ID TLR4_MOUSE Reviewed; 835 AA. AC Q9QUK6; Q9D691; Q9QZF5; Q9Z203; DT 11-FEB-2002, integrated into UniProtKB/Swiss-Prot. DT 01-MAY-2000, sequence version 1. DT 27-MAR-2024, entry version 203. DE RecName: Full=Toll-like receptor 4; DE AltName: CD_antigen=CD284; DE Flags: Precursor; GN Name=Tlr4; Synonyms=Lps; OS Mus musculus (Mouse). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Mus; Mus. OX NCBI_TaxID=10090; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RC STRAIN=C3H/HeJ; RX PubMed=10087992; DOI=10.1006/bcmd.1998.0201; RA Poltorak A., Smirnova I., He X., Liu M.-Y., Van Huffel C., Birdwell D., RA Alejos E., Silva M., Du X., Thompson P., Chan E.K.L., Ledesma J., Roe B., RA Clifton S., Vogel S.N., Beutler B.; RT "Genetic and physical mapping of the Lps locus: identification of the Toll- RT 4 receptor as a candidate gene in the critical region."; RL Blood Cells Mol. Dis. 24:340-355(1998). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND VARIANT LPS-TOLERANT HIS-712. RC STRAIN=C3H/HeJ; RX PubMed=9851930; DOI=10.1126/science.282.5396.2085; RA Poltorak A., He X., Smirnova I., Liu M.-Y., Van Huffel C., Du X., RA Birdwell D., Alejos E., Silva M., Galanos C., Freudenberg M., RA Ricciardi-Castagnoli P., Layton B., Beutler B.; RT "Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in RT Tlr4 gene."; RL Science 282:2085-2088(1998). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND VARIANT LPS-TOLERANT HIS-712. RC STRAIN=C57BL/6J; RX PubMed=9989976; DOI=10.1084/jem.189.4.615; RA Qureshi S.T., Lariviere L., Leveque G., Clermont S., Moore K.J., Gros P., RA Malo D.; RT "Endotoxin-tolerant mice have mutations in Toll-like receptor 4 (Tlr4)."; RL J. Exp. Med. 189:615-625(1999). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Macrophage; RX PubMed=10548109; DOI=10.1038/44605; RA Underhill D.M., Ozinsky A., Hajjar A.M., Stevens A., Wilson C.B., RA Bassetti M., Aderem A.; RT "The Toll-like receptor 2 is recruited to macrophage phagosomes and RT discriminates between pathogens."; RL Nature 401:811-815(1999). RN [5] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS ASN-94; ILE-209; GLY-219; RP ILE-254; LEU-423; SER-477; ALA-516; ASP-593; ILE-600; VAL-607; ILE-637; RP HIS-761 AND LYS-811. RC STRAIN=Various strains; 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 [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-154. RC STRAIN=C57BL/6J; TISSUE=Skin; RX PubMed=16141072; DOI=10.1126/science.1112014; RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J., RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.; RT "The transcriptional landscape of the mammalian genome."; RL Science 309:1559-1563(2005). RN [7] RP FUNCTION. RX PubMed=10952994; DOI=10.1074/jbc.m007386200; RA Rhee S.H., Hwang D.; RT "Murine Toll-like receptor 4 confers lipopolysaccharide responsiveness as RT determined by activation of NF kappa B and expression of the inducible RT cyclooxygenase."; RL J. Biol. Chem. 275:34035-34040(2000). RN [8] 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 [9] RP INTERACTION WITH CNPY3. RX PubMed=18780723; DOI=10.1093/intimm/dxn098; RA Kiyokawa T., Akashi-Takamura S., Shibata T., Matsumoto F., Nishitani C., RA Kuroki Y., Seto Y., Miyake K.; RT "A single base mutation in the PRAT4A gene reveals differential interaction RT of PRAT4A with Toll-like receptors."; RL Int. Immunol. 20:1407-1415(2008). RN [10] RP FUNCTION, SUBUNIT, AND SUBCELLULAR LOCATION. RX PubMed=20133493; DOI=10.1093/intimm/dxq005; RA Tsukamoto H., Fukudome K., Takao S., Tsuneyoshi N., Kimoto M.; RT "Lipopolysaccharide-binding protein-mediated Toll-like receptor 4 RT dimerization enables rapid signal transduction against lipopolysaccharide RT stimulation on membrane-associated CD14-expressing cells."; RL Int. Immunol. 22:271-280(2010). RN [11] 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 [12] 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 [13] RP FUNCTION. 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 [14] RP INTERACTION WITH CEACAM1. RX PubMed=22496641; DOI=10.1371/journal.ppat.1002597; RA Lu R., Pan H., Shively J.E.; RT "CEACAM1 negatively regulates IL-1beta production in LPS activated RT neutrophils by recruiting SHP-1 to a SYK-TLR4-CEACAM1 complex."; RL PLoS Pathog. 8:E1002597-E1002597(2012). RN [15] RP FUNCTION, DISRUPTION PHENOTYPE, AND TISSUE SPECIFICITY. RX PubMed=23812099; DOI=10.1038/ni.2639; RA Sheedy F.J., Grebe A., Rayner K.J., Kalantari P., Ramkhelawon B., RA Carpenter S.B., Becker C.E., Ediriweera H.N., Mullick A.E., Golenbock D.T., RA Stuart L.M., Latz E., Fitzgerald K.A., Moore K.J.; RT "CD36 coordinates NLRP3 inflammasome activation by facilitating RT intracellular nucleation of soluble ligands into particulate ligands in RT sterile inflammation."; RL Nat. Immunol. 14:812-820(2013). RN [16] RP FUNCTION, AND INTERACTION WITH TIRAP AND TICAM2. RX PubMed=24380872; DOI=10.1093/intimm/dxt071; RA Tanimura N., Saitoh S., Ohto U., Akashi-Takamura S., Fujimoto Y., RA Fukase K., Shimizu T., Miyake K.; RT "The attenuated inflammation of MPL is due to the lack of CD14-dependent RT tight dimerization of the TLR4/MD2 complex at the plasma membrane."; RL Int. Immunol. 26:307-314(2014). RN [17] RP INTERACTION WITH SMPDL3B. RX PubMed=26095358; DOI=10.1016/j.celrep.2015.05.006; RA Heinz L.X., Baumann C.L., Koeberlin M.S., Snijder B., Gawish R., Shui G., RA Sharif O., Aspalter I.M., Mueller A.C., Kandasamy R.K., Breitwieser F.P., RA Pichlmair A., Bruckner M., Rebsamen M., Blueml S., Karonitsch T., RA Fauster A., Colinge J., Bennett K.L., Knapp S., Wenk M.R., RA Superti-Furga G.; RT "The lipid-modifying enzyme SMPDL3B negatively regulates innate immunity."; RL Cell Rep. 11:1919-1928(2015). RN [18] RP INTERACTION WITH WDFY1 AND TICAM1. 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 [19] RP IDENTIFICATION BY MASS SPECTROMETRY, INTERACTION WITH SCIMP, SUBCELLULAR RP LOCATION, TISSUE SPECIFICITY, AND PHOSPHORYLATION. RX PubMed=28098138; DOI=10.1038/ncomms14133; RA Luo L., Bokil N.J., Wall A.A., Kapetanovic R., Lansdaal N.M., Marceline F., RA Burgess B.J., Tong S.J., Guo Z., Alexandrov K., Ross I.L., Hibbs M.L., RA Stow J.L., Sweet M.J.; RT "SCIMP is a transmembrane non-TIR TLR adaptor that promotes proinflammatory RT cytokine production from macrophages."; RL Nat. Commun. 8:14133-14133(2017). RN [20] RP FUNCTION (MICROBIAL INFECTION), SUBCELLULAR LOCATION, TISSUE SPECIFICITY, RP AND DISRUPTION PHENOTYPE. RC STRAIN=C57BL/6J {ECO:0000269|PubMed:35896747}; RX PubMed=35896747; DOI=10.1038/s41586-022-05005-4; RA Dang E.V., Lei S., Radkov A., Volk R.F., Zaro B.W., Madhani H.D.; RT "Secreted fungal virulence effector triggers allergic inflammation via RT TLR4."; RL Nature 608:161-167(2022). RN [21] RP X-RAY CRYSTALLOGRAPHY (2.84 ANGSTROMS) OF 27-625 IN COMPLEX WITH LY96, RP DISULFIDE BOND, AND GLYCOSYLATION AT ASN-34; ASN-75; ASN-172; ASN-204; RP ASN-237; ASN-307; ASN-492; ASN-524 AND ASN-572. 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 [22] RP X-RAY CRYSTALLOGRAPHY (2.48 ANGSTROMS) OF 22-627 IN COMPLEX WITH LY96, RP SUBUNIT, DISULFIDE BONDS, AND GLYCOSYLATION AT ASN-172; ASN-204; ASN-524 RP AND ASN-572. RX PubMed=22532668; DOI=10.1073/pnas.1201193109; RA Ohto U., Fukase K., Miyake K., Shimizu T.; RT "Structural basis of species-specific endotoxin sensing by innate immune RT receptor TLR4/MD-2."; RL Proc. Natl. Acad. Sci. U.S.A. 109:7421-7426(2012). 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:9851930, PubMed:9989976, CC PubMed:20133493). At the plasma membrane, cooperates with LY96 to CC mediate the innate immune response to bacterial lipopolysaccharide CC (LPS) (PubMed:9851930, PubMed:9989976, PubMed:20133493). Also involved CC in LPS-independent inflammatory responses triggered by free fatty CC acids, such as palmitate, and Ni(2+). Mechanistically, acts via MYD88, CC TIRAP and TRAF6, leading to NF-kappa-B activation, cytokine secretion CC and the inflammatory response (PubMed:24380872). Alternatively, CD14- CC mediated TLR4 internalization via endocytosis is associated with the CC initiation of a MYD88-independent signaling via the TICAM1-TBK1-IRF3 CC axis leading to type I interferon production. In addition to the CC secretion of proinflammatory cytokines, initiates the activation of CC NLRP3 inflammasome and formation of a positive feedback loop between CC autophagy and NF-kappa-B signaling cascade. In complex with TLR6, CC promotes inflammation in monocytes/macrophages by associating with TLR6 CC and the receptor CD86. Upon ligand binding, such as oxLDL or amyloid- CC beta 42, the TLR4:TLR6 complex is internalized and triggers CC inflammatory response, leading to NF-kappa-B-dependent production of CC CXCL1, CXCL2 and CCL9 cytokines, via MYD88 signaling pathway, and CCL5 CC cytokine, via TICAM1 signaling pathway. 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 (By similarity). {ECO:0000250|UniProtKB:O00206, CC ECO:0000269|PubMed:10952994, ECO:0000269|PubMed:17478729, CC ECO:0000269|PubMed:20037584, ECO:0000269|PubMed:20133493, CC ECO:0000269|PubMed:23812099, ECO:0000269|PubMed:24380872, CC ECO:0000269|PubMed:9851930, ECO:0000269|PubMed:9989976}. CC -!- FUNCTION: (Microbial infection) Required for the virulence of fungus CC C.neoformans var. grubii serotype A (strain KN99) CPL1 CC (PubMed:35896747). Independently of Ly96/Md2, activated by CPL1 which CC results in a type 2 inflammation response characterized by CC Arg1/arginase-1 induction in interstitial macrophages CC (PubMed:35896747). {ECO:0000269|PubMed:35896747}. CC -!- SUBUNIT: Belongs to the lipopolysaccharide (LPS) receptor, a multi- CC protein complex containing at least CD14, LY96 and TLR4 CC (PubMed:24380872). Binding to bacterial LPS leads to homodimerization CC (PubMed:20133493, PubMed:24380872, PubMed:22532668). Interacts with CC LY96 via the extracellular domain (PubMed:17803912, PubMed:22532668). CC Interacts with MYD88 (via the TIR domain). Interacts with TICAM2 and CC TIRAP (PubMed:24380872). Interacts with NOX4 (By similarity). Interacts CC with CNPY3 and HSP90B1; this interaction is required for proper folding CC in the endoplasmic reticulum (PubMed:18780723, PubMed:20865800). CC Interacts with MAP3K21; this interaction leads to negative regulation CC of TLR4 signaling (By similarity). Interacts with CD36, following CD36 CC stimulation by oxLDL or amyloid-beta 42, and forms a heterodimer with CC TLR6. The trimeric complex is internalized and triggers inflammatory CC response. LYN kinase activity facilitates TLR4-TLR6 heterodimerization CC and signal initiation (By similarity). Interacts with TICAM1 in CC response to LPS in a WDFY1-dependent manner (PubMed:25736436). CC Interacts with WDFY1 in response to LPS (PubMed:25736436). Interacts CC with SMPDL3B (PubMed:26095358). Interacts with CEACAM1; upon CC lipopolysaccharide stimulation, forms a complex including TLR4 and the CC phosphorylated form of SYK and CEACAM1, which in turn, recruits PTPN6 CC that dephosphorylates SYK, reducing the production of reactive oxygen CC species (ROS) and lysosome disruption, which in turn, reduces the CC activity of the inflammasome (PubMed:22496641). Interacts with RFTN1; CC the interaction occurs in response to lipopolysaccharide stimulation CC (By similarity). Interacts with SCIMP; the interaction occurs in CC response to lipopolysaccharide stimulation and is enhanced by CC phosphorylation of SCIMP by LYN (PubMed:28098138). This interaction CC facilitates the phosphorylation of TLR4 by LYN which elicits a CC selective cytokine response in macrophages (PubMed:28098138). Interacts CC with TRAF3IP3 (By similarity). Interacts with TREM1; this interaction CC enhances TLR4-mediated inflammatory response (By similarity). Interacts CC with ZG16B/PAUF (By similarity). {ECO:0000250|UniProtKB:O00206, CC ECO:0000269|PubMed:17803912, ECO:0000269|PubMed:18780723, CC ECO:0000269|PubMed:20133493, ECO:0000269|PubMed:20865800, CC ECO:0000269|PubMed:22496641, ECO:0000269|PubMed:22532668, CC ECO:0000269|PubMed:24380872, ECO:0000269|PubMed:25736436, CC ECO:0000269|PubMed:26095358, ECO:0000269|PubMed:28098138}. CC -!- INTERACTION: CC Q9QUK6; Q9JHF9: Ly96; NbExp=8; IntAct=EBI-1534575, EBI-1534566; CC Q9QUK6; P22366: Myd88; NbExp=2; IntAct=EBI-1534575, EBI-525108; CC Q9QUK6; Q91Y57: Siglec12; NbExp=3; IntAct=EBI-1534575, EBI-16826475; CC Q9QUK6; Q3U0V2: Tradd; NbExp=3; IntAct=EBI-1534575, EBI-1544032; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:20133493, CC ECO:0000269|PubMed:28098138, ECO:0000269|PubMed:35896747}; Single-pass CC type I membrane protein {ECO:0000269|PubMed:20133493}. Early endosome CC {ECO:0000250|UniProtKB:O00206}. Cell projection, ruffle CC {ECO:0000269|PubMed:28098138}. Note=Upon complex formation with CD36 CC and TLR6, internalized through dynamin-dependent endocytosis. CC Colocalizes with RFTN1 at cell membrane and then together with RFTN1 CC moves to endosomes, upon lipopolysaccharide stimulation. CC {ECO:0000250|UniProtKB:O00206}. CC -!- SUBCELLULAR LOCATION: Note=(Microbial infection) Endocytosed upon CC interaction with fungus C.neoformans var. grubii serotype A (strain CC KN99) CPL1 at the macrophage cell surface. CC {ECO:0000269|PubMed:35896747}. CC -!- TISSUE SPECIFICITY: Expressed in macrophages (at protein level) CC (PubMed:28098138, PubMed:35896747). Highly expressed in heart, spleen, CC lung and muscle. Lower levels are found in liver and kidney CC (PubMed:23812099). {ECO:0000269|PubMed:23812099, CC ECO:0000269|PubMed:28098138, ECO:0000269|PubMed:35896747}. CC -!- DOMAIN: The TIR domain mediates interaction with NOX4. CC {ECO:0000250|UniProtKB:O00206}. CC -!- PTM: Phosphorylated on tyrosine residues by LYN after binding CC lipopolysaccharide. {ECO:0000269|PubMed:28098138}. CC -!- POLYMORPHISM: Interstrain analysis reveals that TLR4 is a polymorphic CC protein and that the extracellular domain is far more variable than the CC cytoplasmic domain, which is variable at the C-terminal. CC {ECO:0000305|PubMed:11104518}. CC -!- DISEASE: Note=The protein is encoded by the Lps locus, an important CC susceptibility locus, influencing the propensity to develop a CC disseminated Gram-negative infection. {ECO:0000269|PubMed:9851930, CC ECO:0000269|PubMed:9989976}. CC -!- DISRUPTION PHENOTYPE: Mice infected with C.neoformans var. grubii CC serotype A (strain KN99) display reduced Arg1/arginase-1 expression in CC interstitial macrophages as well as reduced pulmonary fungal burden and CC eosinophilia (PubMed:35896747). Animals with a double knockout of Apoe CC and Tlr4, fed a Western diet for 12 weeks, have less aortic plaque CC formation than single Apoe knockout mice. They also show lower serum CC concentrations of Il1a, Ilb and Il18 (PubMed:23812099). CC {ECO:0000269|PubMed:23812099, ECO:0000269|PubMed:35896747}. 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 (By similarity). However, despite CC the presence of the catalytic Asp residue, the isolated TIR domain of CC human TLR4 lacks NADase activity (By similarity). Based on this, it is CC unlikely that Toll-like receptors have NADase activity. CC {ECO:0000250|UniProtKB:O00206, ECO:0000305}. 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; AF095353; AAC99411.1; -; mRNA. DR EMBL; AF110133; AAD29272.1; -; mRNA. DR EMBL; AF185285; AAF04278.1; -; mRNA. DR EMBL; AF177767; AAF05317.1; -; Genomic_DNA. DR EMBL; AK014533; -; NOT_ANNOTATED_CDS; mRNA. DR CCDS; CCDS18271.1; -. DR RefSeq; NP_067272.1; NM_021297.3. DR PDB; 2Z64; X-ray; 2.84 A; A=27-625. DR PDB; 3VQ1; X-ray; 2.70 A; A/B=22-627. DR PDB; 3VQ2; X-ray; 2.48 A; A/B=22-627. DR PDB; 5IJB; X-ray; 2.91 A; A/B=26-544. DR PDB; 5IJC; X-ray; 2.57 A; A/B=26-544. DR PDB; 5IJD; X-ray; 2.70 A; A/B=26-544. DR PDB; 7MLM; X-ray; 2.10 A; A=26-544. DR PDBsum; 2Z64; -. DR PDBsum; 3VQ1; -. DR PDBsum; 3VQ2; -. DR PDBsum; 5IJB; -. DR PDBsum; 5IJC; -. DR PDBsum; 5IJD; -. DR PDBsum; 7MLM; -. DR AlphaFoldDB; Q9QUK6; -. DR SMR; Q9QUK6; -. DR BioGRID; 204224; 28. DR DIP; DIP-38573N; -. DR IntAct; Q9QUK6; 15. DR MINT; Q9QUK6; -. DR STRING; 10090.ENSMUSP00000045770; -. DR BindingDB; Q9QUK6; -. DR ChEMBL; CHEMBL1795167; -. DR GlyCosmos; Q9QUK6; 14 sites, No reported glycans. DR GlyGen; Q9QUK6; 14 sites. DR iPTMnet; Q9QUK6; -. DR PhosphoSitePlus; Q9QUK6; -. DR MaxQB; Q9QUK6; -. DR PaxDb; 10090-ENSMUSP00000045770; -. DR ProteomicsDB; 259208; -. DR Pumba; Q9QUK6; -. DR Antibodypedia; 3410; 2078 antibodies from 51 providers. DR DNASU; 21898; -. DR Ensembl; ENSMUST00000048096.12; ENSMUSP00000045770.6; ENSMUSG00000039005.14. DR GeneID; 21898; -. DR KEGG; mmu:21898; -. DR UCSC; uc008thv.1; mouse. DR AGR; MGI:96824; -. DR CTD; 7099; -. DR MGI; MGI:96824; Tlr4. DR VEuPathDB; HostDB:ENSMUSG00000039005; -. DR eggNOG; KOG4641; Eukaryota. DR GeneTree; ENSGT00940000160778; -. DR HOGENOM; CLU_006000_5_0_1; -. DR InParanoid; Q9QUK6; -. DR OMA; CKHSAER; -. DR OrthoDB; 1207361at2759; -. DR PhylomeDB; Q9QUK6; -. DR TreeFam; TF351113; -. DR Reactome; R-MMU-140534; Caspase activation via Death Receptors in the presence of ligand. DR Reactome; R-MMU-166016; Toll Like Receptor 4 (TLR4) Cascade. DR Reactome; R-MMU-166166; MyD88-independent TLR4 cascade. DR Reactome; R-MMU-2562578; TRIF-mediated programmed cell death. DR Reactome; R-MMU-5686938; Regulation of TLR by endogenous ligand. DR Reactome; R-MMU-936964; Activation of IRF3, IRF7 mediated by TBK1, IKBKE. DR Reactome; R-MMU-937041; IKK complex recruitment mediated by RIP1. DR Reactome; R-MMU-937072; TRAF6-mediated induction of TAK1 complex within TLR4 complex. DR Reactome; R-MMU-9707616; Heme signaling. DR Reactome; R-MMU-975163; IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation. DR BioGRID-ORCS; 21898; 2 hits in 78 CRISPR screens. DR EvolutionaryTrace; Q9QUK6; -. DR PRO; PR:Q9QUK6; -. DR Proteomes; UP000000589; Chromosome 4. DR RNAct; Q9QUK6; Protein. DR Bgee; ENSMUSG00000039005; Expressed in lumbar dorsal root ganglion and 143 other cell types or tissues. DR ExpressionAtlas; Q9QUK6; baseline and differential. DR GO; GO:0009986; C:cell surface; ISO:MGI. DR GO; GO:0005737; C:cytoplasm; ISO:MGI. DR GO; GO:0005769; C:early endosome; IEA:UniProtKB-SubCell. DR GO; GO:0010008; C:endosome membrane; IEA:Ensembl. DR GO; GO:0009897; C:external side of plasma membrane; ISO:MGI. DR GO; GO:0046696; C:lipopolysaccharide receptor complex; ISS:UniProtKB. DR GO; GO:0048471; C:perinuclear region of cytoplasm; ISO:MGI. DR GO; GO:0001891; C:phagocytic cup; ISO:MGI. DR GO; GO:0005886; C:plasma membrane; IDA:ARUK-UCL. DR GO; GO:0043235; C:receptor complex; IDA:UniProtKB. DR GO; GO:0001726; C:ruffle; IEA:UniProtKB-SubCell. DR GO; GO:0042802; F:identical protein binding; ISO:MGI. DR GO; GO:0001530; F:lipopolysaccharide binding; ISO:MGI. 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:0043548; F:phosphatidylinositol 3-kinase binding; ISO:MGI. DR GO; GO:0046982; F:protein heterodimerization activity; ISO:MGI. DR GO; GO:0038023; F:signaling receptor activity; ISO:MGI. DR GO; GO:0005102; F:signaling receptor binding; ISO:MGI. DR GO; GO:0004888; F:transmembrane signaling receptor activity; IEA:InterPro. DR GO; GO:0002218; P:activation of innate immune response; IMP:MGI. DR GO; GO:0007250; P:activation of NF-kappaB-inducing kinase activity; NAS:UniProtKB. DR GO; GO:0014002; P:astrocyte development; IMP:MGI. DR GO; GO:0042100; P:B cell proliferation; IMP:MGI. DR GO; GO:0002322; P:B cell proliferation involved in immune response; IMP:MGI. DR GO; GO:1904646; P:cellular response to amyloid-beta; ISO:MGI. DR GO; GO:0071222; P:cellular response to lipopolysaccharide; IDA:ARUK-UCL. DR GO; GO:0071223; P:cellular response to lipoteichoic acid; IMP:MGI. DR GO; GO:0071260; P:cellular response to mechanical stimulus; IEA:Ensembl. DR GO; GO:0140052; P:cellular response to oxidised low-density lipoprotein particle stimulus; IGI:ARUK-UCL. DR GO; GO:0036120; P:cellular response to platelet-derived growth factor stimulus; IMP:BHF-UCL. DR GO; GO:0071346; P:cellular response to type II interferon; ISO:MGI. DR GO; GO:0042742; P:defense response to bacterium; ISO:MGI. DR GO; GO:0050829; P:defense response to Gram-negative bacterium; IMP:MGI. DR GO; GO:0032497; P:detection of lipopolysaccharide; IDA:UniProtKB. DR GO; GO:0050966; P:detection of mechanical stimulus involved in sensory perception of pain; ISO:MGI. DR GO; GO:0050965; P:detection of temperature stimulus involved in sensory perception of pain; ISO:MGI. DR GO; GO:0070371; P:ERK1 and ERK2 cascade; IDA:MGI. DR GO; GO:0010467; P:gene expression; IMP:MGI. DR GO; GO:0006954; P:inflammatory response; IMP:BHF-UCL. DR GO; GO:0045087; P:innate immune response; TAS:BHF-UCL. DR GO; GO:0002758; P:innate immune response-activating signaling pathway; ISO:MGI. DR GO; GO:0060729; P:intestinal epithelial structure maintenance; IMP:BHF-UCL. DR GO; GO:0007254; P:JNK cascade; IDA:MGI. DR GO; GO:0006691; P:leukotriene metabolic process; ISO:MGI. DR GO; GO:0031663; P:lipopolysaccharide-mediated signaling pathway; IDA:UniProtKB. DR GO; GO:0046651; P:lymphocyte proliferation; IMP:MGI. DR GO; GO:0042116; P:macrophage activation; ISS:UniProtKB. DR GO; GO:0045576; P:mast cell activation; NAS:UniProtKB. DR GO; GO:0045342; P:MHC class II biosynthetic process; IMP:MGI. DR GO; GO:0014004; P:microglia differentiation; IMP:MGI. DR GO; GO:0001774; P:microglial cell activation; ISO:MGI. DR GO; GO:0002755; P:MyD88-dependent toll-like receptor signaling pathway; IGI:ARUK-UCL. DR GO; GO:0120163; P:negative regulation of cold-induced thermogenesis; IMP:YuBioLab. DR GO; GO:0070373; P:negative regulation of ERK1 and ERK2 cascade; IMP:BHF-UCL. DR GO; GO:0032700; P:negative regulation of interleukin-17 production; IMP:BHF-UCL. DR GO; GO:0032707; P:negative regulation of interleukin-23 production; IMP:BHF-UCL. DR GO; GO:0032715; P:negative regulation of interleukin-6 production; IMP:BHF-UCL. DR GO; GO:0032720; P:negative regulation of tumor necrosis factor production; IMP:BHF-UCL. DR GO; GO:0032689; P:negative regulation of type II interferon production; IMP:BHF-UCL. DR GO; GO:0022008; P:neurogenesis; IMP:MGI. DR GO; GO:0006809; P:nitric oxide biosynthetic process; IMP:MGI. DR GO; GO:0002537; P:nitric oxide production involved in inflammatory response; IMP:MGI. DR GO; GO:0070427; P:nucleotide-binding oligomerization domain containing 1 signaling pathway; IDA:MGI. DR GO; GO:0070431; P:nucleotide-binding oligomerization domain containing 2 signaling pathway; IDA:MGI. DR GO; GO:0006909; P:phagocytosis; ISO:MGI. DR GO; GO:0043065; P:positive regulation of apoptotic process; ISO:MGI. DR GO; GO:0030890; P:positive regulation of B cell proliferation; IMP:MGI. DR GO; GO:0043123; P:positive regulation of canonical NF-kappaB signal transduction; IDA:MGI. DR GO; GO:1903974; P:positive regulation of cellular response to macrophage colony-stimulating factor stimulus; ISO:MGI. DR GO; GO:2000343; P:positive regulation of chemokine (C-X-C motif) ligand 2 production; ISO:MGI. 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; IGI:ARUK-UCL. DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IDA:MGI. DR GO; GO:2001238; P:positive regulation of extrinsic apoptotic signaling pathway; IGI:ARUK-UCL. DR GO; GO:0010628; P:positive regulation of gene expression; IMP:ARUK-UCL. DR GO; GO:0050729; P:positive regulation of inflammatory response; IGI:ARUK-UCL. DR GO; GO:0032727; P:positive regulation of interferon-alpha production; IDA:BHF-UCL. DR GO; GO:0032728; P:positive regulation of interferon-beta production; IDA: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; IDA:BHF-UCL. DR GO; GO:0032733; P:positive regulation of interleukin-10 production; IDA:BHF-UCL. DR GO; GO:0032735; P:positive regulation of interleukin-12 production; IDA:UniProtKB. DR GO; GO:0032736; P:positive regulation of interleukin-13 production; NAS:UniProtKB. DR GO; GO:0032755; P:positive regulation of interleukin-6 production; IDA:UniProtKB. DR GO; GO:0032757; P:positive regulation of interleukin-8 production; ISO:MGI. DR GO; GO:0046330; P:positive regulation of JNK cascade; IDA:MGI. DR GO; GO:0050671; P:positive regulation of lymphocyte proliferation; IMP:MGI. DR GO; GO:0043032; P:positive regulation of macrophage activation; IGI:ARUK-UCL. DR GO; GO:0060907; P:positive regulation of macrophage cytokine production; IDA:MGI. DR GO; GO:0043406; P:positive regulation of MAP kinase activity; IMP:BHF-UCL. DR GO; GO:1904466; P:positive regulation of matrix metallopeptidase secretion; ISO:MGI. DR GO; GO:0045348; P:positive regulation of MHC class II biosynthetic process; IMP:MGI. DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IMP:UniProtKB. DR GO; GO:0045429; P:positive regulation of nitric oxide biosynthetic process; IMP:MGI. DR GO; GO:0051770; P:positive regulation of nitric-oxide synthase biosynthetic process; IDA:BHF-UCL. DR GO; GO:1900227; P:positive regulation of NLRP3 inflammasome complex assembly; IDA:UniProtKB. DR GO; GO:1901224; P:positive regulation of non-canonical NF-kappaB signal transduction; ISO:MGI. DR GO; GO:0070430; P:positive regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway; IDA:MGI. DR GO; GO:0070434; P:positive regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway; IDA:MGI. DR GO; GO:0050731; P:positive regulation of peptidyl-tyrosine phosphorylation; ISO:MGI. DR GO; GO:0010572; P:positive regulation of platelet activation; IMP:BHF-UCL. DR GO; GO:1903428; P:positive regulation of reactive oxygen species biosynthetic process; IMP:ARUK-UCL. DR GO; GO:0014911; P:positive regulation of smooth muscle cell migration; IMP:BHF-UCL. DR GO; GO:0048661; P:positive regulation of smooth muscle cell proliferation; IMP:BHF-UCL. DR GO; GO:0032874; P:positive regulation of stress-activated MAPK cascade; IDA:MGI. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:BHF-UCL. DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; IDA:BHF-UCL. DR GO; GO:0032729; P:positive regulation of type II interferon production; IMP:BHF-UCL. DR GO; GO:0002730; P:regulation of dendritic cell cytokine production; IDA:MGI. DR GO; GO:0050727; P:regulation of inflammatory response; IMP:BHF-UCL. DR GO; GO:0032680; P:regulation of tumor necrosis factor production; ISO:MGI. DR GO; GO:0009617; P:response to bacterium; IMP:MGI. DR GO; GO:0045471; P:response to ethanol; ISO:MGI. DR GO; GO:0070542; P:response to fatty acid; ISO:MGI. DR GO; GO:0032496; P:response to lipopolysaccharide; IMP:MGI. DR GO; GO:0006979; P:response to oxidative stress; ISO:MGI. DR GO; GO:0051403; P:stress-activated MAPK cascade; IDA:MGI. DR GO; GO:0034142; P:toll-like receptor 4 signaling pathway; IDA:UniProtKB. DR GO; GO:0002224; P:toll-like receptor signaling pathway; ISO:MGI. DR GO; GO:0035666; P:TRIF-dependent toll-like receptor signaling pathway; IGI:ARUK-UCL. DR GO; GO:0002246; P:wound healing involved in inflammatory response; IMP:BHF-UCL. 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; 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; PF13855; LRR_8; 2. DR Pfam; PF01582; TIR; 1. DR PIRSF; PIRSF037595; Toll-like_receptor; 1. DR SMART; SM00369; LRR_TYP; 8. 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; PS50104; TIR; 1. DR Genevisible; Q9QUK6; MM. PE 1: Evidence at protein level; KW 3D-structure; Cell membrane; Cell projection; Disease variant; KW Disulfide bond; Endosome; Glycoprotein; Immunity; Inflammatory response; KW Innate immunity; Leucine-rich repeat; Membrane; NAD; Receptor; KW Reference proteome; Repeat; Signal; Transmembrane; Transmembrane helix. FT SIGNAL 1..25 FT /evidence="ECO:0000255" FT CHAIN 26..835 FT /note="Toll-like receptor 4" FT /id="PRO_0000034723" FT TOPO_DOM 26..638 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 639..659 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 660..835 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT REPEAT 54..75 FT /note="LRR 1" FT /evidence="ECO:0000255" FT REPEAT 78..99 FT /note="LRR 2" FT /evidence="ECO:0000255" FT REPEAT 102..123 FT /note="LRR 3" FT /evidence="ECO:0000255" FT REPEAT 126..147 FT /note="LRR 4" FT /evidence="ECO:0000255" FT REPEAT 150..171 FT /note="LRR 5" FT /evidence="ECO:0000255" FT REPEAT 175..198 FT /note="LRR 6" FT /evidence="ECO:0000255" FT REPEAT 204..224 FT /note="LRR 7" FT /evidence="ECO:0000255" FT REPEAT 226..247 FT /note="LRR 8" FT /evidence="ECO:0000255" FT REPEAT 248..269 FT /note="LRR 9" FT /evidence="ECO:0000255" FT REPEAT 329..349 FT /note="LRR 10" FT /evidence="ECO:0000255" FT REPEAT 350..370 FT /note="LRR 11" FT /evidence="ECO:0000255" FT REPEAT 372..392 FT /note="LRR 12" FT /evidence="ECO:0000255" FT REPEAT 398..420 FT /note="LRR 13" FT /evidence="ECO:0000255" FT REPEAT 421..442 FT /note="LRR 14" FT /evidence="ECO:0000255" FT REPEAT 446..467 FT /note="LRR 15" FT /evidence="ECO:0000255" FT REPEAT 470..490 FT /note="LRR 16" FT /evidence="ECO:0000255" FT REPEAT 495..516 FT /note="LRR 17" FT /evidence="ECO:0000255" FT REPEAT 519..540 FT /note="LRR 18" FT /evidence="ECO:0000255" FT REPEAT 543..564 FT /note="LRR 19" FT /evidence="ECO:0000255" FT DOMAIN 576..627 FT /note="LRRCT" FT /evidence="ECO:0000255" FT DOMAIN 670..813 FT /note="TIR" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00204" FT REGION 670..835 FT /note="Interaction with SCIMP" FT /evidence="ECO:0000269|PubMed:28098138" FT CARBOHYD 34 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:17803912" FT CARBOHYD 75 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:17803912" FT CARBOHYD 172 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:17803912" FT CARBOHYD 204 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:17803912" FT CARBOHYD 237 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:17803912" FT CARBOHYD 307 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:17803912" FT CARBOHYD 492 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:17803912" FT CARBOHYD 495 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 524 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:17803912" FT CARBOHYD 572 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:17803912" FT CARBOHYD 575 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 613 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 621 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 622 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 28..39 FT /evidence="ECO:0000269|PubMed:17803912" FT DISULFID 280..304 FT /evidence="ECO:0000269|PubMed:17803912" FT DISULFID 388..389 FT /evidence="ECO:0000269|PubMed:17803912" FT DISULFID 580..606 FT /evidence="ECO:0000269|PubMed:17803912" FT DISULFID 582..625 FT /evidence="ECO:0000269|PubMed:17803912" FT VARIANT 94 FT /note="D -> N (in strain: KK/HLJ)" FT /evidence="ECO:0000269|PubMed:11104518" FT VARIANT 209 FT /note="M -> I (in strain: A/J, BALB/cJ, P/J, SODL/EI, FT SEA/GNJ, NZW/LACJ and VM/DK)" FT /evidence="ECO:0000269|PubMed:11104518" FT VARIANT 219 FT /note="D -> G (in strain: SEA/GNJ)" FT /evidence="ECO:0000269|PubMed:11104518" FT VARIANT 254 FT /note="V -> I (in strain: A/J, BALB/cJ and SEA/GNJ)" FT /evidence="ECO:0000269|PubMed:11104518" FT VARIANT 423 FT /note="Q -> L (in strain: SEA/GNJ)" FT /evidence="ECO:0000269|PubMed:11104518" FT VARIANT 477 FT /note="A -> S (in strain: P/J)" FT /evidence="ECO:0000269|PubMed:11104518" FT VARIANT 516 FT /note="T -> A (in strain: LP/J)" FT /evidence="ECO:0000269|PubMed:11104518" FT VARIANT 593 FT /note="E -> D (in strain: A/J, BALB/cJ, P/J, SODL/EI, FT SEA/GNJ, NZW/LACJ and VM/DK)" FT /evidence="ECO:0000269|PubMed:11104518" FT VARIANT 600 FT /note="N -> I (in strain: KK/HLJ)" FT /evidence="ECO:0000269|PubMed:11104518" FT VARIANT 607 FT /note="A -> V (in strain: P/J)" FT /evidence="ECO:0000269|PubMed:11104518" FT VARIANT 637 FT /note="V -> I (in strain: P/J)" FT /evidence="ECO:0000269|PubMed:11104518" FT VARIANT 712 FT /note="P -> H (in Lps-tolerant mice)" FT /evidence="ECO:0000269|PubMed:9851930, FT ECO:0000269|PubMed:9989976" FT VARIANT 761 FT /note="R -> H (in strain: A/J, BALB/cJ, SODL/EI, SEA/GNJ, FT NZW/LACJ and VM/DK)" FT /evidence="ECO:0000269|PubMed:11104518" FT VARIANT 811 FT /note="N -> K (in strain: P/J)" FT /evidence="ECO:0000269|PubMed:11104518" FT CONFLICT 87..154 FT /note="CEIETIEDKAWHGLHHLSNLILTGNPIQSFSPGSFSGLTSLENLVAVETKLA FT SLESFPIGQLITLKKL -> EMNTESKSSEAHALALSHILSPCQPSRRKLRVKLGSLSY FT QRAEEGVRSSEIGYSCLHVDTRHDINAVD (in Ref. 6)" FT /evidence="ECO:0000305" FT STRAND 29..32 FT /evidence="ECO:0007829|PDB:7MLM" FT TURN 33..35 FT /evidence="ECO:0007829|PDB:7MLM" FT STRAND 36..38 FT /evidence="ECO:0007829|PDB:7MLM" FT STRAND 40..42 FT /evidence="ECO:0007829|PDB:2Z64" FT STRAND 49..51 FT /evidence="ECO:0007829|PDB:5IJD" FT STRAND 57..59 FT /evidence="ECO:0007829|PDB:7MLM" FT TURN 70..75 FT /evidence="ECO:0007829|PDB:7MLM" FT STRAND 81..83 FT /evidence="ECO:0007829|PDB:7MLM" FT TURN 94..99 FT /evidence="ECO:0007829|PDB:7MLM" FT STRAND 105..107 FT /evidence="ECO:0007829|PDB:7MLM" FT TURN 118..123 FT /evidence="ECO:0007829|PDB:7MLM" FT STRAND 129..131 FT /evidence="ECO:0007829|PDB:7MLM" FT STRAND 140..143 FT /evidence="ECO:0007829|PDB:3VQ2" FT STRAND 153..155 FT /evidence="ECO:0007829|PDB:7MLM" FT HELIX 168..171 FT /evidence="ECO:0007829|PDB:7MLM" FT STRAND 178..180 FT /evidence="ECO:0007829|PDB:7MLM" FT HELIX 192..194 FT /evidence="ECO:0007829|PDB:7MLM" FT HELIX 195..199 FT /evidence="ECO:0007829|PDB:7MLM" FT STRAND 206..208 FT /evidence="ECO:0007829|PDB:7MLM" FT TURN 219..224 FT /evidence="ECO:0007829|PDB:7MLM" FT STRAND 226..234 FT /evidence="ECO:0007829|PDB:7MLM" FT HELIX 239..247 FT /evidence="ECO:0007829|PDB:7MLM" FT TURN 248..251 FT /evidence="ECO:0007829|PDB:7MLM" FT STRAND 253..260 FT /evidence="ECO:0007829|PDB:7MLM" FT HELIX 273..281 FT /evidence="ECO:0007829|PDB:7MLM" FT STRAND 282..289 FT /evidence="ECO:0007829|PDB:7MLM" FT HELIX 297..301 FT /evidence="ECO:0007829|PDB:7MLM" FT HELIX 303..305 FT /evidence="ECO:0007829|PDB:7MLM" FT STRAND 309..315 FT /evidence="ECO:0007829|PDB:7MLM" FT STRAND 331..337 FT /evidence="ECO:0007829|PDB:7MLM" FT STRAND 353..358 FT /evidence="ECO:0007829|PDB:7MLM" FT STRAND 375..377 FT /evidence="ECO:0007829|PDB:7MLM" FT STRAND 380..382 FT /evidence="ECO:0007829|PDB:2Z64" FT STRAND 384..388 FT /evidence="ECO:0007829|PDB:7MLM" FT HELIX 391..394 FT /evidence="ECO:0007829|PDB:7MLM" FT STRAND 401..403 FT /evidence="ECO:0007829|PDB:7MLM" FT STRAND 408..412 FT /evidence="ECO:0007829|PDB:7MLM" FT STRAND 424..426 FT /evidence="ECO:0007829|PDB:7MLM" FT STRAND 430..434 FT /evidence="ECO:0007829|PDB:7MLM" FT TURN 435..443 FT /evidence="ECO:0007829|PDB:7MLM" FT STRAND 449..451 FT /evidence="ECO:0007829|PDB:7MLM" FT TURN 462..467 FT /evidence="ECO:0007829|PDB:7MLM" FT STRAND 473..475 FT /evidence="ECO:0007829|PDB:7MLM" FT HELIX 482..484 FT /evidence="ECO:0007829|PDB:7MLM" FT TURN 489..492 FT /evidence="ECO:0007829|PDB:5IJD" FT STRAND 498..500 FT /evidence="ECO:0007829|PDB:7MLM" FT TURN 511..516 FT /evidence="ECO:0007829|PDB:7MLM" FT STRAND 522..524 FT /evidence="ECO:0007829|PDB:7MLM" FT STRAND 532..534 FT /evidence="ECO:0007829|PDB:2Z64" FT HELIX 535..538 FT /evidence="ECO:0007829|PDB:7MLM" FT STRAND 546..548 FT /evidence="ECO:0007829|PDB:3VQ2" FT STRAND 557..559 FT /evidence="ECO:0007829|PDB:3VQ2" FT HELIX 561..563 FT /evidence="ECO:0007829|PDB:3VQ2" FT STRAND 570..572 FT /evidence="ECO:0007829|PDB:3VQ2" FT HELIX 582..584 FT /evidence="ECO:0007829|PDB:3VQ1" FT HELIX 585..588 FT /evidence="ECO:0007829|PDB:3VQ2" FT TURN 589..593 FT /evidence="ECO:0007829|PDB:3VQ2" FT STRAND 594..600 FT /evidence="ECO:0007829|PDB:3VQ2" FT HELIX 601..603 FT /evidence="ECO:0007829|PDB:3VQ2" FT STRAND 608..610 FT /evidence="ECO:0007829|PDB:2Z64" FT HELIX 616..618 FT /evidence="ECO:0007829|PDB:2Z64" SQ SEQUENCE 835 AA; 95519 MW; 9C83B59F9A220C17 CRC64; MMPPWLLART LIMALFFSCL TPGSLNPCIE VVPNITYQCM DQKLSKVPDD IPSSTKNIDL SFNPLKILKS YSFSNFSELQ WLDLSRCEIE TIEDKAWHGL HHLSNLILTG NPIQSFSPGS FSGLTSLENL VAVETKLASL ESFPIGQLIT LKKLNVAHNF IHSCKLPAYF SNLTNLVHVD LSYNYIQTIT VNDLQFLREN PQVNLSLDMS LNPIDFIQDQ AFQGIKLHEL TLRGNFNSSN IMKTCLQNLA GLHVHRLILG EFKDERNLEI FEPSIMEGLC DVTIDEFRLT YTNDFSDDIV KFHCLANVSA MSLAGVSIKY LEDVPKHFKW QSLSIIRCQL KQFPTLDLPF LKSLTLTMNK GSISFKKVAL PSLSYLDLSR NALSFSGCCS YSDLGTNSLR HLDLSFNGAI IMSANFMGLE ELQHLDFQHS TLKRVTEFSA FLSLEKLLYL DISYTNTKID FDGIFLGLTS LNTLKMAGNS FKDNTLSNVF ANTTNLTFLD LSKCQLEQIS WGVFDTLHRL QLLNMSHNNL LFLDSSHYNQ LYSLSTLDCS FNRIETSKGI LQHFPKSLAF FNLTNNSVAC ICEHQKFLQW VKEQKQFLVN VEQMTCATPV EMNTSLVLDF NNSTCYMYKT IISVSVVSVI VVSTVAFLIY HFYFHLILIA GCKKYSRGES IYDAFVIYSS QNEDWVRNEL VKNLEEGVPR FHLCLHYRDF IPGVAIAANI IQEGFHKSRK VIVVVSRHFI QSRWCIFEYE IAQTWQFLSS RSGIIFIVLE KVEKSLLRQQ VELYRLLSRN TYLEWEDNPL GRHIFWRRLK NALLDGKASN PEQTAEEEQE TATWT //