ID TLR4_HUMAN Reviewed; 839 AA. AC O00206; A8K1Y8; A9XLP9; A9XLQ0; A9XLQ1; B4E194; D1CS52; D1CS53; Q5VZI8; AC Q5VZI9; Q9UK78; Q9UM57; DT 11-FEB-2002, integrated into UniProtKB/Swiss-Prot. DT 01-JAN-1998, sequence version 2. DT 27-MAR-2024, entry version 230. 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; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, SUBCELLULAR LOCATION, AND RP TISSUE SPECIFICITY. 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 of RT adaptive immunity."; RL Nature 388:394-397(1997). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND TISSUE SPECIFICITY. 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 Toll."; RL Proc. Natl. Acad. Sci. U.S.A. 95:588-593(1998). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, VARIANTS GLY-299 AND ILE-399, RP CHARACTERIZATION OF VARIANTS GLY-299 AND ILE-399, AND POLYMORPHISM. RX PubMed=11104518; DOI=10.1186/gb-2000-1-1-research002; RA Smirnova I., Poltorak A., Chan E.K.L., McBride C., Beutler B.; RT "Phylogenetic variation and polymorphism at the Toll-like receptor 4 locus RT (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., 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 (TLR) RT 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., 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 [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., Howe K.L., RA Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C., Ainscough R., RA Almeida J.P., Ambrose K.D., Ashwell R.I.S., Babbage A.K., Babbage S., RA Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K., RA Beasley H., Beasley O., Bird C.P., Bray-Allen S., Brown A.J., Brown J.Y., RA Burford D., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C., RA Chen Y., Clarke G., Clark S.Y., Clee C.M., Clegg S., Collier R.E., RA Corby N., Crosier M., Cummings A.T., Davies J., Dhami P., Dunn M., RA Dutta I., Dyer L.W., Earthrowl M.E., Faulkner L., Fleming C.J., RA Frankish A., Frankland J.A., French L., Fricker D.G., Garner P., RA Garnett J., 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., Lawlor S., RA Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M., Lovell J., RA Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S., McLay K.E., RA McMurray A., Milne S., Nickerson T., Nisbett J., Nordsiek G., Pearce A.V., RA Peck A.I., Porter K.M., Pandian R., Pelan S., Phillimore B., Povey S., RA Ramsey Y., Rand V., Scharfe M., Sehra H.K., Shownkeen R., Sims S.K., RA Skuce C.D., Smith M., Steward C.A., Swarbreck D., Sycamore N., Tester J., RA Thorpe A., Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., RA West A.P., Whitehead S.L., Willey D.L., Williams S.A., Wilming L., RA Wray P.W., 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., Rogers J., RA 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., 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 (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 project: RT 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 verified RT 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 SUBUNIT, AND SUBCELLULAR LOCATION. RX PubMed=11274165; DOI=10.1074/jbc.m009164200; RA da Silva Correia J., Soldau K., Christen U., Tobias P.S., Ulevitch R.J.; RT "Lipopolysaccharide is in close proximity to each of the proteins in its RT membrane receptor complex. transfer from CD14 to TLR4 and MD-2."; RL J. Biol. Chem. 276:21129-21135(2001). RN [15] 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 [16] RP INTERACTION WITH TICAM2. RX PubMed=14519765; DOI=10.1074/jbc.m305820200; RA Oshiumi H., Sasai M., Shida K., Fujita T., Matsumoto M., Seya T.; RT "TIR-containing adapter molecule (TICAM)-2, a bridging adapter recruiting RT to toll-like receptor 4 TICAM-1 that induces interferon-beta."; RL J. Biol. Chem. 278:49751-49762(2003). RN [17] RP FUNCTION. RX PubMed=14517278; DOI=10.1084/jem.20031023; RA Fitzgerald K.A., Rowe D.C., Barnes B.J., Caffrey D.R., Visintin A., RA Latz E., Monks B., Pitha P.M., Golenbock D.T.; RT "LPS-TLR4 signaling to IRF-3/7 and NF-kappaB involves the toll adapters RT TRAM and TRIF."; RL J. Exp. Med. 198:1043-1055(2003). RN [18] RP FUNCTION, AND INDUCTION BY LPS. RX PubMed=15265881; DOI=10.4049/jimmunol.173.3.1535; RA Dai J., Megjugorac N.J., Amrute S.B., Fitzgerald-Bocarsly P.; RT "Regulation of IFN regulatory factor-7 and IFN-alpha production by RT enveloped virus and lipopolysaccharide in human plasmacytoid dendritic RT cells."; RL J. Immunol. 173:1535-1548(2004). RN [19] RP INTERACTION WITH NOX4. RX PubMed=15356101; DOI=10.4049/jimmunol.173.6.3589; 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 essential for RT lipopolysaccharide-induced production of reactive oxygen species and RT activation of NF-kappa B."; RL J. Immunol. 173:3589-3593(2004). RN [20] RP FUNCTION. RX PubMed=15809303; DOI=10.1074/jbc.m411379200; RA Bulut Y., Michelsen K.S., Hayrapetian L., Naiki Y., Spallek R., Singh M., RA Arditi M.; RT "Mycobacterium tuberculosis heat shock proteins use diverse Toll-like RT receptor pathways to activate pro-inflammatory signals."; RL J. Biol. Chem. 280:20961-20967(2005). RN [21] RP FUNCTION. RC TISSUE=Monocyte; RX PubMed=16622205; DOI=10.1128/iai.74.5.2686-2696.2006; RA Jung S.B., Yang C.S., Lee J.S., Shin A.R., Jung S.S., Son J.W., RA Harding C.V., Kim H.J., Park J.K., Paik T.H., Song C.H., Jo E.K.; RT "The mycobacterial 38-kilodalton glycolipoprotein antigen activates the RT mitogen-activated protein kinase pathway and release of proinflammatory RT cytokines through Toll-like receptors 2 and 4 in human monocytes."; RL Infect. Immun. 74:2686-2696(2006). RN [22] RP FUNCTION. RX PubMed=17292937; DOI=10.1016/j.virol.2006.12.032; RA Georgel P., Jiang Z., Kunz S., Janssen E., Mols J., Hoebe K., Bahram S., RA Oldstone M.B., Beutler B.; RT "Vesicular stomatitis virus glycoprotein G activates a specific antiviral RT Toll-like receptor 4-dependent pathway."; RL Virology 362:304-313(2007). RN [23] RP INTERACTION WITH TREM1, AND SUBCELLULAR LOCATION. RX PubMed=17098818; DOI=10.1093/intimm/dxl119; RA Fortin C.F., Lesur O., Fulop T. Jr.; RT "Effects of TREM-1 activation in human neutrophils: activation of signaling RT pathways, recruitment into lipid rafts and association with TLR4."; RL Int. Immunol. 19:41-50(2007). RN [24] RP FUNCTION. RX PubMed=17478729; DOI=10.1161/circresaha.106.142851; RA Kim F., Pham M., Luttrell I., Bannerman D.D., Tupper J., Thaler J., RA Hawn T.R., Raines E.W., Schwartz M.W.; RT "Toll-like receptor-4 mediates vascular inflammation and insulin resistance RT in diet-induced obesity."; RL Circ. Res. 100:1589-1596(2007). RN [25] 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., Hao B., RA 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 [26] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH TREM1. RX PubMed=21393102; DOI=10.1684/ecn.2011.0274; RA Arts R.J., Joosten L.A., Dinarello C.A., Kullberg B.J., van der Meer J.W., RA Netea M.G.; RT "TREM-1 interaction with the LPS/TLR4 receptor complex."; RL Eur. Cytokine Netw. 22:11-14(2011). RN [27] RP ERRATUM OF PUBMED:20865800. RA Liu B., Yang Y., Qiu Z., Staron M., Hong F., Li Y., Wu S., Li Y., Hao B., RA Bona R., Han D., Li Z.; RL Nat. Commun. 3:653-653(2012). RN [28] RP FUNCTION, INTERACTION WITH CD36 AND TLR6, AND SUBCELLULAR LOCATION. RX PubMed=20037584; DOI=10.1038/ni.1836; RA Stewart C.R., Stuart L.M., Wilkinson K., van Gils J.M., Deng J., Halle A., RA Rayner K.J., Boyer L., Zhong R., Frazier W.A., Lacy-Hulbert A., RA El Khoury J., Golenbock D.T., Moore K.J.; RT "CD36 ligands promote sterile inflammation through assembly of a Toll-like RT receptor 4 and 6 heterodimer."; RL Nat. Immunol. 11:155-161(2010). RN [29] RP FUNCTION, AND INTERACTION WITH EBOLA VIRUS GLYCOPROTEIN (MICROBIAL RP INFECTION). RX PubMed=19846529; DOI=10.1128/jvi.01462-09; RA Okumura A., Pitha P.M., Yoshimura A., Harty R.N.; RT "Interaction between Ebola virus glycoprotein and host toll-like receptor 4 RT leads to induction of proinflammatory cytokines and SOCS1."; RL J. Virol. 84:27-33(2010). RN [30] RP FUNCTION, MUTAGENESIS OF HIS-431; HIS-456 AND HIS-458, AND INVOLVEMENT IN RP 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 contact RT allergy to nickel."; RL Nat. Immunol. 11:814-819(2010). RN [31] RP INTERACTION WITH MAP3K21. 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 [32] RP FUNCTION. RX PubMed=23880187; DOI=10.1016/j.atherosclerosis.2013.05.011; RA Estruch M., Bancells C., Beloki L., Sanchez-Quesada J.L., RA Ordonez-Llanos J., Benitez S.; RT "CD14 and TLR4 mediate cytokine release promoted by electronegative LDL in RT monocytes."; RL Atherosclerosis 229:356-362(2013). RN [33] RP INTERACTION WITH E.COLI PROTEIN TCPC (MICROBIAL INFECTION). RX PubMed=23569230; DOI=10.1073/pnas.1215770110; RA Snyder G.A., Cirl C., Jiang J., Chen K., Waldhuber A., Smith P., RA Roemmler F., Snyder N., Fresquez T., Duerr S., Tjandra N., Miethke T., RA Xiao T.S.; RT "Molecular mechanisms for the subversion of MyD88 signaling by TcpC from RT virulent uropathogenic Escherichia coli."; RL Proc. Natl. Acad. Sci. U.S.A. 110:6985-6990(2013). RN [34] RP INTERACTION WITH B.MELITENSIS PROTEIN TCPB (MICROBIAL INFECTION). RX PubMed=24265315; DOI=10.1074/jbc.m113.523274; RA Alaidarous M., Ve T., Casey L.W., Valkov E., Ericsson D.J., Ullah M.O., RA Schembri M.A., Mansell A., Sweet M.J., Kobe B.; RT "Mechanism of bacterial interference with TLR4 signaling by Brucella RT Toll/interleukin-1 receptor domain-containing protein TcpB."; RL J. Biol. Chem. 289:654-668(2014). RN [35] RP INTERACTION WITH TICAM1 AND TICAM2. 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 [36] RP FUNCTION, INTERACTION WITH RFTN1, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, RP AND INDUCTION BY LPS. RX PubMed=27022195; DOI=10.4049/jimmunol.1501734; RA Tatematsu M., Yoshida R., Morioka Y., Ishii N., Funami K., Watanabe A., RA Saeki K., Seya T., Matsumoto M.; RT "Raftlin controls lipopolysaccharide-induced TLR4 internalization and RT TICAM-1 signaling in a cell type-specific manner."; RL J. Immunol. 196:3865-3876(2016). RN [37] RP FUNCTION. RX PubMed=29038465; DOI=10.1038/s41467-017-00930-9; RA Xiahou Z., Wang X., Shen J., Zhu X., Xu F., Hu R., Guo D., Li H., Tian Y., RA Liu Y., Liang H.; RT "NMI and IFP35 serve as proinflammatory DAMPs during cellular infection and RT injury."; RL Nat. Commun. 8:950-950(2017). RN [38] RP LACK OF NADASE ACTIVITY. RX PubMed=28334607; DOI=10.1016/j.neuron.2017.02.022; RA Essuman K., Summers D.W., Sasaki Y., Mao X., DiAntonio A., Milbrandt J.; RT "The SARM1 Toll/Interleukin-1 receptor domain possesses intrinsic NAD+ RT cleavage activity that promotes pathological axonal degeneration."; RL Neuron 93:1334-1343(2017). RN [39] RP INTERACTION WITH TRAF3IP3. RX PubMed=30573680; DOI=10.1074/jbc.ra118.003137; RA Li Y., Guan J., Wang W., Hou C., Zhou L., Ma J., Cheng Y., Jiao S., RA Zhou Z.; RT "TRAF3-interacting JNK-activating modulator promotes inflammation by RT stimulating translocation of Toll-like receptor 4 to lipid rafts."; RL J. Biol. Chem. 294:2744-2756(2019). RN [40] RP FUNCTION. RX PubMed=32894580; DOI=10.1111/cei.13510; RA Luo H., He J., Qin L., Chen Y., Chen L., Li R., Zeng Y., Zhu C., You X., RA Wu Y.; RT "Mycoplasma pneumoniae lipids license TLR-4 for activation of NLRP3 RT inflammasome and autophagy to evoke a proinflammatory response."; RL Clin. Exp. Immunol. 203:66-79(2021). RN [41] RP FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND INTERACTION WITH RP ZG16B/PAUF; TICAM1 AND MYD88. RX PubMed=36232715; DOI=10.3390/ijms231911414; RA Youn S.E., Jiang F., Won H.Y., Hong D.E., Kang T.H., Park Y.Y., Koh S.S.; RT "PAUF Induces Migration of Human Pancreatic Cancer Cells Exclusively via RT the TLR4/MyD88/NF-kappaB Signaling Pathway."; RL Int. J. Mol. Sci. 23:0-0(2022). RN [42] RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 27-228 IN COMPLEX WITH LY96, RP SUBUNIT, DISULFIDE BONDS, AND 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., Enkhbayar P., RA Matsushima N., Lee H., Yoo O.J., Lee J.-O.; RT "Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist RT Eritoran."; RL Cell 130:906-917(2007). RN [43] RP X-RAY CRYSTALLOGRAPHY (3.1 ANGSTROMS) OF 27-631 IN COMPLEX WITH LY96 AND RP LIPOPOLYSACCHARIDE, SUBUNIT, 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-MD-2 RT complex."; RL Nature 458:1191-1195(2009). RN [44] RP X-RAY CRYSTALLOGRAPHY (2.37 ANGSTROMS) OF 28-228, GLYCOSYLATION AT ASN-35 RP 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) decoy RT receptor with high binding affinity for a target protein."; RL PLoS ONE 7:E30929-E30929(2012). RN [45] RP VARIANTS ARG-188; SER-246; GLY-299; SER-329; ILE-399; LEU-443; LYS-474; RP HIS-510; ARG-694; HIS-763 AND HIS-834. RX PubMed=11514453; DOI=10.1093/genetics/158.4.1657; 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 in RT humans."; RL Genetics 158:1657-1664(2001). RN [46] 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., Richards J.E., RA Abecasis G.R., Elner V.M., Swaroop A.; RT "Toll-like receptor 4 variant D299G is associated with susceptibility to RT age-related macular degeneration."; RL Hum. Mol. Genet. 14:1449-1455(2005). RN [47] RP VARIANT ASP-287. RX PubMed=25787250; DOI=10.1073/pnas.1503696112; RA Cromer M.K., Choi M., Nelson-Williams C., Fonseca A.L., Kunstman J.W., RA Korah R.M., Overton J.D., Mane S., Kenney B., Malchoff C.D., Stalberg P., RA Akerstroem G., Westin G., Hellman P., Carling T., Bjoerklund P., RA Lifton R.P.; RT "Neomorphic effects of recurrent somatic mutations in Yin Yang 1 in RT insulin-producing adenomas."; RL Proc. Natl. Acad. Sci. U.S.A. 112:4062-4067(2015). CC -!- FUNCTION: Transmembrane receptor that functions as a pattern CC recognition receptor recognizing pathogen- and damage-associated CC molecular patterns (PAMPs and DAMPs) to induce innate immune responses CC via downstream signaling pathways (PubMed:16622205, PubMed:10835634, CC PubMed:15809303, PubMed:17478729, PubMed:20037584, PubMed:20711192, CC PubMed:23880187, PubMed:27022195, PubMed:17292937, PubMed:29038465). At CC the plasma membrane, cooperates with LY96 to mediate the innate immune CC response to bacterial lipopolysaccharide (LPS) (PubMed:27022195). Also CC involved in LPS-independent inflammatory responses triggered by free CC fatty acids, such as palmitate, and Ni(2+) (PubMed:20711192). CC Mechanistically, acts via MYD88, TIRAP and TRAF6, leading to NF-kappa-B CC activation, cytokine secretion and the inflammatory response CC (PubMed:9237759, PubMed:10835634, PubMed:27022195, PubMed:21393102). CC Alternatively, CD14-mediated TLR4 internalization via endocytosis is CC associated with the initiation of a MYD88-independent signaling via the CC TICAM1-TBK1-IRF3 axis leading to type I interferon production CC (PubMed:14517278). In addition to the secretion of proinflammatory CC cytokines, initiates the activation of NLRP3 inflammasome and formation CC of a positive feedback loop between autophagy and NF-kappa-B signaling CC cascade (PubMed:32894580). In complex with TLR6, promotes inflammation CC in monocytes/macrophages by associating with TLR6 and the receptor CD86 CC (PubMed:23880187). Upon ligand binding, such as oxLDL or amyloid-beta CC 42, the TLR4:TLR6 complex is internalized and triggers inflammatory CC response, leading to NF-kappa-B-dependent production of CXCL1, CXCL2 CC and CCL9 cytokines, via MYD88 signaling pathway, and CCL5 cytokine, via CC TICAM1 signaling pathway (PubMed:23880187). In myeloid dendritic cells, CC vesicular stomatitis virus glycoprotein G but not LPS promotes the CC activation of IRF7, leading to type I IFN production in a CD14- CC dependent manner (PubMed:23880187, PubMed:15265881). Required for the CC migration-promoting effects of ZG16B/PAUF on pancreatic cancer cells. CC {ECO:0000269|PubMed:10835634, ECO:0000269|PubMed:14517278, CC ECO:0000269|PubMed:15265881, ECO:0000269|PubMed:15809303, CC ECO:0000269|PubMed:16622205, ECO:0000269|PubMed:17292937, CC ECO:0000269|PubMed:17478729, ECO:0000269|PubMed:20037584, CC ECO:0000269|PubMed:20711192, ECO:0000269|PubMed:23880187, CC ECO:0000269|PubMed:27022195, ECO:0000269|PubMed:29038465, CC ECO:0000269|PubMed:9237759}. CC -!- SUBUNIT: Belongs to the lipopolysaccharide (LPS) receptor, a multi- CC protein complex containing at least CD14, LY96 and TLR4 CC (PubMed:11274165). Binding to bacterial LPS leads to homodimerization. CC Interacts with LY96 via the extracellular domain (PubMed:17803912, CC PubMed:19252480). Interacts with MYD88 (PubMed:36232715). Interacts CC (via TIR domains) with TIRAP (By similarity). Interacts with TICAM2 CC (PubMed:14519765, PubMed:25736436). Interacts with NOX4 CC (PubMed:15356101). Interacts with CNPY3 (By similarity). Interacts with CC HSP90B1. The interaction with both CNPY3 and HSP90B1 is required for CC proper folding in the endoplasmic reticulum. Interacts with MAP3K21; CC this interaction leads to negative regulation of TLR4 signaling CC (PubMed:21602844). Interacts with CD36, following CD36 stimulation by CC oxLDL or amyloid-beta 42, and forms a heterodimer with TLR6 CC (PubMed:20037584). The trimeric complex is internalized and triggers CC inflammatory response. LYN kinase activity facilitates TLR4-TLR6 CC heterodimerization and signal initiation. Interacts with TICAM1 in CC response to LPS in a WDFY1-dependent manner (PubMed:25736436, CC PubMed:36232715). Interacts with WDFY1 in response to LPS (By CC similarity). Interacts with SMPDL3B (By similarity). Interacts with CC CEACAM1; upon lipopolysaccharide stimulation, forms a complex including CC TLR4 and the phosphorylated form of SYK and CEACAM1, which in turn, CC recruits PTPN6 that dephosphorylates SYK, reducing the production of CC reactive oxygen species (ROS) and lysosome disruption, which in turn, CC reduces the activity of the inflammasome (By similarity). Interacts CC with RFTN1; the interaction occurs in response to lipopolysaccharide CC stimulation (PubMed:27022195). Interacts with SCIMP; the interaction CC occurs in response to lipopolysaccharide stimulation and is enhanced by CC phosphorylation of SCIMP by LYN (By similarity). This interaction CC facilitates the phosphorylation of TLR4 by LYN which elicits a CC selective cytokine response in macrophages (By similarity). Interacts CC with TRAF3IP3 (PubMed:30573680). Interacts with TREM1; this interaction CC enhances TLR4-mediated inflammatory response (PubMed:21393102, CC PubMed:17098818). Interacts with ZG16B/PAUF (PubMed:36232715). CC {ECO:0000250|UniProtKB:Q9QUK6, ECO:0000269|PubMed:11274165, CC ECO:0000269|PubMed:14519765, ECO:0000269|PubMed:15356101, CC ECO:0000269|PubMed:17098818, ECO:0000269|PubMed:17803912, CC ECO:0000269|PubMed:19252480, ECO:0000269|PubMed:20037584, CC ECO:0000269|PubMed:20865800, ECO:0000269|PubMed:21393102, CC ECO:0000269|PubMed:21602844, ECO:0000269|PubMed:25736436, CC ECO:0000269|PubMed:27022195, ECO:0000269|PubMed:30573680, CC ECO:0000269|PubMed:36232715}. CC -!- SUBUNIT: (Microbial infection) In case of infection, interacts with CC uropathogenic E.coli protein TcpC. {ECO:0000269|PubMed:23569230}. CC -!- SUBUNIT: (Microbial infection) In case of infection, interacts with CC B.melitensis protein TcpB; TcpB abolishes the TLR4-TIRAP interaction in CC vitro. {ECO:0000269|PubMed:24265315}. CC -!- SUBUNIT: (Microbial infection) Interacts with ebolavirus protein GP; CC this interaction leads to the production of proinflammatory cytokines CC and suppressor of cytokine signaling 1/SOCS1. CC {ECO:0000269|PubMed:19846529}. CC -!- INTERACTION: CC O00206; Q96A54: ADIPOR1; NbExp=2; IntAct=EBI-528701, EBI-1632076; CC O00206; Q9Y6Y9: LY96; NbExp=7; IntAct=EBI-528701, EBI-1539247; CC O00206; P11226: MBL2; NbExp=2; IntAct=EBI-528701, EBI-5325353; CC O00206; Q99836: MYD88; NbExp=4; IntAct=EBI-528701, EBI-447677; CC O00206; Q9NPH5: NOX4; NbExp=4; IntAct=EBI-528701, EBI-11301574; CC O00206; O15389: SIGLEC5; NbExp=2; IntAct=EBI-528701, EBI-750381; CC O00206; O43699-3: SIGLEC6; NbExp=2; IntAct=EBI-528701, EBI-12161783; CC O00206; Q9Y336: SIGLEC9; NbExp=2; IntAct=EBI-528701, EBI-12857926; CC O00206; Q86XR7: TICAM2; NbExp=3; IntAct=EBI-528701, EBI-525927; CC O00206; P58753: TIRAP; NbExp=6; IntAct=EBI-528701, EBI-528644; CC O00206; O00206: TLR4; NbExp=3; IntAct=EBI-528701, EBI-528701; CC O00206; Q9Y2C9: TLR6; NbExp=2; IntAct=EBI-528701, EBI-13940779; CC O00206; P24821: TNC; NbExp=4; IntAct=EBI-528701, EBI-9979894; CC O00206-1; Q9Y6Y9: LY96; NbExp=5; IntAct=EBI-15745059, EBI-1539247; CC O00206-1; P49278: DERP2; Xeno; NbExp=3; IntAct=EBI-15745059, EBI-15745025; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:11274165, CC ECO:0000269|PubMed:17098818, ECO:0000269|PubMed:20037584, CC ECO:0000269|PubMed:21393102, ECO:0000269|PubMed:27022195, CC ECO:0000269|PubMed:36232715, ECO:0000269|PubMed:9237759}; Single-pass CC type I membrane protein {ECO:0000269|PubMed:11274165}. Early endosome CC {ECO:0000269|PubMed:27022195}. Cell projection, ruffle CC {ECO:0000250|UniProtKB:Q9QUK6}. Note=Upon complex formation with CD36 CC and TLR6, internalized through dynamin-dependent endocytosis CC (PubMed:20037584). Colocalizes with RFTN1 at cell membrane and then CC together with RFTN1 moves to endosomes, upon lipopolysaccharide CC stimulation. Co-localizes with ZG16B/PAUF at the cell membrane of CC pancreatic cancer cells (PubMed:36232715). CC {ECO:0000269|PubMed:20037584, ECO:0000269|PubMed:36232715}. 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 -!- TISSUE SPECIFICITY: Highly expressed in placenta, spleen and peripheral CC blood leukocytes (PubMed:9435236, PubMed:9237759). Detected in CC monocytes, macrophages, dendritic cells and several types of T-cells CC (PubMed:9237759, PubMed:27022195). Expressed in pancreatic cancer cells CC but not in normal pancreatic cells (at protein level) CC (PubMed:36232715). {ECO:0000269|PubMed:27022195, CC ECO:0000269|PubMed:36232715, ECO:0000269|PubMed:9237759, CC ECO:0000269|PubMed:9435236}. CC -!- INDUCTION: By LPS in plasmacytoid dendritic cells. CC {ECO:0000269|PubMed:15265881}. CC -!- DOMAIN: The TIR domain mediates interaction with NOX4. CC {ECO:0000269|PubMed:15356101}. CC -!- PTM: N-glycosylated. Glycosylation of Asn-526 and Asn-575 seems to be CC necessary for the expression of TLR4 on the cell surface and the LPS- CC response. Likewise, mutants lacking two or more of the other N- CC glycosylation sites were deficient in interaction with LPS. CC {ECO:0000269|PubMed:11706042, ECO:0000269|PubMed:17803912, CC ECO:0000269|PubMed:19252480, ECO:0000269|PubMed:22363519}. CC -!- PTM: Phosphorylated on tyrosine residues by LYN after binding CC lipopolysaccharide. {ECO:0000250|UniProtKB:Q9QUK6}. CC -!- POLYMORPHISM: Allele TLR4*B (Gly-299, Ile-399) is associated with a CC blunted response to inhaled LPS. {ECO:0000269|PubMed:10835634}. CC -!- MISCELLANEOUS: His-456 and His-458 are found in TLR4 of human and CC several other primate species and may be responsible for inflammatory CC responses triggered by nickel (Ni(2+)). Ni(2+) may cross-link the two CC receptor monomers through specific histidines, triggering the formation CC of a dimer that structurally resembles that induced by LPS. This CC process may be the basis for the development of contact allergy to CC Ni(2+). A mouse model of contact allergy to Ni(2+) in which TLR4- CC deficient mice expresses human TLR4 has been proposed. CC {ECO:0000305|PubMed:20711192}. CC -!- SIMILARITY: Belongs to the Toll-like receptor family. {ECO:0000305}. CC -!- CAUTION: In some plant proteins and in human SARM1, the TIR domain has CC NAD(+) hydrolase (NADase) activity (PubMed:28334607). However, despite CC the presence of the catalytic Asp residue, the isolated TIR domain of CC human TLR4 lacks NADase activity (PubMed:28334607). Based on this, it CC is unlikely that Toll-like receptors have NADase activity. CC {ECO:0000269|PubMed:28334607, ECO:0000305}. CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=Zips, necklaces and mobile CC telephones - Issue 134 of December 2011; CC URL="https://web.expasy.org/spotlight/back_issues/134"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) 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; -; NOT_ANNOTATED_CDS; 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 CCDS; CCDS6818.1; -. [O00206-1] DR RefSeq; NP_003257.1; NM_003266.3. [O00206-2] DR RefSeq; NP_612564.1; NM_138554.4. [O00206-1] DR RefSeq; NP_612567.1; NM_138557.2. [O00206-3] 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=381-627. DR PDB; 3FXI; X-ray; 3.10 A; A/B=27-631. DR PDB; 3UL7; X-ray; 2.37 A; A=28-226. 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 PDB; 5NAM; NMR; -; A=623-670. DR PDB; 5NAO; NMR; -; A=623-657. 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 PDBsum; 5NAM; -. DR PDBsum; 5NAO; -. DR AlphaFoldDB; O00206; -. DR SMR; O00206; -. DR BioGRID; 112954; 44. DR ComplexPortal; CPX-2545; LY96-TLR4 toll-like receptor complex. DR ComplexPortal; CPX-945; TLR4-TLR6 toll-like receptor complex. DR CORUM; O00206; -. DR DIP; DIP-34769N; -. DR ELM; O00206; -. DR IntAct; O00206; 35. DR MINT; O00206; -. DR STRING; 9606.ENSP00000363089; -. DR BindingDB; O00206; -. DR ChEMBL; CHEMBL5255; -. DR DrugBank; DB02767; (R)-3-hydroxytetradecanoic acid. DR DrugBank; DB00924; Cyclobenzaprine. DR DrugBank; DB06447; E5531. DR DrugBank; DB04933; Eritoran. DR DrugBank; DB05475; Golotimod. DR DrugBank; DB03017; Lauric acid. DR DrugBank; DB13615; Mifamurtide. DR DrugBank; DB08231; Myristic acid. DR DrugBank; DB01183; Naloxone. DR DrugBank; DB11193; Papain. DR DrugCentral; O00206; -. DR GuidetoPHARMACOLOGY; 1754; -. DR TCDB; 8.A.43.1.9; the neat-domain containing methaemoglobin heme sequestration (n-mhs) family. DR GlyCosmos; O00206; 10 sites, No reported glycans. DR GlyGen; O00206; 10 sites. DR iPTMnet; O00206; -. DR PhosphoSitePlus; O00206; -. DR BioMuta; TLR4; -. DR MassIVE; O00206; -. DR PaxDb; 9606-ENSP00000363089; -. DR PeptideAtlas; O00206; -. DR ProteomicsDB; 47779; -. [O00206-1] DR ProteomicsDB; 47780; -. [O00206-2] DR ProteomicsDB; 47781; -. [O00206-3] DR ABCD; O00206; 25 sequenced antibodies. DR Antibodypedia; 3410; 2078 antibodies from 51 providers. DR DNASU; 7099; -. DR Ensembl; ENST00000355622.8; ENSP00000363089.5; ENSG00000136869.16. [O00206-1] DR Ensembl; ENST00000394487.5; ENSP00000377997.4; ENSG00000136869.16. [O00206-2] DR GeneID; 7099; -. DR KEGG; hsa:7099; -. DR MANE-Select; ENST00000355622.8; ENSP00000363089.5; NM_138554.5; NP_612564.1. DR UCSC; uc004bjz.5; human. [O00206-1] DR AGR; HGNC:11850; -. DR CTD; 7099; -. DR DisGeNET; 7099; -. DR GeneCards; TLR4; -. DR HGNC; HGNC:11850; TLR4. DR HPA; ENSG00000136869; Low tissue specificity. DR MalaCards; TLR4; -. DR MIM; 603030; gene. DR neXtProt; NX_O00206; -. DR OpenTargets; ENSG00000136869; -. DR Orphanet; 117; Behcet disease. DR PharmGKB; PA36552; -. DR VEuPathDB; HostDB:ENSG00000136869; -. DR eggNOG; KOG4641; Eukaryota. DR GeneTree; ENSGT00940000160778; -. DR HOGENOM; CLU_006000_5_0_1; -. DR InParanoid; O00206; -. DR OMA; CKHSAER; -. DR OrthoDB; 1207361at2759; -. DR PhylomeDB; O00206; -. DR TreeFam; TF351113; -. DR PathwayCommons; O00206; -. DR Reactome; R-HSA-1236974; ER-Phagosome pathway. DR Reactome; R-HSA-140534; Caspase activation via Death Receptors in the presence of ligand. DR Reactome; R-HSA-166016; Toll Like Receptor 4 (TLR4) Cascade. DR Reactome; R-HSA-166058; MyD88:MAL(TIRAP) cascade initiated on plasma membrane. DR Reactome; R-HSA-166166; MyD88-independent TLR4 cascade. DR Reactome; R-HSA-2562578; TRIF-mediated programmed cell death. DR Reactome; R-HSA-5602498; MyD88 deficiency (TLR2/4). DR Reactome; R-HSA-5603041; IRAK4 deficiency (TLR2/4). DR Reactome; R-HSA-5686938; Regulation of TLR by endogenous ligand. DR Reactome; R-HSA-936964; Activation of IRF3, IRF7 mediated by TBK1, IKBKE. DR Reactome; R-HSA-937041; IKK complex recruitment mediated by RIP1. DR Reactome; R-HSA-937072; TRAF6-mediated induction of TAK1 complex within TLR4 complex. DR Reactome; R-HSA-9707616; Heme signaling. DR Reactome; R-HSA-975163; IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation. DR SignaLink; O00206; -. DR SIGNOR; O00206; -. DR BioGRID-ORCS; 7099; 7 hits in 1145 CRISPR screens. DR EvolutionaryTrace; O00206; -. DR GeneWiki; TLR_4; -. DR GenomeRNAi; 7099; -. DR Pharos; O00206; Tchem. DR PRO; PR:O00206; -. DR Proteomes; UP000005640; Chromosome 9. DR RNAct; O00206; Protein. DR Bgee; ENSG00000136869; Expressed in monocyte and 156 other cell types or tissues. DR ExpressionAtlas; O00206; baseline and differential. DR GO; GO:0009986; C:cell surface; IDA:UniProtKB. DR GO; GO:0005737; C:cytoplasm; IDA:BHF-UCL. DR GO; GO:0005769; C:early endosome; IEA:UniProtKB-SubCell. DR GO; GO:0010008; C:endosome membrane; IDA:UniProt. DR GO; GO:0009897; C:external side of plasma membrane; IDA:BHF-UCL. DR GO; GO:0046696; C:lipopolysaccharide receptor complex; IDA:UniProtKB. DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB. DR GO; GO:0001891; C:phagocytic cup; IDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0043235; C:receptor complex; IPI:ARUK-UCL. DR GO; GO:0001726; C:ruffle; IEA:UniProtKB-SubCell. DR GO; GO:0001540; F:amyloid-beta binding; IC:ARUK-UCL. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0001530; F:lipopolysaccharide binding; IMP:BHF-UCL. DR GO; GO:0001875; F:lipopolysaccharide immune receptor activity; IDA:UniProtKB. DR GO; GO:0050135; F:NAD(P)+ nucleosidase activity; IEA:UniProtKB-EC. DR GO; GO:0061809; F:NAD+ nucleotidase, cyclic ADP-ribose generating; IEA:UniProtKB-EC. DR GO; GO:0046982; F:protein heterodimerization activity; IPI:ARUK-UCL. DR GO; GO:0038023; F:signaling receptor activity; IDA:UniProt. DR GO; GO:0005102; F:signaling receptor binding; IPI:ARUK-UCL. DR GO; GO:0004888; F:transmembrane signaling receptor activity; NAS:UniProtKB. DR GO; GO:0014002; P:astrocyte development; IEA:Ensembl. DR GO; GO:0002322; P:B cell proliferation involved in immune response; IEA:Ensembl. DR GO; GO:1904646; P:cellular response to amyloid-beta; IDA:ComplexPortal. DR GO; GO:0071222; P:cellular response to lipopolysaccharide; IDA:UniProtKB. DR GO; GO:0071223; P:cellular response to lipoteichoic acid; IEA:Ensembl. DR GO; GO:0071260; P:cellular response to mechanical stimulus; IEP:UniProtKB. DR GO; GO:0140052; P:cellular response to oxidised low-density lipoprotein particle stimulus; IDA:ComplexPortal. DR GO; GO:0036120; P:cellular response to platelet-derived growth factor stimulus; IEA:Ensembl. DR GO; GO:0071346; P:cellular response to type II interferon; IDA:UniProtKB. DR GO; GO:0042742; P:defense response to bacterium; IGI:ARUK-UCL. DR GO; GO:0050829; P:defense response to Gram-negative bacterium; IBA:GO_Central. DR GO; GO:0016046; P:detection of fungus; NAS:UniProtKB. DR GO; GO:0032497; P:detection of lipopolysaccharide; IDA:UniProtKB. DR GO; GO:0070371; P:ERK1 and ERK2 cascade; IEA:Ensembl. DR GO; GO:0010467; P:gene expression; IEA:Ensembl. DR GO; GO:0007252; P:I-kappaB phosphorylation; IDA:BHF-UCL. DR GO; GO:0006955; P:immune response; TAS:ProtInc. DR GO; GO:0006954; P:inflammatory response; IBA:GO_Central. DR GO; GO:0045087; P:innate immune response; TAS:BHF-UCL. DR GO; GO:0060729; P:intestinal epithelial structure maintenance; ISS:BHF-UCL. DR GO; GO:0007254; P:JNK cascade; IEA:Ensembl. DR GO; GO:0031663; P:lipopolysaccharide-mediated signaling pathway; IGI:MGI. DR GO; GO:0042116; P:macrophage activation; IMP:UniProtKB. DR GO; GO:0045342; P:MHC class II biosynthetic process; IEA:Ensembl. DR GO; GO:0014004; P:microglia differentiation; IEA:Ensembl. DR GO; GO:0002755; P:MyD88-dependent toll-like receptor signaling pathway; IDA:ComplexPortal. DR GO; GO:0120163; P:negative regulation of cold-induced thermogenesis; ISS:YuBioLab. DR GO; GO:0070373; P:negative regulation of ERK1 and ERK2 cascade; 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:0032689; P:negative regulation of type II interferon production; ISS:BHF-UCL. DR GO; GO:0006809; P:nitric oxide biosynthetic process; IEA:Ensembl. DR GO; GO:0002537; P:nitric oxide production involved in inflammatory response; IEA:Ensembl. DR GO; GO:0070427; P:nucleotide-binding oligomerization domain containing 1 signaling pathway; IEA:Ensembl. DR GO; GO:0070431; P:nucleotide-binding oligomerization domain containing 2 signaling pathway; IEA:Ensembl. DR GO; GO:0006909; P:phagocytosis; IDA:UniProtKB. DR GO; GO:0030890; P:positive regulation of B cell proliferation; IEA:Ensembl. DR GO; GO:0043123; P:positive regulation of canonical NF-kappaB signal transduction; IEA:Ensembl. DR GO; GO:1903974; P:positive regulation of cellular response to macrophage colony-stimulating factor stimulus; IDA:UniProtKB. DR GO; GO:2000343; P:positive regulation of chemokine (C-X-C motif) ligand 2 production; IMP:ARUK-UCL. 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; IMP:ARUK-UCL. DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IEA:Ensembl. DR GO; GO:2001238; P:positive regulation of extrinsic apoptotic signaling pathway; ISS:ARUK-UCL. DR GO; GO:0010628; P:positive regulation of gene expression; IMP:UniProtKB. DR GO; GO:0050729; P:positive regulation of inflammatory response; IMP:ARUK-UCL. DR GO; GO:0032727; P:positive regulation of interferon-alpha production; ISS:BHF-UCL. DR GO; GO:0032728; P:positive regulation of interferon-beta production; ISS:BHF-UCL. DR GO; GO:0032731; P:positive regulation of interleukin-1 beta production; IDA:UniProtKB. 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:0032735; P:positive regulation of interleukin-12 production; IDA:UniProtKB. 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:UniProtKB. DR GO; GO:0046330; P:positive regulation of JNK cascade; IEA:Ensembl. DR GO; GO:0043032; P:positive regulation of macrophage activation; ISS:ARUK-UCL. DR GO; GO:0060907; P:positive regulation of macrophage cytokine production; IEA:Ensembl. DR GO; GO:0043406; P:positive regulation of MAP kinase activity; ISS:BHF-UCL. DR GO; GO:1904466; P:positive regulation of matrix metallopeptidase secretion; IMP:ARUK-UCL. DR GO; GO:0045348; P:positive regulation of MHC class II biosynthetic process; IEA:Ensembl. DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IDA:UniProtKB. DR GO; GO:0045429; P:positive regulation of nitric oxide biosynthetic process; ISS:ARUK-UCL. DR GO; GO:0051770; P:positive regulation of nitric-oxide synthase biosynthetic process; ISS:BHF-UCL. DR GO; GO:1900227; P:positive regulation of NLRP3 inflammasome complex assembly; ISS:UniProtKB. DR GO; GO:1901224; P:positive regulation of non-canonical NF-kappaB signal transduction; IDA:BHF-UCL. DR GO; GO:0070430; P:positive regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway; IEA:Ensembl. DR GO; GO:0070434; P:positive regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway; IEA:Ensembl. DR GO; GO:0010572; P:positive regulation of platelet activation; ISS:BHF-UCL. DR GO; GO:1903428; P:positive regulation of reactive oxygen species biosynthetic process; ISS:ARUK-UCL. DR GO; GO:0014911; P:positive regulation of smooth muscle cell migration; IEA:Ensembl. DR GO; GO:0048661; P:positive regulation of smooth muscle cell proliferation; IEA:Ensembl. 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; IDA:UniProtKB. DR GO; GO:0032729; P:positive regulation of type II interferon production; ISS:BHF-UCL. DR GO; GO:0002730; P:regulation of dendritic cell cytokine production; IEA:Ensembl. DR GO; GO:0032496; P:response to lipopolysaccharide; IDA:MGI. DR GO; GO:0042088; P:T-helper 1 type immune response; NAS:UniProtKB. DR GO; GO:0034142; P:toll-like receptor 4 signaling pathway; IDA:UniProt. DR GO; GO:0002224; P:toll-like receptor signaling pathway; IDA:ComplexPortal. DR GO; GO:0035666; P:TRIF-dependent toll-like receptor signaling pathway; ISS:ARUK-UCL. DR GO; GO:0002246; P:wound healing involved in inflammatory response; 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; IPR025875; Leu-rich_rpt_4. DR InterPro; IPR003591; Leu-rich_rpt_typical-subtyp. DR InterPro; IPR032675; LRR_dom_sf. DR InterPro; IPR000157; TIR_dom. DR InterPro; IPR017241; Toll-like_receptor. DR InterPro; IPR035897; Toll_tir_struct_dom_sf. DR PANTHER; PTHR24365; TOLL-LIKE RECEPTOR; 1. DR PANTHER; PTHR24365:SF521; TOLL-LIKE RECEPTOR 4; 1. DR Pfam; PF12799; LRR_4; 1. DR Pfam; PF13516; LRR_6; 1. DR Pfam; PF13855; LRR_8; 2. DR Pfam; PF01582; TIR; 1. DR PIRSF; PIRSF037595; Toll-like_receptor; 1. DR PRINTS; PR00019; LEURICHRPT. DR SMART; SM00365; LRR_SD22; 5. DR SMART; SM00369; LRR_TYP; 11. DR SMART; SM00082; LRRCT; 1. DR SMART; SM00255; TIR; 1. DR SUPFAM; SSF52075; Outer arm dynein light chain 1; 1. DR SUPFAM; SSF52047; RNI-like; 1. DR SUPFAM; SSF52200; Toll/Interleukin receptor TIR domain; 1. DR PROSITE; PS51450; LRR; 11. DR PROSITE; PS50104; TIR; 1. DR Genevisible; O00206; HS. PE 1: Evidence at protein level; KW 3D-structure; Age-related macular degeneration; Alternative splicing; KW Cell membrane; Cell projection; Direct protein sequencing; Disulfide bond; KW Endosome; Glycoprotein; Immunity; Inflammatory response; Innate immunity; KW Leucine-rich repeat; Membrane; NAD; Receptor; Reference proteome; Repeat; KW Signal; Transmembrane; Transmembrane helix. FT SIGNAL 1..23 FT /evidence="ECO:0000269|PubMed:15340161" FT CHAIN 24..839 FT /note="Toll-like receptor 4" FT /id="PRO_0000034722" FT TOPO_DOM 24..631 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 632..652 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 653..839 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT REPEAT 55..76 FT /note="LRR 1" FT REPEAT 79..100 FT /note="LRR 2" FT REPEAT 103..124 FT /note="LRR 3" FT REPEAT 127..148 FT /note="LRR 4" FT REPEAT 151..172 FT /note="LRR 5" FT REPEAT 176..199 FT /note="LRR 6" FT REPEAT 205..225 FT /note="LRR 7" FT REPEAT 227..247 FT /note="LRR 8" FT REPEAT 331..351 FT /note="LRR 9" FT REPEAT 352..373 FT /note="LRR 10" FT REPEAT 374..394 FT /note="LRR 11" FT REPEAT 400..422 FT /note="LRR 12" FT REPEAT 423..444 FT /note="LRR 13" FT REPEAT 448..456 FT /note="LRR 14" FT REPEAT 472..495 FT /note="LRR 15" FT REPEAT 497..518 FT /note="LRR 16" FT REPEAT 521..542 FT /note="LRR 17" FT REPEAT 545..565 FT /note="LRR 18" FT DOMAIN 579..629 FT /note="LRRCT" FT DOMAIN 672..815 FT /note="TIR" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00204" FT CARBOHYD 35 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:11706042, FT ECO:0000269|PubMed:17803912, ECO:0000269|PubMed:22363519" FT CARBOHYD 173 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:11706042, FT ECO:0000269|PubMed:17803912, ECO:0000269|PubMed:19252480, FT ECO:0000269|PubMed:22363519" FT CARBOHYD 205 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:11706042, FT ECO:0000269|PubMed:17803912, ECO:0000269|PubMed:19252480" FT CARBOHYD 282 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:11706042" FT CARBOHYD 309 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:11706042" FT CARBOHYD 497 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:11706042, FT ECO:0000269|PubMed:19252480" FT CARBOHYD 526 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:11706042, FT ECO:0000269|PubMed:19252480" FT CARBOHYD 575 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:11706042, FT ECO:0000269|PubMed:19252480" FT CARBOHYD 624 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:11706042" FT CARBOHYD 630 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 29..40 FT /evidence="ECO:0000269|PubMed:17803912, FT ECO:0000269|PubMed:19252480" FT DISULFID 281..306 FT /evidence="ECO:0000269|PubMed:19252480" FT DISULFID 390..391 FT /evidence="ECO:0000269|PubMed:19252480" FT DISULFID 583..609 FT /evidence="ECO:0000269|PubMed:19252480" FT DISULFID 585..627 FT /evidence="ECO:0000269|PubMed:19252480" FT VAR_SEQ 1..200 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_035793" FT VAR_SEQ 1..40 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039, FT ECO:0000303|PubMed:9435236" FT /id="VSP_035794" FT VARIANT 175 FT /note="T -> A (in dbSNP:rs16906079)" FT /id="VAR_021977" FT VARIANT 188 FT /note="Q -> R (in dbSNP:rs5030713)" FT /evidence="ECO:0000269|PubMed:11514453" FT /id="VAR_018729" FT VARIANT 246 FT /note="C -> S (in dbSNP:rs5030714)" FT /evidence="ECO:0000269|PubMed:11514453" FT /id="VAR_018730" FT VARIANT 287 FT /note="E -> D" FT /evidence="ECO:0000269|PubMed:25787250" FT /id="VAR_074187" FT VARIANT 299 FT /note="D -> G (in allele TLR4*B; reduced LPS-response; FT associated with an increased risk for age-related macular FT degeneration in Caucasian carriers; dbSNP:rs4986790)" FT /evidence="ECO:0000269|PubMed:10835634, FT ECO:0000269|PubMed:11104518, ECO:0000269|PubMed:11514453, FT ECO:0000269|PubMed:15829498, ECO:0000269|PubMed:19924287" FT /id="VAR_012739" FT VARIANT 306 FT /note="C -> W (in dbSNP:rs2770145)" FT /id="VAR_047563" FT VARIANT 310 FT /note="V -> G (in dbSNP:rs2770144)" FT /id="VAR_047564" FT VARIANT 329 FT /note="N -> S (in dbSNP:rs5030715)" FT /evidence="ECO:0000269|PubMed:11514453" FT /id="VAR_018731" FT VARIANT 342 FT /note="F -> Y (in dbSNP:rs5031050)" FT /id="VAR_020334" FT VARIANT 385 FT /note="L -> F (in dbSNP:rs11536884)" FT /id="VAR_037668" FT VARIANT 399 FT /note="T -> I (in allele TLR4*B; reduced LPS-response; FT dbSNP:rs4986791)" FT /evidence="ECO:0000269|PubMed:10835634, FT ECO:0000269|PubMed:11104518, ECO:0000269|PubMed:11514453, FT ECO:0000269|PubMed:19924287" FT /id="VAR_012740" FT VARIANT 400 FT /note="S -> N (in dbSNP:rs4987233)" FT /id="VAR_020335" FT VARIANT 443 FT /note="F -> L (in dbSNP:rs5030716)" FT /evidence="ECO:0000269|PubMed:11514453" FT /id="VAR_018732" FT VARIANT 474 FT /note="E -> K (in dbSNP:rs5030718)" FT /evidence="ECO:0000269|PubMed:11514453" FT /id="VAR_018733" FT VARIANT 510 FT /note="Q -> H (in dbSNP:rs5030719)" FT /evidence="ECO:0000269|PubMed:11514453" FT /id="VAR_018734" FT VARIANT 694 FT /note="K -> R (in dbSNP:rs5030722)" FT /evidence="ECO:0000269|PubMed:11514453" FT /id="VAR_018735" FT VARIANT 763 FT /note="R -> H (in dbSNP:rs5030723)" FT /evidence="ECO:0000269|PubMed:11514453" FT /id="VAR_018736" FT VARIANT 834 FT /note="Q -> H" FT /evidence="ECO:0000269|PubMed:11514453" FT /id="VAR_018737" FT MUTAGEN 431 FT /note="H->A: Partially diminishes NF-kappa-B activation FT induced by Ni(2+). Strongly reduces NF-kappa-B activation FT induced by Ni(2+); when associated with A-456 or A-458." FT /evidence="ECO:0000269|PubMed:20711192" FT MUTAGEN 456 FT /note="H->A: Partially diminishes NF-kappa-B activation FT induced by Ni(2+). Strongly reduces NF-kappa-B activation FT induced by Ni(2+); when associated with A-431. Suppresses FT NF-kappa-B activation induced by Ni(2+); when associated FT with A-458." FT /evidence="ECO:0000269|PubMed:20711192" FT MUTAGEN 458 FT /note="H->A: Partially diminishes NF-kappa-B activation FT induced by Ni(2+). Strongly reduces NF-kappa-B activation FT induced by Ni(2+); when associated with A-431. Suppresses FT NF-kappa-B activation induced by Ni(2+); when associated FT with A-456." FT /evidence="ECO:0000269|PubMed:20711192" FT MUTAGEN 526 FT /note="N->A: Abolishes LPS-response and prevents the cell FT surface expression." FT /evidence="ECO:0000269|PubMed:11706042" FT MUTAGEN 575 FT /note="N->A: Abolishes LPS-response and prevents the cell FT surface expression." FT /evidence="ECO:0000269|PubMed:11706042" FT MUTAGEN 697 FT /note="E->R: Abolishes LPS-response." FT /evidence="ECO:0000269|PubMed:11081518" FT MUTAGEN 710 FT /note="R->E: Abolishes LPS-response." FT /evidence="ECO:0000269|PubMed:11081518" FT MUTAGEN 711 FT /note="D->K: Abolishes LPS-response." FT /evidence="ECO:0000269|PubMed:11081518" FT MUTAGEN 714 FT /note="P->H,R,E: Abolishes MYD88-binding and LPS-response." FT /evidence="ECO:0000269|PubMed:11081518" FT CONFLICT 73 FT /note="S -> R (in Ref. 11; ABU41664)" FT /evidence="ECO:0000305" FT CONFLICT 400 FT /note="S -> C (in Ref. 7; BAF82742)" FT /evidence="ECO:0000305" FT CONFLICT 581 FT /note="F -> S (in Ref. 7; BAG64706)" FT /evidence="ECO:0000305" FT STRAND 29..33 FT /evidence="ECO:0007829|PDB:2Z62" FT TURN 34..36 FT /evidence="ECO:0007829|PDB:2Z62" FT STRAND 37..39 FT /evidence="ECO:0007829|PDB:2Z62" FT STRAND 50..52 FT /evidence="ECO:0007829|PDB:2Z62" FT STRAND 58..60 FT /evidence="ECO:0007829|PDB:2Z62" FT TURN 71..76 FT /evidence="ECO:0007829|PDB:2Z62" FT STRAND 81..84 FT /evidence="ECO:0007829|PDB:2Z62" FT TURN 95..100 FT /evidence="ECO:0007829|PDB:2Z62" FT STRAND 106..108 FT /evidence="ECO:0007829|PDB:2Z62" FT STRAND 115..117 FT /evidence="ECO:0007829|PDB:3UL9" FT TURN 119..124 FT /evidence="ECO:0007829|PDB:2Z62" FT STRAND 130..132 FT /evidence="ECO:0007829|PDB:2Z62" FT HELIX 141..143 FT /evidence="ECO:0007829|PDB:3UL8" FT TURN 145..148 FT /evidence="ECO:0007829|PDB:3FXI" FT STRAND 154..156 FT /evidence="ECO:0007829|PDB:2Z62" FT HELIX 169..173 FT /evidence="ECO:0007829|PDB:2Z62" FT STRAND 179..181 FT /evidence="ECO:0007829|PDB:2Z62" FT HELIX 192..195 FT /evidence="ECO:0007829|PDB:2Z62" FT HELIX 196..199 FT /evidence="ECO:0007829|PDB:2Z62" FT STRAND 206..209 FT /evidence="ECO:0007829|PDB:2Z62" FT TURN 220..225 FT /evidence="ECO:0007829|PDB:2Z63" FT STRAND 227..235 FT /evidence="ECO:0007829|PDB:2Z63" FT HELIX 242..248 FT /evidence="ECO:0007829|PDB:2Z63" FT TURN 249..252 FT /evidence="ECO:0007829|PDB:2Z63" FT STRAND 254..262 FT /evidence="ECO:0007829|PDB:2Z63" FT TURN 274..277 FT /evidence="ECO:0007829|PDB:2Z63" FT HELIX 278..282 FT /evidence="ECO:0007829|PDB:2Z63" FT STRAND 283..292 FT /evidence="ECO:0007829|PDB:2Z63" FT STRAND 295..298 FT /evidence="ECO:0007829|PDB:2Z63" FT TURN 301..304 FT /evidence="ECO:0007829|PDB:2Z63" FT HELIX 305..307 FT /evidence="ECO:0007829|PDB:2Z63" FT STRAND 311..317 FT /evidence="ECO:0007829|PDB:2Z63" FT STRAND 319..322 FT /evidence="ECO:0007829|PDB:4G8A" FT HELIX 324..327 FT /evidence="ECO:0007829|PDB:4G8A" FT STRAND 333..339 FT /evidence="ECO:0007829|PDB:2Z63" FT STRAND 341..344 FT /evidence="ECO:0007829|PDB:4G8A" FT STRAND 355..360 FT /evidence="ECO:0007829|PDB:2Z63" FT STRAND 377..379 FT /evidence="ECO:0007829|PDB:2Z63" FT STRAND 387..392 FT /evidence="ECO:0007829|PDB:2Z66" FT HELIX 393..396 FT /evidence="ECO:0007829|PDB:2Z66" FT STRAND 403..405 FT /evidence="ECO:0007829|PDB:2Z66" FT STRAND 410..419 FT /evidence="ECO:0007829|PDB:2Z66" FT STRAND 426..428 FT /evidence="ECO:0007829|PDB:2Z66" FT STRAND 432..437 FT /evidence="ECO:0007829|PDB:2Z66" FT TURN 438..445 FT /evidence="ECO:0007829|PDB:2Z66" FT STRAND 451..453 FT /evidence="ECO:0007829|PDB:2Z66" FT TURN 464..469 FT /evidence="ECO:0007829|PDB:2Z66" FT STRAND 475..477 FT /evidence="ECO:0007829|PDB:2Z66" FT HELIX 484..486 FT /evidence="ECO:0007829|PDB:2Z66" FT STRAND 500..502 FT /evidence="ECO:0007829|PDB:2Z66" FT TURN 513..518 FT /evidence="ECO:0007829|PDB:2Z66" FT STRAND 524..526 FT /evidence="ECO:0007829|PDB:2Z66" FT HELIX 538..540 FT /evidence="ECO:0007829|PDB:2Z66" FT STRAND 548..550 FT /evidence="ECO:0007829|PDB:2Z66" FT STRAND 560..563 FT /evidence="ECO:0007829|PDB:2Z66" FT STRAND 573..575 FT /evidence="ECO:0007829|PDB:2Z66" FT HELIX 585..587 FT /evidence="ECO:0007829|PDB:2Z66" FT HELIX 588..596 FT /evidence="ECO:0007829|PDB:2Z66" FT HELIX 597..600 FT /evidence="ECO:0007829|PDB:2Z66" FT HELIX 604..606 FT /evidence="ECO:0007829|PDB:2Z66" FT STRAND 608..612 FT /evidence="ECO:0007829|PDB:2Z66" FT HELIX 613..615 FT /evidence="ECO:0007829|PDB:2Z66" FT STRAND 617..619 FT /evidence="ECO:0007829|PDB:3FXI" FT HELIX 620..622 FT /evidence="ECO:0007829|PDB:2Z66" FT STRAND 627..629 FT /evidence="ECO:0007829|PDB:5NAM" FT HELIX 630..662 FT /evidence="ECO:0007829|PDB:5NAM" 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 //