-mediated TICAM1-dependent programmed cell death.
DR Reactome; R-HSA-9013973; TICAM1-dependent activation of IRF3/IRF7.
DR Reactome; R-HSA-9014325; TICAM1,TRAF6-dependent induction of TAK1 complex.
DR SignaLink; O15455; -.
DR SIGNOR; O15455; -.
DR BioGRID-ORCS; 7098; 12 hits in 1155 CRISPR screens.
DR ChiTaRS; TLR3; human.
DR EvolutionaryTrace; O15455; -.
DR GeneWiki; TLR_3; -.
DR GenomeRNAi; 7098; -.
DR Pharos; O15455; Tbio.
DR PRO; PR:O15455; -.
DR Proteomes; UP000005640; Chromosome 4.
DR RNAct; O15455; Protein.
DR Bgee; ENSG00000164342; Expressed in jejunal mucosa and 169 other cell types or tissues.
DR ExpressionAtlas; O15455; baseline and differential.
DR Genevisible; O15455; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:BHF-UCL.
DR GO; GO:0005769; C:early endosome; IDA:UniProt.
DR GO; GO:0036020; C:endolysosome membrane; TAS:Reactome.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome.
DR GO; GO:0010008; C:endosome membrane; ISS:UniProt.
DR GO; GO:0031012; C:extracellular matrix; IBA:GO_Central.
DR GO; GO:0005615; C:extracellular space; IBA:GO_Central.
DR GO; GO:0000139; C:Golgi membrane; TAS:Reactome.
DR GO; GO:0005765; C:lysosomal membrane; HDA:UniProtKB.
DR GO; GO:0016020; C:membrane; NAS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; TAS:ProtInc.
DR GO; GO:0003725; F:double-stranded RNA binding; IDA:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0038187; F:pattern recognition receptor activity; IDA:BHF-UCL.
DR GO; GO:0038023; F:signaling receptor activity; TAS:ProtInc.
DR GO; GO:0004888; F:transmembrane signaling receptor activity; NAS:UniProtKB.
DR GO; GO:0007250; P:activation of NF-kappaB-inducing kinase activity; NAS:UniProtKB.
DR GO; GO:0071360; P:cellular response to exogenous dsRNA; IEA:Ensembl.
DR GO; GO:0035458; P:cellular response to interferon-beta; IEA:Ensembl.
DR GO; GO:0071260; P:cellular response to mechanical stimulus; IEP:UniProtKB.
DR GO; GO:0071346; P:cellular response to type II interferon; IEA:Ensembl.
DR GO; GO:0098586; P:cellular response to virus; IEA:Ensembl.
DR GO; GO:0071466; P:cellular response to xenobiotic stimulus; IEA:Ensembl.
DR GO; GO:0042742; P:defense response to bacterium; TAS:ProtInc.
DR GO; GO:0051607; P:defense response to virus; IEP:ARUK-UCL.
DR GO; GO:0009597; P:detection of virus; NAS:UniProtKB.
DR GO; GO:0097191; P:extrinsic apoptotic signaling pathway; IDA:UniProtKB.
DR GO; GO:0006972; P:hyperosmotic response; NAS:UniProtKB.
DR GO; GO:0007252; P:I-kappaB phosphorylation; IDA:BHF-UCL.
DR GO; GO:0090594; P:inflammatory response to wounding; IDA:UniProt.
DR GO; GO:0045087; P:innate immune response; TAS:BHF-UCL.
DR GO; GO:0007254; P:JNK cascade; IEA:Ensembl.
DR GO; GO:0008584; P:male gonad development; IEA:Ensembl.
DR GO; GO:0001774; P:microglial cell activation; IEA:Ensembl.
DR GO; GO:0097527; P:necroptotic signaling pathway; IDA:UniProtKB.
DR GO; GO:0045671; P:negative regulation of osteoclast differentiation; NAS:UniProtKB.
DR GO; GO:0045766; P:positive regulation of angiogenesis; IEA:Ensembl.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IEA:Ensembl.
DR GO; GO:0043123; P:positive regulation of canonical NF-kappaB signal transduction; IEA:Ensembl.
DR GO; GO:0032722; P:positive regulation of chemokine production; IDA:BHF-UCL.
DR GO; GO:1900017; P:positive regulation of cytokine production involved in inflammatory response; IEA:Ensembl.
DR GO; GO:0010628; P:positive regulation of gene expression; IMP:UniProtKB.
DR GO; GO:0050729; P:positive regulation of inflammatory response; IC:BHF-UCL.
DR GO; GO:0032727; P:positive regulation of interferon-alpha production; IDA:UniProtKB.
DR GO; GO:0032728; P:positive regulation of interferon-beta production; IDA:UniProtKB.
DR GO; GO:0032735; P:positive regulation of interleukin-12 production; ISS:BHF-UCL.
DR GO; GO:0032755; P:positive regulation of interleukin-6 production; IDA:BHF-UCL.
DR GO; GO:0032757; P:positive regulation of interleukin-8 production; IDA:BHF-UCL.
DR GO; GO:0046330; P:positive regulation of JNK cascade; IDA:UniProt.
DR GO; GO:0060907; P:positive regulation of macrophage cytokine production; IEA:Ensembl.
DR GO; GO:1901224; P:positive regulation of non-canonical NF-kappaB signal transduction; IDA:BHF-UCL.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISS:BHF-UCL.
DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; ISS:BHF-UCL.
DR GO; GO:0032729; P:positive regulation of type II interferon production; IDA:UniProtKB.
DR GO; GO:0034346; P:positive regulation of type III interferon production; IEA:Ensembl.
DR GO; GO:0002730; P:regulation of dendritic cell cytokine production; IEA:Ensembl.
DR GO; GO:0043331; P:response to dsRNA; IBA:GO_Central.
DR GO; GO:0043330; P:response to exogenous dsRNA; IDA:MGI.
DR GO; GO:0007165; P:signal transduction; TAS:ProtInc.
DR GO; GO:0034138; P:toll-like receptor 3 signaling pathway; IDA:BHF-UCL.
DR GO; GO:0002224; P:toll-like receptor signaling pathway; IDA:UniProt.
DR GO; GO:0034343; P:type III interferon production; IEA:Ensembl.
DR Gene3D; 3.80.10.10; Ribonuclease Inhibitor; 1.
DR Gene3D; 3.40.50.10140; Toll/interleukin-1 receptor homology (TIR) domain; 1.
DR InterPro; IPR000483; Cys-rich_flank_reg_C.
DR InterPro; IPR001611; Leu-rich_rpt.
DR InterPro; IPR003591; Leu-rich_rpt_typical-subtyp.
DR InterPro; IPR032675; LRR_dom_sf.
DR InterPro; IPR000157; TIR_dom.
DR InterPro; IPR041015; TLR3_TMD.
DR InterPro; IPR017241; Toll-like_receptor.
DR InterPro; IPR035897; Toll_tir_struct_dom_sf.
DR PANTHER; PTHR24365; TOLL-LIKE RECEPTOR; 1.
DR PANTHER; PTHR24365:SF524; TOLL-LIKE RECEPTOR 3; 1.
DR Pfam; PF13516; LRR_6; 1.
DR Pfam; PF13855; LRR_8; 6.
DR Pfam; PF01582; TIR; 1.
DR Pfam; PF17968; Tlr3_TMD; 1.
DR PRINTS; PR00019; LEURICHRPT.
DR SMART; SM00365; LRR_SD22; 8.
DR SMART; SM00369; LRR_TYP; 16.
DR SMART; SM00082; LRRCT; 1.
DR SMART; SM00255; TIR; 1.
DR SUPFAM; SSF52058; L domain-like; 2.
DR SUPFAM; SSF52200; Toll/Interleukin receptor TIR domain; 1.
DR PROSITE; PS51450; LRR; 19.
DR PROSITE; PS50104; TIR; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Direct protein sequencing;
KW Disease variant; Disulfide bond; Endoplasmic reticulum; Endosome;
KW Glycoprotein; Immunity; Inflammatory response; Innate immunity;
KW Isopeptide bond; Leucine-rich repeat; Membrane; Phosphoprotein; Receptor;
KW Reference proteome; Repeat; RNA-binding; Signal; Transmembrane;
KW Transmembrane helix; Ubl conjugation.
FT SIGNAL 1..23
FT /evidence="ECO:0000269|PubMed:15340161"
FT CHAIN 24..904
FT /note="Toll-like receptor 3"
FT /id="PRO_0000034715"
FT TOPO_DOM 24..704
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT TRANSMEM 705..725
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 726..904
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 24..51
FT /note="LRRNT"
FT REPEAT 52..73
FT /note="LRR 1"
FT REPEAT 76..97
FT /note="LRR 2"
FT REPEAT 100..121
FT /note="LRR 3"
FT REPEAT 124..145
FT /note="LRR 4"
FT REPEAT 148..168
FT /note="LRR 5"
FT REPEAT 172..193
FT /note="LRR 6"
FT REPEAT 198..219
FT /note="LRR 7"
FT REPEAT 222..244
FT /note="LRR 8"
FT REPEAT 249..270
FT /note="LRR 9"
FT REPEAT 275..296
FT /note="LRR 10"
FT REPEAT 299..320
FT /note="LRR 11"
FT REPEAT 323..344
FT /note="LRR 12"
FT REPEAT 356..377
FT /note="LRR 13"
FT REPEAT 380..400
FT /note="LRR 14"
FT REPEAT 408..429
FT /note="LRR 15"
FT REPEAT 432..454
FT /note="LRR 16"
FT REPEAT 465..486
FT /note="LRR 17"
FT REPEAT 507..528
FT /note="LRR 18"
FT REPEAT 531..552
FT /note="LRR 19"
FT REPEAT 563..584
FT /note="LRR 20"
FT REPEAT 587..608
FT /note="LRR 21"
FT REPEAT 611..632
FT /note="LRR 22"
FT DOMAIN 645..698
FT /note="LRRCT"
FT DOMAIN 754..897
FT /note="TIR"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00204"
FT MOD_RES 759
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000269|PubMed:17178723"
FT MOD_RES 858
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000269|PubMed:17178723"
FT CARBOHYD 52
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:16043704,
FT ECO:0000269|PubMed:19159218, ECO:0000269|PubMed:22579623"
FT CARBOHYD 57
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:19159218"
FT CARBOHYD 70
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:16043704,
FT ECO:0000269|PubMed:22579623"
FT CARBOHYD 124
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:15961631,
FT ECO:0000269|PubMed:22579623"
FT CARBOHYD 196
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:16043704"
FT CARBOHYD 247
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:22579623"
FT CARBOHYD 252
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:15961631,
FT ECO:0000269|PubMed:16043704, ECO:0000269|PubMed:22579623"
FT CARBOHYD 265
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:16043704,
FT ECO:0000269|PubMed:22579623"
FT CARBOHYD 275
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:15961631,
FT ECO:0000269|PubMed:16043704, ECO:0000269|PubMed:22579623"
FT CARBOHYD 291
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:15961631,
FT ECO:0000269|PubMed:16043704, ECO:0000269|PubMed:22579623"
FT CARBOHYD 398
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:15961631,
FT ECO:0000269|PubMed:16043704, ECO:0000269|PubMed:22579623"
FT CARBOHYD 413
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:15961631,
FT ECO:0000269|PubMed:16043704, ECO:0000269|PubMed:22579623"
FT CARBOHYD 507
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:15961631,
FT ECO:0000269|PubMed:16043704, ECO:0000269|PubMed:22579623"
FT CARBOHYD 636
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:16043704"
FT CARBOHYD 662
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 28..37
FT DISULFID 95..122
FT DISULFID 649..677
FT DISULFID 651..696
FT CROSSLNK 765
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:37158982"
FT CROSSLNK 812
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:37158982"
FT CROSSLNK 831
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:32878999"
FT VAR_SEQ 1..277
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_054188"
FT VARIANT 134
FT /note="S -> P (no effect on IFNL1 induction)"
FT /evidence="ECO:0000269|PubMed:32972995"
FT /id="VAR_084046"
FT VARIANT 251
FT /note="R -> G (no effect on IFNL1 induction;
FT dbSNP:rs780051344)"
FT /evidence="ECO:0000269|PubMed:32972995"
FT /id="VAR_084047"
FT VARIANT 284
FT /note="N -> I (in dbSNP:rs5743316)"
FT /id="VAR_052361"
FT VARIANT 307
FT /note="Y -> D (in dbSNP:rs5743317)"
FT /id="VAR_052362"
FT VARIANT 412
FT /note="L -> F (in dbSNP:rs3775291)"
FT /evidence="ECO:0000269|PubMed:14702039,
FT ECO:0000269|PubMed:18753640, ECO:0000269|PubMed:22174453,
FT ECO:0000269|Ref.4"
FT /id="VAR_021976"
FT VARIANT 554
FT /note="P -> S (in IMD83; causes TLR3 deficiency and
FT predisposition to herpes simplex encephalitis; inhibition
FT of IFNL1 induction; dbSNP:rs121434431)"
FT /evidence="ECO:0000269|PubMed:17872438,
FT ECO:0000269|PubMed:32972995"
FT /id="VAR_054887"
FT VARIANT 732
FT /note="F -> L (no effect on IFNL1 induction;
FT dbSNP:rs988586598 and dbSNP:rs774476397)"
FT /evidence="ECO:0000269|PubMed:32972995"
FT /id="VAR_084048"
FT VARIANT 737
FT /note="S -> T (in dbSNP:rs5743318)"
FT /id="VAR_024664"
FT VARIANT 746..904
FT /note="Missing (inhibition of IFNL1 induction)"
FT /evidence="ECO:0000269|PubMed:32972995"
FT /id="VAR_084049"
FT VARIANT 769..904
FT /note="Missing (inhibition of IFNL1 induction)"
FT /evidence="ECO:0000269|PubMed:32972995"
FT /id="VAR_084050"
FT VARIANT 867
FT /note="R -> Q (inhibition of IFNL1 induction;
FT dbSNP:rs199768900)"
FT /evidence="ECO:0000269|PubMed:32972995"
FT /id="VAR_084051"
FT VARIANT 870
FT /note="M -> V (inhibition of IFNL1 induction)"
FT /evidence="ECO:0000269|PubMed:32972995"
FT /id="VAR_084052"
FT MUTAGEN 95
FT /note="C->A: Reduced response to ds-RNA."
FT /evidence="ECO:0000269|PubMed:16144834"
FT MUTAGEN 122
FT /note="C->A: Reduced response to ds-RNA."
FT /evidence="ECO:0000269|PubMed:16144834"
FT MUTAGEN 196
FT /note="N->G: Reduced expression levels; when associated
FT with R-247."
FT /evidence="ECO:0000269|PubMed:16144834"
FT MUTAGEN 247
FT /note="N->R: Reduced response to ds-RNA. Reduced expression
FT levels; when associated with G-196."
FT /evidence="ECO:0000269|PubMed:16144834"
FT MUTAGEN 539
FT /note="H->A: No effect."
FT /evidence="ECO:0000269|PubMed:16720699"
FT MUTAGEN 539
FT /note="H->E: Loss of RNA binding. Constitutive activation
FT of NF-kappa-B."
FT /evidence="ECO:0000269|PubMed:16720699"
FT MUTAGEN 541
FT /note="N->A: Loss of RNA binding. Abolishes activation of
FT NF-kappa-B."
FT /evidence="ECO:0000269|PubMed:16720699"
FT MUTAGEN 759
FT /note="Y->F: Reduced activation of NF-kappa-B in response
FT to ds-RNA. Reduced induction of IL-8 in response to ds-RNA.
FT Loss of interaction with WDFY1."
FT /evidence="ECO:0000269|PubMed:17178723,
FT ECO:0000269|PubMed:25736436"
FT MUTAGEN 812
FT /note="K->R: Loss of ubiquitination by ZNRF1."
FT /evidence="ECO:0000269|PubMed:37158982"
FT MUTAGEN 831
FT /note="K->R: Loss of ubiquitination by TRIM3."
FT /evidence="ECO:0000269|PubMed:32878999"
FT MUTAGEN 858
FT /note="Y->F: Loss of interaction with WDFY1."
FT /evidence="ECO:0000269|PubMed:25736436"
FT CONFLICT 290
FT /note="G -> R (in Ref. 5; BAG36884)"
FT /evidence="ECO:0000305"
FT CONFLICT 575
FT /note="D -> N (in Ref. 8; AAH94737)"
FT /evidence="ECO:0000305"
FT CONFLICT 605
FT /note="V -> A (in Ref. 5; BAG36884)"
FT /evidence="ECO:0000305"
FT CONFLICT 663
FT /note="E -> G (in Ref. 5; BAG36884)"
FT /evidence="ECO:0000305"
FT STRAND 31..36
FT /evidence="ECO:0007829|PDB:1ZIW"
FT STRAND 47..49
FT /evidence="ECO:0007829|PDB:2A0Z"
FT STRAND 54..57
FT /evidence="ECO:0007829|PDB:1ZIW"
FT HELIX 68..74
FT /evidence="ECO:0007829|PDB:1ZIW"
FT STRAND 78..81
FT /evidence="ECO:0007829|PDB:1ZIW"
FT HELIX 94..97
FT /evidence="ECO:0007829|PDB:1ZIW"
FT STRAND 103..105
FT /evidence="ECO:0007829|PDB:1ZIW"
FT STRAND 108..110
FT /evidence="ECO:0007829|PDB:5GS0"
FT TURN 118..121
FT /evidence="ECO:0007829|PDB:1ZIW"
FT STRAND 126..129
FT /evidence="ECO:0007829|PDB:1ZIW"
FT TURN 142..145
FT /evidence="ECO:0007829|PDB:1ZIW"
FT STRAND 151..153
FT /evidence="ECO:0007829|PDB:1ZIW"
FT STRAND 166..168
FT /evidence="ECO:0007829|PDB:1ZIW"
FT STRAND 175..177
FT /evidence="ECO:0007829|PDB:1ZIW"
FT HELIX 188..191
FT /evidence="ECO:0007829|PDB:1ZIW"
FT HELIX 192..194
FT /evidence="ECO:0007829|PDB:1ZIW"
FT STRAND 198..203
FT /evidence="ECO:0007829|PDB:1ZIW"
FT HELIX 216..219
FT /evidence="ECO:0007829|PDB:1ZIW"
FT STRAND 220..223
FT /evidence="ECO:0007829|PDB:1ZIW"
FT STRAND 225..227
FT /evidence="ECO:0007829|PDB:1ZIW"
FT HELIX 234..245
FT /evidence="ECO:0007829|PDB:1ZIW"
FT STRAND 252..254
FT /evidence="ECO:0007829|PDB:1ZIW"
FT TURN 265..268
FT /evidence="ECO:0007829|PDB:1ZIW"
FT HELIX 269..273
FT /evidence="ECO:0007829|PDB:1ZIW"
FT STRAND 278..280
FT /evidence="ECO:0007829|PDB:1ZIW"
FT TURN 291..296
FT /evidence="ECO:0007829|PDB:1ZIW"
FT STRAND 302..304
FT /evidence="ECO:0007829|PDB:1ZIW"
FT STRAND 310..313
FT /evidence="ECO:0007829|PDB:1ZIW"
FT TURN 315..320
FT /evidence="ECO:0007829|PDB:1ZIW"
FT STRAND 326..328
FT /evidence="ECO:0007829|PDB:1ZIW"
FT TURN 338..340
FT /evidence="ECO:0007829|PDB:7WV3"
FT TURN 348..353
FT /evidence="ECO:0007829|PDB:1ZIW"
FT STRAND 359..361
FT /evidence="ECO:0007829|PDB:1ZIW"
FT TURN 372..377
FT /evidence="ECO:0007829|PDB:1ZIW"
FT STRAND 383..385
FT /evidence="ECO:0007829|PDB:1ZIW"
FT STRAND 390..392
FT /evidence="ECO:0007829|PDB:7WV3"
FT TURN 398..401
FT /evidence="ECO:0007829|PDB:1ZIW"
FT HELIX 402..404
FT /evidence="ECO:0007829|PDB:1ZIW"
FT STRAND 405..407
FT /evidence="ECO:0007829|PDB:7WV5"
FT STRAND 411..413
FT /evidence="ECO:0007829|PDB:1ZIW"
FT TURN 424..429
FT /evidence="ECO:0007829|PDB:1ZIW"
FT STRAND 435..437
FT /evidence="ECO:0007829|PDB:1ZIW"
FT STRAND 444..446
FT /evidence="ECO:0007829|PDB:1ZIW"
FT HELIX 450..452
FT /evidence="ECO:0007829|PDB:1ZIW"
FT STRAND 460..462
FT /evidence="ECO:0007829|PDB:1ZIW"
FT STRAND 467..470
FT /evidence="ECO:0007829|PDB:1ZIW"
FT TURN 473..478
FT /evidence="ECO:0007829|PDB:1ZIW"
FT STRAND 484..486
FT /evidence="ECO:0007829|PDB:1ZIW"
FT STRAND 492..494
FT /evidence="ECO:0007829|PDB:7WV5"
FT TURN 501..504
FT /evidence="ECO:0007829|PDB:1ZIW"
FT STRAND 510..512
FT /evidence="ECO:0007829|PDB:1ZIW"
FT TURN 523..528
FT /evidence="ECO:0007829|PDB:1ZIW"
FT STRAND 534..536
FT /evidence="ECO:0007829|PDB:1ZIW"
FT HELIX 543..546
FT /evidence="ECO:0007829|PDB:1ZIW"
FT STRAND 548..550
FT /evidence="ECO:0007829|PDB:7C76"
FT TURN 557..560
FT /evidence="ECO:0007829|PDB:1ZIW"
FT STRAND 566..568
FT /evidence="ECO:0007829|PDB:1ZIW"
FT TURN 579..584
FT /evidence="ECO:0007829|PDB:1ZIW"
FT STRAND 590..592
FT /evidence="ECO:0007829|PDB:1ZIW"
FT TURN 603..608
FT /evidence="ECO:0007829|PDB:1ZIW"
FT STRAND 614..616
FT /evidence="ECO:0007829|PDB:1ZIW"
FT HELIX 627..634
FT /evidence="ECO:0007829|PDB:1ZIW"
FT STRAND 638..641
FT /evidence="ECO:0007829|PDB:1ZIW"
FT TURN 651..653
FT /evidence="ECO:0007829|PDB:7WV3"
FT STRAND 655..658
FT /evidence="ECO:0007829|PDB:1ZIW"
FT HELIX 671..674
FT /evidence="ECO:0007829|PDB:7WV3"
FT STRAND 676..680
FT /evidence="ECO:0007829|PDB:7WV3"
FT TURN 681..685
FT /evidence="ECO:0007829|PDB:7WV3"
FT HELIX 688..690
FT /evidence="ECO:0007829|PDB:2A0Z"
FT STRAND 694..696
FT /evidence="ECO:0007829|PDB:7C76"
FT TURN 697..699
FT /evidence="ECO:0007829|PDB:7C76"
FT HELIX 702..725
FT /evidence="ECO:0007829|PDB:7C76"
FT HELIX 738..745
FT /evidence="ECO:0007829|PDB:8AR1"
SQ SEQUENCE 904 AA; 103829 MW; 034E05ECA7A4D2F7 CRC64;
MRQTLPCIYF WGGLLPFGML CASSTTKCTV SHEVADCSHL KLTQVPDDLP TNITVLNLTH
NQLRRLPAAN FTRYSQLTSL DVGFNTISKL EPELCQKLPM LKVLNLQHNE LSQLSDKTFA
FCTNLTELHL MSNSIQKIKN NPFVKQKNLI TLDLSHNGLS STKLGTQVQL ENLQELLLSN
NKIQALKSEE LDIFANSSLK KLELSSNQIK EFSPGCFHAI GRLFGLFLNN VQLGPSLTEK
LCLELANTSI RNLSLSNSQL STTSNTTFLG LKWTNLTMLD LSYNNLNVVG NDSFAWLPQL
EYFFLEYNNI QHLFSHSLHG LFNVRYLNLK RSFTKQSISL ASLPKIDDFS FQWLKCLEHL
NMEDNDIPGI KSNMFTGLIN LKYLSLSNSF TSLRTLTNET FVSLAHSPLH ILNLTKNKIS
KIESDAFSWL GHLEVLDLGL NEIGQELTGQ EWRGLENIFE IYLSYNKYLQ LTRNSFALVP
SLQRLMLRRV ALKNVDSSPS PFQPLRNLTI LDLSNNNIAN INDDMLEGLE KLEILDLQHN
NLARLWKHAN PGGPIYFLKG LSHLHILNLE SNGFDEIPVE VFKDLFELKI IDLGLNNLNT
LPASVFNNQV SLKSLNLQKN LITSVEKKVF GPAFRNLTEL DMRFNPFDCT CESIAWFVNW
INETHTNIPE LSSHYLCNTP PHYHGFPVRL FDTSSCKDSA PFELFFMINT SILLIFIFIV
LLIHFEGWRI SFYWNVSVHR VLGFKEIDRQ TEQFEYAAYI IHAYKDKDWV WEHFSSMEKE
DQSLKFCLEE RDFEAGVFEL EAIVNSIKRS RKIIFVITHH LLKDPLCKRF KVHHAVQQAI
EQNLDSIILV FLEEIPDYKL NHALCLRRGM FKSHCILNWP VQKERIGAFR HKLQVALGSK
NSVH
//