ID TLR4_HUMAN Reviewed; 839 AA. AC O00206; A8K1Y8; A9XLP9; A9XLQ0; A9XLQ1; B4E194; D1CS52; D1CS53; AC Q5VZI8; Q5VZI9; Q9UK78; Q9UM57; DT 11-FEB-2002, integrated into UniProtKB/Swiss-Prot. DT 01-JAN-1998, sequence version 2. DT 01-MAY-2013, entry version 139. DE RecName: Full=Toll-like receptor 4; DE AltName: Full=hToll; DE AltName: CD_antigen=CD284; DE Flags: Precursor; GN Name=TLR4; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Spleen; RX PubMed=9237759; DOI=10.1038/41131; RA Medzhitov R., Preston-Hurlburt P., Janeway C.A. Jr.; RT "A human homologue of the Drosophila Toll protein signals activation RT of adaptive immunity."; RL Nature 388:394-397(1997). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). RC TISSUE=Fetal liver, Lung, and Placenta; 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 RT Toll."; RL Proc. Natl. Acad. Sci. U.S.A. 95:588-593(1998). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS GLY-299 AND ILE-399. RX PubMed=11104518; RA Smirnova I., Poltorak A., Chan E.K.L., McBride C., Beutler B.; RT "Phylogenetic variation and polymorphism at the Toll-like receptor 4 RT locus (TLR4)."; RL Genome Biol. 1:RESEARCH002.1-RESEARCH002.10(2000). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS GLY-299 AND ILE-399. RX PubMed=10835634; DOI=10.1038/76048; RA Arbour N.C., Lorenz E., Schutte B.C., Zabner J., Kline J.N., Jones M., RA Frees K., Watt J.L., Schwartz D.A.; RT "TLR4 mutations are associated with endotoxin hyporesponsiveness in RT humans."; RL Nat. Genet. 25:187-191(2000). RN [5] 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., RA Kimura A.; RT "Natural selection in the TLR-related genes in the course of primate RT evolution."; RL Immunogenetics 60:727-735(2008). RN [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS GLY-299 AND ILE-399. RX PubMed=19924287; DOI=10.1371/journal.pone.0007803; RA Georgel P., Macquin C., Bahram S.; RT "The heterogeneous allelic repertoire of human Toll-Like receptor RT (TLR) genes."; RL PLoS ONE 4:E7803-E7803(2009). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 2 AND 3). RC TISSUE=Hippocampus, Kidney, and Uterus; 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., RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., RA 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., RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., RA Nakai K., Yada T., Nakamura Y., Ohara O., 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 [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15164053; DOI=10.1038/nature02465; RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E., RA Howe K.L., Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C., RA Ainscough R., Almeida J.P., Ambrose K.D., Ashwell R.I.S., RA Babbage A.K., Babbage S., Bagguley C.L., Bailey J., Banerjee R., RA Barker D.J., Barlow K.F., Bates K., Beasley H., Beasley O., Bird C.P., RA Bray-Allen S., Brown A.J., Brown J.Y., Burford D., Burrill W., RA Burton J., Carder C., Carter N.P., Chapman J.C., Chen Y., Clarke G., RA Clark S.Y., Clee C.M., Clegg S., Collier R.E., Corby N., Crosier M., RA Cummings A.T., Davies J., Dhami P., Dunn M., Dutta I., Dyer L.W., RA Earthrowl M.E., Faulkner L., Fleming C.J., Frankish A., RA Frankland J.A., French L., Fricker D.G., Garner P., Garnett J., RA Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S., RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E., RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D., RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E., RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K., RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C., RA Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M., RA Lovell J., Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S., RA McLay K.E., McMurray A., Milne S., Nickerson T., Nisbett J., RA Nordsiek G., Pearce A.V., Peck A.I., Porter K.M., Pandian R., RA Pelan S., Phillimore B., Povey S., Ramsey Y., Rand V., Scharfe M., RA Sehra H.K., Shownkeen R., Sims S.K., Skuce C.D., Smith M., RA Steward C.A., Swarbreck D., Sycamore N., Tester J., Thorpe A., RA Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., West A.P., RA Whitehead S.L., Willey D.L., Williams S.A., Wilming L., Wray P.W., RA Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M., RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S., RA Rogers J., Dunham I.; RT "DNA sequence and analysis of human chromosome 9."; RL Nature 429:369-374(2004). RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R., RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., RA Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [10] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Cerebellum; 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 RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [11] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-86. RA Liu Z., Li N., Wang J., Xiao W.; RL Submitted (MAR-2007) to the EMBL/GenBank/DDBJ databases. RN [12] 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 RT verified cleavage sites."; RL Protein Sci. 13:2819-2824(2004). RN [13] RP MUTAGENESIS OF GLU-697; ARG-710; ASP-711 AND PRO-714. RX PubMed=11081518; DOI=10.1038/35040600; RA Xu Y., Tao X., Shen B., Horng T., Medzhitov R., Manley J.L., Tong L.; RT "Structural basis for signal transduction by the Toll/interleukin-1 RT receptor domains."; RL Nature 408:111-115(2000). RN [14] RP GLYCOSYLATION AT ASN-35; ASN-173; ASN-205; ASN-282; ASN-309; ASN-497; RP ASN-526; ASN-575 AND ASN-624, AND MUTAGENESIS OF ASN-526 AND ASN-575. RX PubMed=11706042; DOI=10.1074/jbc.M109910200; RA da Silva Correia J., Ulevitch R.J.; RT "MD-2 and TLR4 N-linked glycosylations are important for a functional RT lipopolysaccharide receptor."; RL J. Biol. Chem. 277:1845-1854(2002). RN [15] RP INTERACTION WITH NOX4. RX PubMed=15356101; RA Park H.S., Jung H.Y., Park E.Y., Kim J., Lee W.J., Bae Y.S.; RT "Direct interaction of TLR4 with NAD(P)H oxidase 4 isozyme is RT essential for lipopolysaccharide-induced production of reactive oxygen RT species and activation of NF-kappa B."; RL J. Immunol. 173:3589-3593(2004). RN [16] RP INTERACTION WITH HSP90B1. RX PubMed=20865800; DOI=10.1038/ncomms1070; RA Liu B., Yang Y., Qiu Z., Staron M., Hong F., Li Y., Wu S., Li Y., RA Hao B., Bona R., Han D., Li Z.; RT "Folding of Toll-like receptors by the HSP90 paralogue gp96 requires a RT substrate-specific cochaperone."; RL Nat. Commun. 1:79-79(2010). RN [17] RP ERRATUM. RA Liu B., Yang Y., Qiu Z., Staron M., Hong F., Li Y., Wu S., Li Y., RA Hao B., Bona R., Han D., Li Z.; RL Nat. Commun. 3:653-653(2012). RN [18] RP FUNCTION, MUTAGENESIS OF HIS-431; HIS-456 AND HIS-458, AND INVOLVEMENT RP IN CONTACT ALLERGY TO NICKEL. RX PubMed=20711192; DOI=10.1038/ni.1919; RA Schmidt M., Raghavan B., Mueller V., Vogl T., Fejer G., Tchaptchet S., RA Keck S., Kalis C., Nielsen P.J., Galanos C., Roth J., Skerra A., RA Martin S.F., Freudenberg M.A., Goebeler M.; RT "Crucial role for human Toll-like receptor 4 in the development of RT contact allergy to nickel."; RL Nat. Immunol. 11:814-819(2010). RN [19] RP INTERACTION WITH MLK4. RX PubMed=21602844; DOI=10.1038/cmi.2011.15; RA Seit-Nebi A., Cheng W., Xu H., Han J.; RT "MLK4 has negative effect on TLR4 signaling."; RL Cell. Mol. Immunol. 9:27-33(2012). RN [20] RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 27-228, DISULFIDE BONDS, AND RP GLYCOSYLATION AT ASN-35; ASN-173 AND ASN-205. RX PubMed=17803912; DOI=10.1016/j.cell.2007.08.002; RA Kim H.M., Park B.S., Kim J.-I., Kim S.E., Lee J., Oh S.C., RA Enkhbayar P., Matsushima N., Lee H., Yoo O.J., Lee J.-O.; RT "Crystal structure of the TLR4-MD-2 complex with bound endotoxin RT antagonist Eritoran."; RL Cell 130:906-917(2007). RN [21] RP X-RAY CRYSTALLOGRAPHY (3.1 ANGSTROMS) OF 27-631 IN COMPLEX WITH LY96 RP AND LIPOPOLYSACCHARIDE, DISULFIDE BONDS, AND GLYCOSYLATION AT ASN-173; RP ASN-205; ASN-497 AND ASN-526 AND ASN-575. RX PubMed=19252480; DOI=10.1038/nature07830; RA Park B.S., Song D.H., Kim H.M., Choi B.-S., Lee H., Lee J.-O.; RT "The structural basis of lipopolysaccharide recognition by the TLR4- RT MD-2 complex."; RL Nature 458:1191-1195(2009). RN [22] RP X-RAY CRYSTALLOGRAPHY (2.37 ANGSTROMS) OF 28-228, GLYCOSYLATION AT RP ASN-35 AND ASN-173, AND DISULFIDE BONDS. RX PubMed=22363519; DOI=10.1371/journal.pone.0030929; RA Han J., Kim H.J., Lee S.C., Hong S., Park K., Jeon Y.H., Kim D., RA Cheong H.K., Kim H.S.; RT "Structure-based rational design of a Toll-like receptor 4 (TLR4) RT decoy receptor with high binding affinity for a target protein."; RL PLoS ONE 7:E30929-E30929(2012). RN [23] RP VARIANTS ARG-188; SER-246; GLY-299; SER-329; ILE-399; LEU-443; RP LYS-474; HIS-510; ARG-694; HIS-763 AND HIS-834. RX PubMed=11514453; RA Smirnova I., Hamblin M.T., McBride C., Beutler B., Di Rienzo A.; RT "Excess of rare amino acid polymorphisms in the Toll-like receptor 4 RT in humans."; RL Genetics 158:1657-1664(2001). RN [24] RP VARIANT GLY-299, AND ASSOCIATION WITH ARMD SUSCEPTIBILITY. RX PubMed=15829498; DOI=10.1093/hmg/ddi154; RA Zareparsi S., Buraczynska M., Branham K.E.H., Shah S., Eng D., Li M., RA Pawar H., Yashar B.M., Moroi S.E., Lichter P.R., Petty H.R., RA Richards J.E., Abecasis G.R., Elner V.M., Swaroop A.; RT "Toll-like receptor 4 variant D299G is associated with susceptibility RT to age-related macular degeneration."; RL Hum. Mol. Genet. 14:1449-1455(2005). CC -!- FUNCTION: Cooperates with LY96 and CD14 to mediate the innate CC immune response to bacterial lipopolysaccharide (LPS). Acts via CC MYD88, TIRAP and TRAF6, leading to NF-kappa-B activation, cytokine CC secretion and the inflammatory response. Also involved in LPS- CC independent inflammatory responses triggered by Ni(2+). These CC responses require non-conserved histidines and are, therefore, CC species-specific. CC -!- SUBUNIT: Belongs to the lipopolysaccharide (LPS) receptor, a CC multi-protein complex containing at least CD14, LY96 and TLR4. CC Binding to bacterial LPS leads to homodimerization. Interacts with CC LY96 via the extracellular domain. Interacts with MYD88 and TIRAP CC via their respective TIR domains. Interacts with NOX4. Interacts CC with CNPY3 (By similarity). Interacts with HSP90B1. The CC interaction with both CNPY3 and HSP90B1 is required for proper CC folding in the endoplasmic reticulum. Interacts with MLK4; this CC interaction leads to negative regulation of TLR4 signaling. CC -!- INTERACTION: CC O76552:- (xeno); NbExp=3; IntAct=EBI-528701, EBI-3870694; CC Q9Y6Y9:LY96; NbExp=3; IntAct=EBI-528701, EBI-1539247; CC P58753:TIRAP; NbExp=2; IntAct=EBI-528701, EBI-528644; CC -!- SUBCELLULAR LOCATION: Membrane; Single-pass type I membrane CC protein. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=O00206-1; Sequence=Displayed; CC Name=2; CC IsoId=O00206-2; Sequence=VSP_035794; CC Name=3; CC IsoId=O00206-3; Sequence=VSP_035793; CC Note=No experimental confirmation available; CC -!- TISSUE SPECIFICITY: Highly expressed in placenta, spleen and CC peripheral blood leukocytes. Detected in monocytes, macrophages, CC dendritic cells and several types of T-cells. CC -!- DOMAIN: The TIR domain mediates interaction with NOX4. CC -!- PTM: N-glycosylated. Glycosylation of Asn-526 and Asn-575 seems to CC be necessary for the expression of TLR4 on the cell surface and CC the LPS-response. Likewise, mutants lacking two or more of the CC other N-glycosylation sites were deficient in interaction with CC LPS. CC -!- POLYMORPHISM: Allele TLR4*B (Gly-299, Ile-399) is associated with CC a blunted response to inhaled LPS. CC -!- DISEASE: Age-related macular degeneration 10 (ARMD10) CC [MIM:611488]: A form of age-related macular degeneration, a CC multifactorial eye disease and the most common cause of CC irreversible vision loss in the developed world. In most patients, CC the disease is manifest as ophthalmoscopically visible yellowish CC accumulations of protein and lipid that lie beneath the retinal CC pigment epithelium and within an elastin-containing structure CC known as Bruch membrane. Note=Disease susceptibility is associated CC with variations affecting the gene represented in this entry. CC -!- MISCELLANEOUS: His-456 and His-458 are found in TLR4 of human and CC several other primate species and may be responsible for CC inflammatory responses triggered by nickel (Ni(2+)). Ni(2+) may CC cross-link the two receptor monomers through specific histidines, CC triggering the formation of a dimer that structurally resembles CC that induced by LPS. This process may be the basis for the CC development of contact allergy to Ni(2+). A mouse model of contact CC allergy to Ni(2+) in which TLR4-deficient mice expresses human CC TLR4 has been proposed. CC -!- SIMILARITY: Belongs to the Toll-like receptor family. CC -!- SIMILARITY: Contains 18 LRR (leucine-rich) repeats. CC -!- SIMILARITY: Contains 1 LRRCT domain. CC -!- SIMILARITY: Contains 1 TIR domain. CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=Zips, necklaces and CC mobile telephones - Issue 134 of December 2011; CC URL="http://web.expasy.org/spotlight/back_issues/sptlt134.shtml"; CC ----------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution-NoDerivs License CC ----------------------------------------------------------------------- DR EMBL; U93091; AAC80227.1; -; mRNA. DR EMBL; AB445638; BAG55035.1; -; mRNA. DR EMBL; DQ018107; AAY82267.1; -; Genomic_DNA. DR EMBL; DQ018108; AAY82268.1; -; Genomic_DNA. DR EMBL; DQ018109; AAY82269.1; -; Genomic_DNA. DR EMBL; AK290053; BAF82742.1; -; mRNA. DR EMBL; AK293068; BAF85757.1; -; mRNA. DR EMBL; AK303730; BAG64706.1; -; mRNA. DR EMBL; AL160272; CAH72618.1; -; Genomic_DNA. DR EMBL; AL160272; CAH72619.1; -; Genomic_DNA. DR EMBL; CH471090; EAW87448.1; -; Genomic_DNA. DR EMBL; CH471090; EAW87451.1; -; Genomic_DNA. DR EMBL; BC117422; AAI17423.1; -; mRNA. DR EMBL; EF535831; ABU41662.1; -; Genomic_DNA. DR EMBL; EF535832; ABU41663.1; -; Genomic_DNA. DR EMBL; EF535833; ABU41664.1; -; Genomic_DNA. DR EMBL; AF177765; AAF05316.1; -; Genomic_DNA. DR EMBL; AF177766; AAF07823.1; -; Genomic_DNA. DR EMBL; AF172171; AAF89753.1; -; Genomic_DNA. DR EMBL; AF172169; AAF89753.1; JOINED; Genomic_DNA. DR EMBL; AF172170; AAF89753.1; JOINED; Genomic_DNA. DR EMBL; U88880; AAC34135.1; -; mRNA. DR IPI; IPI00008673; -. DR IPI; IPI00374265; -. DR IPI; IPI00914904; -. DR RefSeq; NP_003257.1; NM_003266.3. DR RefSeq; NP_612564.1; NM_138554.4. DR RefSeq; NP_612567.1; NM_138557.2. DR UniGene; Hs.174312; -. DR PDB; 2Z62; X-ray; 1.70 A; A=27-228. DR PDB; 2Z63; X-ray; 2.00 A; A=27-527. DR PDB; 2Z65; X-ray; 2.70 A; A/B=27-228. DR PDB; 2Z66; X-ray; 1.90 A; A/B/C/D=380-627. DR PDB; 3FXI; X-ray; 3.10 A; A/B=27-631. DR PDB; 3UL7; X-ray; 2.37 A; A=28-228. DR PDB; 3UL8; X-ray; 2.50 A; A=27-228. DR PDB; 3UL9; X-ray; 2.45 A; A=28-228. DR PDB; 3ULA; X-ray; 3.60 A; A/C=27-228. DR PDB; 4G8A; X-ray; 2.40 A; A/B=23-629. DR PDBsum; 2Z62; -. DR PDBsum; 2Z63; -. DR PDBsum; 2Z65; -. DR PDBsum; 2Z66; -. DR PDBsum; 3FXI; -. DR PDBsum; 3UL7; -. DR PDBsum; 3UL8; -. DR PDBsum; 3UL9; -. DR PDBsum; 3ULA; -. DR PDBsum; 4G8A; -. DR ProteinModelPortal; O00206; -. DR DIP; DIP-34769N; -. DR IntAct; O00206; 11. DR MINT; MINT-3981856; -. DR PhosphoSite; O00206; -. DR PaxDb; O00206; -. DR PRIDE; O00206; -. DR Ensembl; ENST00000355622; ENSP00000363089; ENSG00000136869. DR Ensembl; ENST00000394487; ENSP00000377997; ENSG00000136869. DR GeneID; 7099; -. DR KEGG; hsa:7099; -. DR UCSC; uc004bjz.3; human. DR CTD; 7099; -. DR GeneCards; GC09P120466; -. DR HGNC; HGNC:11850; TLR4. DR HPA; CAB004025; -. DR MIM; 603030; gene+phenotype. DR MIM; 611488; phenotype. DR neXtProt; NX_O00206; -. DR PharmGKB; PA36552; -. DR eggNOG; NOG249751; -. DR HOVERGEN; HBG018823; -. DR InParanoid; O00206; -. DR KO; K10160; -. DR OMA; PESWDPC; -. DR PhylomeDB; O00206; -. DR Reactome; REACT_6900; Immune System. DR BindingDB; O00206; -. DR ChEMBL; CHEMBL5255; -. DR EvolutionaryTrace; O00206; -. DR GenomeRNAi; 7099; -. DR NextBio; 27773; -. DR ArrayExpress; O00206; -. DR Bgee; O00206; -. DR Genevestigator; O00206; -. DR GermOnline; ENSG00000136869; Homo sapiens. DR GO; GO:0010008; C:endosome membrane; TAS:Reactome. DR GO; GO:0009897; C:external side of plasma membrane; IDA:BHF-UCL. DR GO; GO:0005887; C:integral to plasma membrane; IDA:UniProtKB. DR GO; GO:0046696; C:lipopolysaccharide receptor complex; IDA:UniProtKB. DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB. DR GO; GO:0001530; F:lipopolysaccharide binding; NAS:UniProtKB. DR GO; GO:0001875; F:lipopolysaccharide receptor activity; IDA:UniProtKB. DR GO; GO:0004888; F:transmembrane signaling receptor activity; NAS:UniProtKB. DR GO; GO:0000187; P:activation of MAPK activity; ISS:BHF-UCL. DR GO; GO:0071223; P:cellular response to lipoteichoic acid; IEA:Compara. DR GO; GO:0071260; P:cellular response to mechanical stimulus; IEP:UniProtKB. DR GO; GO:0050829; P:defense response to Gram-negative bacterium; IC:BHF-UCL. DR GO; GO:0016046; P:detection of fungus; NAS:UniProtKB. DR GO; GO:0032497; P:detection of lipopolysaccharide; IDA:UniProtKB. DR GO; GO:0007252; P:I-kappaB phosphorylation; IDA:BHF-UCL. DR GO; GO:0045087; P:innate immune response; TAS:BHF-UCL. DR GO; GO:0032609; P:interferon-gamma production; IEA:Compara. DR GO; GO:0060729; P:intestinal epithelial structure maintenance; ISS:BHF-UCL. DR GO; GO:0042116; P:macrophage activation; IMP:UniProtKB. DR GO; GO:0002755; P:MyD88-dependent toll-like receptor signaling pathway; TAS:Reactome. DR GO; GO:0070373; P:negative regulation of ERK1 and ERK2 cascade; ISS:BHF-UCL. DR GO; GO:0032689; P:negative regulation of interferon-gamma production; ISS:BHF-UCL. DR GO; GO:0032700; P:negative regulation of interleukin-17 production; ISS:BHF-UCL. DR GO; GO:0032707; P:negative regulation of interleukin-23 production; ISS:BHF-UCL. DR GO; GO:0032715; P:negative regulation of interleukin-6 production; ISS:BHF-UCL. DR GO; GO:0045671; P:negative regulation of osteoclast differentiation; NAS:UniProtKB. DR GO; GO:0032720; P:negative regulation of tumor necrosis factor production; ISS:BHF-UCL. DR GO; GO:0002537; P:nitric oxide production involved in inflammatory response; IEA:Compara. DR GO; GO:0030890; P:positive regulation of B cell proliferation; IEA:Compara. DR GO; GO:0032722; P:positive regulation of chemokine production; IDA:BHF-UCL. DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IEA:Compara. DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB cascade; IEA:Compara. DR GO; GO:0050729; P:positive regulation of inflammatory response; IC:BHF-UCL. DR GO; GO:0032727; P:positive regulation of interferon-alpha production; ISS:BHF-UCL. DR GO; GO:0045359; P:positive regulation of interferon-beta biosynthetic process; IEA:Compara. DR GO; GO:0032728; P:positive regulation of interferon-beta production; ISS:BHF-UCL. DR GO; GO:0032729; P:positive regulation of interferon-gamma production; ISS:BHF-UCL. DR GO; GO:0032732; P:positive regulation of interleukin-1 production; ISS:BHF-UCL. DR GO; GO:0032733; P:positive regulation of interleukin-10 production; ISS:BHF-UCL. DR GO; GO:0045084; P:positive regulation of interleukin-12 biosynthetic process; 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:0045416; P:positive regulation of interleukin-8 biosynthetic process; IDA:UniProtKB. DR GO; GO:0032757; P:positive regulation of interleukin-8 production; IDA:BHF-UCL. DR GO; GO:0046330; P:positive regulation of JNK cascade; IEA:Compara. DR GO; GO:0060907; P:positive regulation of macrophage cytokine production; IEA:Compara. DR GO; GO:0045348; P:positive regulation of MHC class II biosynthetic process; IEA:Compara. DR GO; GO:0042346; P:positive regulation of NF-kappaB import into nucleus; IDA:BHF-UCL. DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IDA:MGI. DR GO; GO:0045429; P:positive regulation of nitric oxide biosynthetic process; IEA:Compara. DR GO; GO:0051770; P:positive regulation of nitric-oxide synthase biosynthetic process; ISS:BHF-UCL. DR GO; GO:0070430; P:positive regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway; IEA:Compara. DR GO; GO:0070434; P:positive regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway; IEA:Compara. DR GO; GO:0010572; P:positive regulation of platelet activation; ISS:BHF-UCL. DR GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; ISS:BHF-UCL. DR GO; GO:0042535; P:positive regulation of tumor necrosis factor biosynthetic process; IDA:UniProtKB. DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; ISS:BHF-UCL. DR GO; GO:0050707; P:regulation of cytokine secretion; IEA:InterPro. DR GO; GO:0042088; P:T-helper 1 type immune response; NAS:UniProtKB. DR GO; GO:0008063; P:Toll signaling pathway; TAS:Reactome. DR GO; GO:0034130; P:toll-like receptor 1 signaling pathway; TAS:Reactome. DR GO; GO:0034134; P:toll-like receptor 2 signaling pathway; TAS:Reactome. DR GO; GO:0034138; P:toll-like receptor 3 signaling pathway; TAS:Reactome. DR GO; GO:0034142; P:toll-like receptor 4 signaling pathway; TAS:Reactome. DR GO; GO:0035666; P:TRIF-dependent toll-like receptor signaling pathway; TAS:Reactome. DR InterPro; IPR000483; Cys-rich_flank_reg_C. DR InterPro; IPR001611; Leu-rich_rpt. DR InterPro; IPR025875; Leu-rich_rpt_4. DR InterPro; IPR003591; Leu-rich_rpt_typical-subtyp. DR InterPro; IPR000157; TIR_dom. DR InterPro; IPR027168; TLR4. DR InterPro; IPR017241; Toll-like_receptor. DR PANTHER; PTHR24365:SF9; PTHR24365:SF9; 1. DR Pfam; PF12799; LRR_4; 1. DR Pfam; PF01582; TIR; 1. DR PIRSF; PIRSF037595; Toll-like_receptor; 1. DR SMART; SM00369; LRR_TYP; 2. DR SMART; SM00082; LRRCT; 1. DR SMART; SM00255; TIR; 1. DR SUPFAM; SSF52200; TIR; 1. DR PROSITE; PS51450; LRR; 11. DR PROSITE; PS50104; TIR; 1. PE 1: Evidence at protein level; KW 3D-structure; Age-related macular degeneration; Alternative splicing; KW Complete proteome; Direct protein sequencing; Disulfide bond; KW Glycoprotein; Immunity; Inflammatory response; Innate immunity; KW Leucine-rich repeat; Membrane; Polymorphism; Receptor; KW Reference proteome; Repeat; Signal; Transmembrane; KW Transmembrane helix. FT SIGNAL 1 23 FT CHAIN 24 839 Toll-like receptor 4. FT /FTId=PRO_0000034722. FT TOPO_DOM 24 631 Extracellular (Potential). FT TRANSMEM 632 652 Helical; (Potential). FT TOPO_DOM 653 839 Cytoplasmic (Potential). FT REPEAT 55 76 LRR 1. FT REPEAT 79 100 LRR 2. FT REPEAT 103 124 LRR 3. FT REPEAT 127 148 LRR 4. FT REPEAT 151 172 LRR 5. FT REPEAT 176 199 LRR 6. FT REPEAT 205 225 LRR 7. FT REPEAT 227 247 LRR 8. FT REPEAT 331 351 LRR 9. FT REPEAT 352 373 LRR 10. FT REPEAT 374 394 LRR 11. FT REPEAT 400 422 LRR 12. FT REPEAT 423 444 LRR 13. FT REPEAT 448 456 LRR 14. FT REPEAT 472 495 LRR 15. FT REPEAT 497 518 LRR 16. FT REPEAT 521 542 LRR 17. FT REPEAT 545 565 LRR 18. FT DOMAIN 579 629 LRRCT. FT DOMAIN 672 818 TIR. FT CARBOHYD 35 35 N-linked (GlcNAc...). FT CARBOHYD 173 173 N-linked (GlcNAc...). FT CARBOHYD 205 205 N-linked (GlcNAc...). FT CARBOHYD 282 282 N-linked (GlcNAc...). FT CARBOHYD 309 309 N-linked (GlcNAc...). FT CARBOHYD 497 497 N-linked (GlcNAc...). FT CARBOHYD 526 526 N-linked (GlcNAc...). FT CARBOHYD 575 575 N-linked (GlcNAc...). FT CARBOHYD 624 624 N-linked (GlcNAc...). FT CARBOHYD 630 630 N-linked (GlcNAc...) (Potential). FT DISULFID 29 40 FT DISULFID 281 306 FT DISULFID 390 391 FT DISULFID 583 609 FT DISULFID 585 627 FT VAR_SEQ 1 200 Missing (in isoform 3). FT /FTId=VSP_035793. FT VAR_SEQ 1 40 Missing (in isoform 2). FT /FTId=VSP_035794. FT VARIANT 175 175 T -> A (in dbSNP:rs16906079). FT /FTId=VAR_021977. FT VARIANT 188 188 Q -> R (in dbSNP:rs5030713). FT /FTId=VAR_018729. FT VARIANT 246 246 C -> S (in dbSNP:rs5030714). FT /FTId=VAR_018730. FT VARIANT 299 299 D -> G (in allele TLR4*B; reduced LPS- FT response; associated with an increased FT risk for ARMD10 in Caucasian patients FT carriers; dbSNP:rs4986790). FT /FTId=VAR_012739. FT VARIANT 306 306 C -> W (in dbSNP:rs2770145). FT /FTId=VAR_047563. FT VARIANT 310 310 V -> G (in dbSNP:rs2770144). FT /FTId=VAR_047564. FT VARIANT 329 329 N -> S (in dbSNP:rs5030715). FT /FTId=VAR_018731. FT VARIANT 342 342 F -> Y (in dbSNP:rs5031050). FT /FTId=VAR_020334. FT VARIANT 385 385 L -> F (in dbSNP:rs11536884). FT /FTId=VAR_037668. FT VARIANT 399 399 T -> I (in allele TLR4*B; reduced LPS- FT response; dbSNP:rs4986791). FT /FTId=VAR_012740. FT VARIANT 400 400 S -> N (in dbSNP:rs4987233). FT /FTId=VAR_020335. FT VARIANT 443 443 F -> L (in dbSNP:rs5030716). FT /FTId=VAR_018732. FT VARIANT 474 474 E -> K (in dbSNP:rs5030718). FT /FTId=VAR_018733. FT VARIANT 510 510 Q -> H (in dbSNP:rs5030719). FT /FTId=VAR_018734. FT VARIANT 694 694 K -> R (in dbSNP:rs5030722). FT /FTId=VAR_018735. FT VARIANT 763 763 R -> H (in dbSNP:rs5030723). FT /FTId=VAR_018736. FT VARIANT 834 834 Q -> H. FT /FTId=VAR_018737. FT MUTAGEN 431 431 H->A: Partially diminishes NF-kappa-B FT activation induced by Ni(2+). Strongly FT reduces NF-kappa-B activation induced by FT Ni(2+); when associated with A-456 or A- FT 458. FT MUTAGEN 456 456 H->A: Partially diminishes NF-kappa-B FT activation induced by Ni(2+). Strongly FT reduces NF-kappa-B activation induced by FT Ni(2+); when associated with A-431. FT Suppresses NF-kappa-B activation induced FT by Ni(2+); when associated with A-458. FT MUTAGEN 458 458 H->A: Partially diminishes NF-kappa-B FT activation induced by Ni(2+). Strongly FT reduces NF-kappa-B activation induced by FT Ni(2+); when associated with A-431. FT Suppresses NF-kappa-B activation induced FT by Ni(2+); when associated with A-456. FT MUTAGEN 526 526 N->A: Abolishes LPS-response and prevents FT the cell surface expression. FT MUTAGEN 575 575 N->A: Abolishes LPS-response and prevents FT the cell surface expression. FT MUTAGEN 697 697 E->R: Abolishes LPS-response. FT MUTAGEN 710 710 R->E: Abolishes LPS-response. FT MUTAGEN 711 711 D->K: Abolishes LPS-response. FT MUTAGEN 714 714 P->H,R,E: Abolishes MYD88-binding and FT LPS-response. FT CONFLICT 73 73 S -> R (in Ref. 11; ABU41664). FT CONFLICT 400 400 S -> C (in Ref. 7; BAF82742). FT CONFLICT 581 581 F -> S (in Ref. 7; BAG64706). FT STRAND 29 33 FT TURN 34 36 FT STRAND 37 39 FT STRAND 50 52 FT STRAND 58 60 FT TURN 71 76 FT STRAND 81 84 FT TURN 95 100 FT STRAND 106 108 FT STRAND 115 117 FT TURN 119 124 FT STRAND 130 132 FT HELIX 141 143 FT TURN 145 148 FT STRAND 154 156 FT HELIX 169 173 FT STRAND 179 181 FT HELIX 192 195 FT HELIX 196 199 FT STRAND 206 209 FT TURN 220 225 FT STRAND 227 235 FT HELIX 242 248 FT TURN 249 252 FT STRAND 254 262 FT TURN 274 277 FT HELIX 278 282 FT STRAND 283 292 FT STRAND 295 298 FT TURN 301 304 FT HELIX 305 307 FT STRAND 311 317 FT STRAND 319 322 FT HELIX 324 327 FT STRAND 333 339 FT STRAND 341 344 FT STRAND 355 360 FT STRAND 377 379 FT STRAND 387 392 FT HELIX 393 396 FT STRAND 403 405 FT STRAND 410 419 FT STRAND 426 428 FT STRAND 432 437 FT TURN 438 445 FT STRAND 451 453 FT TURN 464 469 FT STRAND 475 477 FT HELIX 484 486 FT STRAND 500 502 FT TURN 513 518 FT STRAND 524 526 FT HELIX 538 540 FT STRAND 548 550 FT STRAND 560 563 FT STRAND 573 575 FT HELIX 585 587 FT HELIX 588 596 FT HELIX 597 600 FT HELIX 604 606 FT STRAND 608 612 FT HELIX 613 615 FT STRAND 617 619 FT HELIX 620 622 SQ SEQUENCE 839 AA; 95680 MW; 92C48F55821133E8 CRC64; MMSASRLAGT LIPAMAFLSC VRPESWEPCV EVVPNITYQC MELNFYKIPD NLPFSTKNLD LSFNPLRHLG SYSFFSFPEL QVLDLSRCEI QTIEDGAYQS LSHLSTLILT GNPIQSLALG AFSGLSSLQK LVAVETNLAS LENFPIGHLK TLKELNVAHN LIQSFKLPEY FSNLTNLEHL DLSSNKIQSI YCTDLRVLHQ MPLLNLSLDL SLNPMNFIQP GAFKEIRLHK LTLRNNFDSL NVMKTCIQGL AGLEVHRLVL GEFRNEGNLE KFDKSALEGL CNLTIEEFRL AYLDYYLDDI IDLFNCLTNV SSFSLVSVTI ERVKDFSYNF GWQHLELVNC KFGQFPTLKL KSLKRLTFTS NKGGNAFSEV DLPSLEFLDL SRNGLSFKGC CSQSDFGTTS LKYLDLSFNG VITMSSNFLG LEQLEHLDFQ HSNLKQMSEF SVFLSLRNLI YLDISHTHTR VAFNGIFNGL SSLEVLKMAG NSFQENFLPD IFTELRNLTF LDLSQCQLEQ LSPTAFNSLS SLQVLNMSHN NFFSLDTFPY KCLNSLQVLD YSLNHIMTSK KQELQHFPSS LAFLNLTQND FACTCEHQSF LQWIKDQRQL LVEVERMECA TPSDKQGMPV LSLNITCQMN KTIIGVSVLS VLVVSVVAVL VYKFYFHLML LAGCIKYGRG ENIYDAFVIY SSQDEDWVRN ELVKNLEEGV PPFQLCLHYR DFIPGVAIAA NIIHEGFHKS RKVIVVVSQH FIQSRWCIFE YEIAQTWQFL SSRAGIIFIV LQKVEKTLLR QQVELYRLLS RNTYLEWEDS VLGRHIFWRR LRKALLDGKS WNPEGTVGTG CNWQEATSI //