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Toll-like receptor 4 (hToll) (CD antigen CD284)

 TLR4_HUMAN              Reviewed;         839 AA.
O00206; A8K1Y8; A9XLP9; A9XLQ0; A9XLQ1; B4E194; D1CS52; D1CS53;
Q5VZI8; Q5VZI9; Q9UK78; Q9UM57;
11-FEB-2002, integrated into UniProtKB/Swiss-Prot.
01-JAN-1998, sequence version 2.
27-SEP-2017, entry version 185.
RecName: Full=Toll-like receptor 4;
AltName: Full=hToll;
AltName: CD_antigen=CD284;
Flags: Precursor;
Name=TLR4;
Homo sapiens (Human).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
Catarrhini; Hominidae; Homo.
NCBI_TaxID=9606;
[1]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, SUBCELLULAR
LOCATION, AND TISSUE SPECIFICITY.
TISSUE=Spleen;
PubMed=9237759; DOI=10.1038/41131;
Medzhitov R., Preston-Hurlburt P., Janeway C.A. Jr.;
"A human homologue of the Drosophila Toll protein signals activation
of adaptive immunity.";
Nature 388:394-397(1997).
[2]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND TISSUE SPECIFICITY.
TISSUE=Fetal liver, Lung, and Placenta;
PubMed=9435236; DOI=10.1073/pnas.95.2.588;
Rock F.L., Hardiman G., Timans J.C., Kastelein R.A., Bazan J.F.;
"A family of human receptors structurally related to Drosophila
Toll.";
Proc. Natl. Acad. Sci. U.S.A. 95:588-593(1998).
[3]
NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, VARIANTS GLY-299 AND
ILE-399, CHARACTERIZATION OF VARIANTS GLY-299 AND ILE-399, AND
POLYMORPHISM.
PubMed=11104518; DOI=10.1186/gb-2000-1-1-research002;
Smirnova I., Poltorak A., Chan E.K.L., McBride C., Beutler B.;
"Phylogenetic variation and polymorphism at the Toll-like receptor 4
locus (TLR4).";
Genome Biol. 1:RESEARCH002.1-RESEARCH002.10(2000).
[4]
NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS GLY-299 AND ILE-399.
PubMed=10835634; DOI=10.1038/76048;
Arbour N.C., Lorenz E., Schutte B.C., Zabner J., Kline J.N., Jones M.,
Frees K., Watt J.L., Schwartz D.A.;
"TLR4 mutations are associated with endotoxin hyporesponsiveness in
humans.";
Nat. Genet. 25:187-191(2000).
[5]
NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
PubMed=18810425; DOI=10.1007/s00251-008-0332-0;
Nakajima T., Ohtani H., Satta Y., Uno Y., Akari H., Ishida T.,
Kimura A.;
"Natural selection in the TLR-related genes in the course of primate
evolution.";
Immunogenetics 60:727-735(2008).
[6]
NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS GLY-299 AND ILE-399.
PubMed=19924287; DOI=10.1371/journal.pone.0007803;
Georgel P., Macquin C., Bahram S.;
"The heterogeneous allelic repertoire of human Toll-Like receptor
(TLR) genes.";
PLoS ONE 4:E7803-E7803(2009).
[7]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 2 AND 3).
TISSUE=Hippocampus, Kidney, and Uterus;
PubMed=14702039; DOI=10.1038/ng1285;
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
"Complete sequencing and characterization of 21,243 full-length human
cDNAs.";
Nat. Genet. 36:40-45(2004).
[8]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
PubMed=15164053; DOI=10.1038/nature02465;
Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E.,
Howe K.L., Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C.,
Ainscough R., Almeida J.P., Ambrose K.D., Ashwell R.I.S.,
Babbage A.K., Babbage S., Bagguley C.L., Bailey J., Banerjee R.,
Barker D.J., Barlow K.F., Bates K., Beasley H., Beasley O., Bird C.P.,
Bray-Allen S., Brown A.J., Brown J.Y., Burford D., Burrill W.,
Burton J., Carder C., Carter N.P., Chapman J.C., Chen Y., Clarke G.,
Clark S.Y., Clee C.M., Clegg S., Collier R.E., Corby N., Crosier M.,
Cummings A.T., Davies J., Dhami P., Dunn M., Dutta I., Dyer L.W.,
Earthrowl M.E., Faulkner L., Fleming C.J., Frankish A.,
Frankland J.A., French L., Fricker D.G., Garner P., Garnett J.,
Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S.,
Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E.,
Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D.,
Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E.,
Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K.,
Kimberley A.M., King A., Knights A., Laird G.K., Langford C.,
Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M.,
Lovell J., Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S.,
McLay K.E., McMurray A., Milne S., Nickerson T., Nisbett J.,
Nordsiek G., Pearce A.V., Peck A.I., Porter K.M., Pandian R.,
Pelan S., Phillimore B., Povey S., Ramsey Y., Rand V., Scharfe M.,
Sehra H.K., Shownkeen R., Sims S.K., Skuce C.D., Smith M.,
Steward C.A., Swarbreck D., Sycamore N., Tester J., Thorpe A.,
Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., West A.P.,
Whitehead S.L., Willey D.L., Williams S.A., Wilming L., Wray P.W.,
Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M.,
Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S.,
Rogers J., Dunham I.;
"DNA sequence and analysis of human chromosome 9.";
Nature 429:369-374(2004).
[9]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
Venter J.C.;
Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
[10]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
TISSUE=Cerebellum;
PubMed=15489334; DOI=10.1101/gr.2596504;
The MGC Project Team;
"The status, quality, and expansion of the NIH full-length cDNA
project: the Mammalian Gene Collection (MGC).";
Genome Res. 14:2121-2127(2004).
[11]
NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-86.
Liu Z., Li N., Wang J., Xiao W.;
Submitted (MAR-2007) to the EMBL/GenBank/DDBJ databases.
[12]
PROTEIN SEQUENCE OF 24-38.
PubMed=15340161; DOI=10.1110/ps.04682504;
Zhang Z., Henzel W.J.;
"Signal peptide prediction based on analysis of experimentally
verified cleavage sites.";
Protein Sci. 13:2819-2824(2004).
[13]
MUTAGENESIS OF GLU-697; ARG-710; ASP-711 AND PRO-714.
PubMed=11081518; DOI=10.1038/35040600;
Xu Y., Tao X., Shen B., Horng T., Medzhitov R., Manley J.L., Tong L.;
"Structural basis for signal transduction by the Toll/interleukin-1
receptor domains.";
Nature 408:111-115(2000).
[14]
SUBUNIT, AND SUBCELLULAR LOCATION.
PubMed=11274165; DOI=10.1074/jbc.M009164200;
da Silva Correia J., Soldau K., Christen U., Tobias P.S.,
Ulevitch R.J.;
"Lipopolysaccharide is in close proximity to each of the proteins in
its membrane receptor complex. transfer from CD14 to TLR4 and MD-2.";
J. Biol. Chem. 276:21129-21135(2001).
[15]
GLYCOSYLATION AT ASN-35; ASN-173; ASN-205; ASN-282; ASN-309; ASN-497;
ASN-526; ASN-575 AND ASN-624, AND MUTAGENESIS OF ASN-526 AND ASN-575.
PubMed=11706042; DOI=10.1074/jbc.M109910200;
da Silva Correia J., Ulevitch R.J.;
"MD-2 and TLR4 N-linked glycosylations are important for a functional
lipopolysaccharide receptor.";
J. Biol. Chem. 277:1845-1854(2002).
[16]
INTERACTION WITH TICAM2.
PubMed=14519765; DOI=10.1074/jbc.M305820200;
Oshiumi H., Sasai M., Shida K., Fujita T., Matsumoto M., Seya T.;
"TIR-containing adapter molecule (TICAM)-2, a bridging adapter
recruiting to toll-like receptor 4 TICAM-1 that induces interferon-
beta.";
J. Biol. Chem. 278:49751-49762(2003).
[17]
INTERACTION WITH NOX4.
PubMed=15356101; DOI=10.4049/jimmunol.173.6.3589;
Park H.S., Jung H.Y., Park E.Y., Kim J., Lee W.J., Bae Y.S.;
"Direct interaction of TLR4 with NAD(P)H oxidase 4 isozyme is
essential for lipopolysaccharide-induced production of reactive oxygen
species and activation of NF-kappa B.";
J. Immunol. 173:3589-3593(2004).
[18]
FUNCTION.
PubMed=15809303; DOI=10.1074/jbc.M411379200;
Bulut Y., Michelsen K.S., Hayrapetian L., Naiki Y., Spallek R.,
Singh M., Arditi M.;
"Mycobacterium tuberculosis heat shock proteins use diverse Toll-like
receptor pathways to activate pro-inflammatory signals.";
J. Biol. Chem. 280:20961-20967(2005).
[19]
FUNCTION.
TISSUE=Monocyte;
PubMed=16622205; DOI=10.1128/IAI.74.5.2686-2696.2006;
Jung S.B., Yang C.S., Lee J.S., Shin A.R., Jung S.S., Son J.W.,
Harding C.V., Kim H.J., Park J.K., Paik T.H., Song C.H., Jo E.K.;
"The mycobacterial 38-kilodalton glycolipoprotein antigen activates
the mitogen-activated protein kinase pathway and release of
proinflammatory cytokines through Toll-like receptors 2 and 4 in human
monocytes.";
Infect. Immun. 74:2686-2696(2006).
[20]
FUNCTION.
PubMed=17478729; DOI=10.1161/CIRCRESAHA.106.142851;
Kim F., Pham M., Luttrell I., Bannerman D.D., Tupper J., Thaler J.,
Hawn T.R., Raines E.W., Schwartz M.W.;
"Toll-like receptor-4 mediates vascular inflammation and insulin
resistance in diet-induced obesity.";
Circ. Res. 100:1589-1596(2007).
[21]
INTERACTION WITH HSP90B1.
PubMed=20865800; DOI=10.1038/ncomms1070;
Liu B., Yang Y., Qiu Z., Staron M., Hong F., Li Y., Wu S., Li Y.,
Hao B., Bona R., Han D., Li Z.;
"Folding of Toll-like receptors by the HSP90 paralogue gp96 requires a
substrate-specific cochaperone.";
Nat. Commun. 1:79-79(2010).
[22]
ERRATUM.
Liu B., Yang Y., Qiu Z., Staron M., Hong F., Li Y., Wu S., Li Y.,
Hao B., Bona R., Han D., Li Z.;
Nat. Commun. 3:653-653(2012).
[23]
FUNCTION, INTERACTION WITH CD36 AND TLR6, AND SUBCELLULAR LOCATION.
PubMed=20037584; DOI=10.1038/ni.1836;
Stewart C.R., Stuart L.M., Wilkinson K., van Gils J.M., Deng J.,
Halle A., Rayner K.J., Boyer L., Zhong R., Frazier W.A.,
Lacy-Hulbert A., El Khoury J., Golenbock D.T., Moore K.J.;
"CD36 ligands promote sterile inflammation through assembly of a Toll-
like receptor 4 and 6 heterodimer.";
Nat. Immunol. 11:155-161(2010).
[24]
FUNCTION, MUTAGENESIS OF HIS-431; HIS-456 AND HIS-458, AND INVOLVEMENT
IN CONTACT ALLERGY TO NICKEL.
PubMed=20711192; DOI=10.1038/ni.1919;
Schmidt M., Raghavan B., Mueller V., Vogl T., Fejer G., Tchaptchet S.,
Keck S., Kalis C., Nielsen P.J., Galanos C., Roth J., Skerra A.,
Martin S.F., Freudenberg M.A., Goebeler M.;
"Crucial role for human Toll-like receptor 4 in the development of
contact allergy to nickel.";
Nat. Immunol. 11:814-819(2010).
[25]
INTERACTION WITH MAP3K21.
PubMed=21602844; DOI=10.1038/cmi.2011.15;
Seit-Nebi A., Cheng W., Xu H., Han J.;
"MLK4 has negative effect on TLR4 signaling.";
Cell. Mol. Immunol. 9:27-33(2012).
[26]
FUNCTION.
PubMed=23880187; DOI=10.1016/j.atherosclerosis.2013.05.011;
Estruch M., Bancells C., Beloki L., Sanchez-Quesada J.L.,
Ordonez-Llanos J., Benitez S.;
"CD14 and TLR4 mediate cytokine release promoted by electronegative
LDL in monocytes.";
Atherosclerosis 229:356-362(2013).
[27]
INTERACTION WITH TICAM1 AND TICAM2.
PubMed=25736436; DOI=10.15252/embr.201439637;
Hu Y.H., Zhang Y., Jiang L.Q., Wang S., Lei C.Q., Sun M.S., Shu H.B.,
Liu Y.;
"WDFY1 mediates TLR3/4 signaling by recruiting TRIF.";
EMBO Rep. 16:447-455(2015).
[28]
X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 27-228 IN COMPLEX WITH LY96,
SUBUNIT, DISULFIDE BONDS, AND GLYCOSYLATION AT ASN-35; ASN-173 AND
ASN-205.
PubMed=17803912; DOI=10.1016/j.cell.2007.08.002;
Kim H.M., Park B.S., Kim J.-I., Kim S.E., Lee J., Oh S.C.,
Enkhbayar P., Matsushima N., Lee H., Yoo O.J., Lee J.-O.;
"Crystal structure of the TLR4-MD-2 complex with bound endotoxin
antagonist Eritoran.";
Cell 130:906-917(2007).
[29]
X-RAY CRYSTALLOGRAPHY (3.1 ANGSTROMS) OF 27-631 IN COMPLEX WITH LY96
AND LIPOPOLYSACCHARIDE, SUBUNIT, DISULFIDE BONDS, AND GLYCOSYLATION AT
ASN-173; ASN-205; ASN-497 AND ASN-526 AND ASN-575.
PubMed=19252480; DOI=10.1038/nature07830;
Park B.S., Song D.H., Kim H.M., Choi B.-S., Lee H., Lee J.-O.;
"The structural basis of lipopolysaccharide recognition by the TLR4-
MD-2 complex.";
Nature 458:1191-1195(2009).
[30]
X-RAY CRYSTALLOGRAPHY (2.37 ANGSTROMS) OF 28-228, GLYCOSYLATION AT
ASN-35 AND ASN-173, AND DISULFIDE BONDS.
PubMed=22363519; DOI=10.1371/journal.pone.0030929;
Han J., Kim H.J., Lee S.C., Hong S., Park K., Jeon Y.H., Kim D.,
Cheong H.K., Kim H.S.;
"Structure-based rational design of a Toll-like receptor 4 (TLR4)
decoy receptor with high binding affinity for a target protein.";
PLoS ONE 7:E30929-E30929(2012).
[31]
VARIANTS ARG-188; SER-246; GLY-299; SER-329; ILE-399; LEU-443;
LYS-474; HIS-510; ARG-694; HIS-763 AND HIS-834.
PubMed=11514453;
Smirnova I., Hamblin M.T., McBride C., Beutler B., Di Rienzo A.;
"Excess of rare amino acid polymorphisms in the Toll-like receptor 4
in humans.";
Genetics 158:1657-1664(2001).
[32]
VARIANT GLY-299, AND ASSOCIATION WITH ARMD SUSCEPTIBILITY.
PubMed=15829498; DOI=10.1093/hmg/ddi154;
Zareparsi S., Buraczynska M., Branham K.E.H., Shah S., Eng D., Li M.,
Pawar H., Yashar B.M., Moroi S.E., Lichter P.R., Petty H.R.,
Richards J.E., Abecasis G.R., Elner V.M., Swaroop A.;
"Toll-like receptor 4 variant D299G is associated with susceptibility
to age-related macular degeneration.";
Hum. Mol. Genet. 14:1449-1455(2005).
[33]
VARIANT ASP-287.
PubMed=25787250; DOI=10.1073/pnas.1503696112;
Cromer M.K., Choi M., Nelson-Williams C., Fonseca A.L., Kunstman J.W.,
Korah R.M., Overton J.D., Mane S., Kenney B., Malchoff C.D.,
Stalberg P., Akerstroem G., Westin G., Hellman P., Carling T.,
Bjoerklund P., Lifton R.P.;
"Neomorphic effects of recurrent somatic mutations in Yin Yang 1 in
insulin-producing adenomas.";
Proc. Natl. Acad. Sci. U.S.A. 112:4062-4067(2015).
-!- FUNCTION: Cooperates with LY96 and CD14 to mediate the innate
immune response to bacterial lipopolysaccharide (LPS). Acts via
MYD88, TIRAP and TRAF6, leading to NF-kappa-B activation, cytokine
secretion and the inflammatory response (PubMed:9237759,
PubMed:10835634). Also involved in LPS-independent inflammatory
responses triggered by free fatty acids, such as palmitate, and
Ni(2+). Responses triggered by Ni(2+) require non-conserved
histidines and are, therefore, species-specific (PubMed:20711192).
Both M.tuberculosis HSP70 (dnaK) and HSP65 (groEL-2) act via this
protein to stimulate NF-kappa-B expression (PubMed:15809303). In
complex with TLR6, promotes sterile inflammation in
monocytes/macrophages in response to oxidized low-density
lipoprotein (oxLDL) or amyloid-beta 42. In this context, the
initial signal is provided by oxLDL- or amyloid-beta 42-binding to
CD36. This event induces the formation of a heterodimer of TLR4
and TLR6, which is rapidly internalized and triggers inflammatory
response, leading to the NF-kappa-B-dependent production of CXCL1,
CXCL2 and CCL9 cytokines, via MYD88 signaling pathway, and CCL5
cytokine, via TICAM1 signaling pathway, as well as IL1B secretion.
Binds electronegative LDL (LDL(-)) and mediates the cytokine
release induced by LDL(-) (PubMed:23880187). Stimulation of
monocytes in vitro with M.tuberculosis PstS1 induces p38 MAPK and
ERK1/2 activation primarily via TLR2, but also partially via this
receptor (PubMed:16622205). {ECO:0000269|PubMed:10835634,
ECO:0000269|PubMed:15809303, ECO:0000269|PubMed:16622205,
ECO:0000269|PubMed:17478729, ECO:0000269|PubMed:20037584,
ECO:0000269|PubMed:20711192, ECO:0000269|PubMed:23880187,
ECO:0000269|PubMed:9237759}.
-!- SUBUNIT: Belongs to the lipopolysaccharide (LPS) receptor, a
multi-protein complex containing at least CD14, LY96 and TLR4
(PubMed:11274165). Binding to bacterial LPS leads to
homodimerization. Interacts with LY96 via the extracellular domain
(PubMed:17803912, PubMed:19252480). Interacts with MYD88 and TIRAP
via their respective TIR domains (By similarity). Interacts with
TICAM2 (PubMed:14519765, PubMed:25736436). Interacts with NOX4
(PubMed:15356101). Interacts with CNPY3 (By similarity). Interacts
with HSP90B1. The interaction with both CNPY3 and HSP90B1 is
required for proper folding in the endoplasmic reticulum.
Interacts with MAP3K21; this interaction leads to negative
regulation of TLR4 signaling (PubMed:21602844). Interacts with
CD36, following CD36 stimulation by oxLDL or amyloid-beta 42, and
forms a heterodimer with TLR6 (PubMed:20037584). The trimeric
complex is internalized and triggers inflammatory response. LYN
kinase activity facilitates TLR4-TLR6 heterodimerization and
signal initiation. Interacts with TICAM1 in response to LPS in a
WDFY1-dependent manner (PubMed:25736436). Interacts with WDFY1 in
response to LPS (By similarity). Interacts with SMPDL3B (By
similarity). Interacts with CEACAM1; upon lipopolysaccharide
stimulation, forms a complex including TLR4 and the phosphorylated
form of SYK and CEACAM1, which in turn, recruits PTPN6 that
dephosphorylates SYK, reducing the production of reactive oxygen
species (ROS) and lysosome disruption, which in turn, reduces the
activity of the inflammasome (By similarity).
{ECO:0000250|UniProtKB:Q9QUK6, ECO:0000269|PubMed:11274165,
ECO:0000269|PubMed:14519765, ECO:0000269|PubMed:15356101,
ECO:0000269|PubMed:17803912, ECO:0000269|PubMed:19252480,
ECO:0000269|PubMed:20037584, ECO:0000269|PubMed:20865800,
ECO:0000269|PubMed:21602844, ECO:0000269|PubMed:25736436}.
-!- INTERACTION:
O76552:- (xeno); NbExp=3; IntAct=EBI-528701, EBI-3870694;
Q9Y6Y9:LY96; NbExp=5; IntAct=EBI-528701, EBI-1539247;
Q99836:MYD88; NbExp=2; IntAct=EBI-528701, EBI-447677;
Q9NPH5:NOX4; NbExp=4; IntAct=EBI-528701, EBI-11301574;
Q86XR7:TICAM2; NbExp=2; IntAct=EBI-528701, EBI-525927;
P58753:TIRAP; NbExp=5; IntAct=EBI-528701, EBI-528644;
Q9Y2C9:TLR6; NbExp=2; IntAct=EBI-528701, EBI-13940779;
-!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:11274165,
ECO:0000269|PubMed:20037584, ECO:0000269|PubMed:9237759}; Single-
pass type I membrane protein {ECO:0000269|PubMed:11274165}.
Note=Upon complex formation with CD36 and TLR6, internalized
through dynamin-dependent endocytosis.
{ECO:0000269|PubMed:20037584}.
-!- ALTERNATIVE PRODUCTS:
Event=Alternative splicing; Named isoforms=3;
Name=1;
IsoId=O00206-1; Sequence=Displayed;
Name=2;
IsoId=O00206-2; Sequence=VSP_035794;
Name=3;
IsoId=O00206-3; Sequence=VSP_035793;
Note=No experimental confirmation available.;
-!- TISSUE SPECIFICITY: Highly expressed in placenta, spleen and
peripheral blood leukocytes. Detected in monocytes, macrophages,
dendritic cells and several types of T-cells.
{ECO:0000269|PubMed:9237759, ECO:0000269|PubMed:9435236}.
-!- DOMAIN: The TIR domain mediates interaction with NOX4.
{ECO:0000269|PubMed:15356101}.
-!- PTM: N-glycosylated. Glycosylation of Asn-526 and Asn-575 seems to
be necessary for the expression of TLR4 on the cell surface and
the LPS-response. Likewise, mutants lacking two or more of the
other N-glycosylation sites were deficient in interaction with
LPS. {ECO:0000269|PubMed:11706042, ECO:0000269|PubMed:17803912,
ECO:0000269|PubMed:19252480, ECO:0000269|PubMed:22363519}.
-!- POLYMORPHISM: Allele TLR4*B (Gly-299, Ile-399) is associated with
a blunted response to inhaled LPS. {ECO:0000269|PubMed:10835634}.
-!- MISCELLANEOUS: His-456 and His-458 are found in TLR4 of human and
several other primate species and may be responsible for
inflammatory responses triggered by nickel (Ni(2+)). Ni(2+) may
cross-link the two receptor monomers through specific histidines,
triggering the formation of a dimer that structurally resembles
that induced by LPS. This process may be the basis for the
development of contact allergy to Ni(2+). A mouse model of contact
allergy to Ni(2+) in which TLR4-deficient mice expresses human
TLR4 has been proposed. {ECO:0000305|PubMed:20711192}.
-!- SIMILARITY: Belongs to the Toll-like receptor family.
{ECO:0000305}.
-!- WEB RESOURCE: Name=Protein Spotlight; Note=Zips, necklaces and
mobile telephones - Issue 134 of December 2011;
URL="http://web.expasy.org/spotlight/back_issues/134";
-----------------------------------------------------------------------
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Distributed under the Creative Commons Attribution-NoDerivs License
-----------------------------------------------------------------------
EMBL; U93091; AAC80227.1; -; mRNA.
EMBL; AB445638; BAG55035.1; -; mRNA.
EMBL; DQ018107; AAY82267.1; -; Genomic_DNA.
EMBL; DQ018108; AAY82268.1; -; Genomic_DNA.
EMBL; DQ018109; AAY82269.1; -; Genomic_DNA.
EMBL; AK290053; BAF82742.1; -; mRNA.
EMBL; AK293068; BAF85757.1; -; mRNA.
EMBL; AK303730; BAG64706.1; -; mRNA.
EMBL; AL160272; CAH72618.1; -; Genomic_DNA.
EMBL; AL160272; CAH72619.1; -; Genomic_DNA.
EMBL; CH471090; EAW87448.1; -; Genomic_DNA.
EMBL; CH471090; EAW87451.1; -; Genomic_DNA.
EMBL; BC117422; AAI17423.1; -; mRNA.
EMBL; EF535831; ABU41662.1; -; Genomic_DNA.
EMBL; EF535832; ABU41663.1; -; Genomic_DNA.
EMBL; EF535833; ABU41664.1; -; Genomic_DNA.
EMBL; AF177765; AAF05316.1; -; Genomic_DNA.
EMBL; AF177766; AAF07823.1; -; Genomic_DNA.
EMBL; AF172171; AAF89753.1; -; Genomic_DNA.
EMBL; AF172169; AAF89753.1; JOINED; Genomic_DNA.
EMBL; AF172170; AAF89753.1; JOINED; Genomic_DNA.
EMBL; U88880; AAC34135.1; -; mRNA.
CCDS; CCDS6818.1; -. [O00206-1]
RefSeq; NP_003257.1; NM_003266.3. [O00206-2]
RefSeq; NP_612564.1; NM_138554.4. [O00206-1]
RefSeq; NP_612567.1; NM_138557.2. [O00206-3]
UniGene; Hs.174312; -.
PDB; 2Z62; X-ray; 1.70 A; A=27-228.
PDB; 2Z63; X-ray; 2.00 A; A=27-527.
PDB; 2Z65; X-ray; 2.70 A; A/B=27-228.
PDB; 2Z66; X-ray; 1.90 A; A/B/C/D=381-627.
PDB; 3FXI; X-ray; 3.10 A; A/B=27-631.
PDB; 3UL7; X-ray; 2.37 A; A=28-226.
PDB; 3UL8; X-ray; 2.50 A; A=27-228.
PDB; 3UL9; X-ray; 2.45 A; A=28-228.
PDB; 3ULA; X-ray; 3.60 A; A/C=27-228.
PDB; 4G8A; X-ray; 2.40 A; A/B=23-629.
PDBsum; 2Z62; -.
PDBsum; 2Z63; -.
PDBsum; 2Z65; -.
PDBsum; 2Z66; -.
PDBsum; 3FXI; -.
PDBsum; 3UL7; -.
PDBsum; 3UL8; -.
PDBsum; 3UL9; -.
PDBsum; 3ULA; -.
PDBsum; 4G8A; -.
ProteinModelPortal; O00206; -.
SMR; O00206; -.
BioGrid; 112954; 31.
CORUM; O00206; -.
DIP; DIP-34769N; -.
ELM; O00206; -.
IntAct; O00206; 20.
MINT; MINT-3981856; -.
STRING; 9606.ENSP00000363089; -.
BindingDB; O00206; -.
ChEMBL; CHEMBL5255; -.
DrugBank; DB02767; 3-Hydroxy-Myristic Acid.
DrugBank; DB04933; Eritoran.
DrugBank; DB03017; Lauric Acid.
DrugBank; DB08231; MYRISTIC ACID.
DrugBank; DB01183; Naloxone.
DrugBank; DB05475; SCV-07.
iPTMnet; O00206; -.
PhosphoSitePlus; O00206; -.
BioMuta; TLR4; -.
EPD; O00206; -.
PaxDb; O00206; -.
PeptideAtlas; O00206; -.
PRIDE; O00206; -.
Ensembl; ENST00000355622; ENSP00000363089; ENSG00000136869. [O00206-1]
Ensembl; ENST00000394487; ENSP00000377997; ENSG00000136869. [O00206-2]
GeneID; 7099; -.
KEGG; hsa:7099; -.
UCSC; uc004bjz.5; human. [O00206-1]
CTD; 7099; -.
DisGeNET; 7099; -.
EuPathDB; HostDB:ENSG00000136869.13; -.
GeneCards; TLR4; -.
HGNC; HGNC:11850; TLR4.
HPA; CAB004025; -.
HPA; HPA049174; -.
MalaCards; TLR4; -.
MIM; 603030; gene.
neXtProt; NX_O00206; -.
OpenTargets; ENSG00000136869; -.
Orphanet; 117; Behcet disease.
PharmGKB; PA36552; -.
eggNOG; KOG4641; Eukaryota.
eggNOG; COG4886; LUCA.
GeneTree; ENSGT00760000119006; -.
HOVERGEN; HBG018823; -.
InParanoid; O00206; -.
KO; K10160; -.
OMA; EDWVRNE; -.
OrthoDB; EOG091G01RC; -.
PhylomeDB; O00206; -.
TreeFam; TF351113; -.
Reactome; R-HSA-1236974; ER-Phagosome pathway.
Reactome; R-HSA-140534; Ligand-dependent caspase activation.
Reactome; R-HSA-166016; Toll Like Receptor 4 (TLR4) Cascade.
Reactome; R-HSA-166058; MyD88:Mal cascade initiated on plasma membrane.
Reactome; R-HSA-166166; MyD88-independent TLR3/TLR4 cascade.
Reactome; R-HSA-2562578; TRIF-mediated programmed cell death.
Reactome; R-HSA-5602498; MyD88 deficiency (TLR2/4).
Reactome; R-HSA-5603041; IRAK4 deficiency (TLR2/4).
Reactome; R-HSA-5686938; Regulation of TLR by endogenous ligand.
Reactome; R-HSA-936964; Activation of IRF3/IRF7 mediated by TBK1/IKK epsilon.
Reactome; R-HSA-937041; IKK complex recruitment mediated by RIP1.
Reactome; R-HSA-937072; TRAF6 mediated induction of TAK1 complex.
Reactome; R-HSA-975163; IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation.
SignaLink; O00206; -.
SIGNOR; O00206; -.
EvolutionaryTrace; O00206; -.
GeneWiki; TLR_4; -.
GenomeRNAi; 7099; -.
PRO; PR:O00206; -.
Proteomes; UP000005640; Chromosome 9.
Bgee; ENSG00000136869; -.
Genevisible; O00206; HS.
GO; GO:0009986; C:cell surface; IDA:UniProtKB.
GO; GO:0005737; C:cytoplasm; IDA:BHF-UCL.
GO; GO:0010008; C:endosome membrane; TAS:Reactome.
GO; GO:0009897; C:external side of plasma membrane; IDA:BHF-UCL.
GO; GO:0005887; C:integral component of plasma membrane; IDA:UniProtKB.
GO; GO:0005622; C:intracellular; IPI:ARUK-UCL.
GO; GO:0031226; C:intrinsic component of plasma membrane; IDA:UniProtKB.
GO; GO:0046696; C:lipopolysaccharide receptor complex; IDA:UniProtKB.
GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB.
GO; GO:0005886; C:plasma membrane; IDA:BHF-UCL.
GO; GO:0043235; C:receptor complex; IPI:ARUK-UCL.
GO; GO:0001530; F:lipopolysaccharide binding; IMP:BHF-UCL.
GO; GO:0001875; F:lipopolysaccharide receptor activity; IDA:UniProtKB.
GO; GO:0046982; F:protein heterodimerization activity; IPI:ARUK-UCL.
GO; GO:0004872; F:receptor activity; TAS:ProtInc.
GO; GO:0005102; F:receptor binding; IPI:ARUK-UCL.
GO; GO:0004888; F:transmembrane signaling receptor activity; NAS:UniProtKB.
GO; GO:0000187; P:activation of MAPK activity; ISS:BHF-UCL.
GO; GO:0097190; P:apoptotic signaling pathway; TAS:Reactome.
GO; GO:0014002; P:astrocyte development; IEA:Ensembl.
GO; GO:0002322; P:B cell proliferation involved in immune response; IEA:Ensembl.
GO; GO:1904646; P:cellular response to amyloid-beta; IGI:ARUK-UCL.
GO; GO:0071222; P:cellular response to lipopolysaccharide; IDA:UniProtKB.
GO; GO:0071223; P:cellular response to lipoteichoic acid; IEA:Ensembl.
GO; GO:0071260; P:cellular response to mechanical stimulus; IEP:UniProtKB.
GO; GO:0140052; P:cellular response to oxidised low-density lipoprotein particle stimulus; ISS:ARUK-UCL.
GO; GO:0042742; P:defense response to bacterium; TAS:UniProtKB.
GO; GO:0050829; P:defense response to Gram-negative bacterium; IBA:GO_Central.
GO; GO:0016046; P:detection of fungus; NAS:UniProtKB.
GO; GO:0032497; P:detection of lipopolysaccharide; IDA:UniProtKB.
GO; GO:0007249; P:I-kappaB kinase/NF-kappaB signaling; TAS:Reactome.
GO; GO:0007252; P:I-kappaB phosphorylation; IDA:BHF-UCL.
GO; GO:0006955; P:immune response; TAS:ProtInc.
GO; GO:0006954; P:inflammatory response; IBA:GO_Central.
GO; GO:0045087; P:innate immune response; TAS:BHF-UCL.
GO; GO:0032609; P:interferon-gamma production; IEA:Ensembl.
GO; GO:0050702; P:interleukin-1 beta secretion; ISS:UniProtKB.
GO; GO:0060729; P:intestinal epithelial structure maintenance; ISS:BHF-UCL.
GO; GO:0031663; P:lipopolysaccharide-mediated signaling pathway; IGI:MGI.
GO; GO:0042116; P:macrophage activation; IMP:UniProtKB.
GO; GO:0002755; P:MyD88-dependent toll-like receptor signaling pathway; ISS:ARUK-UCL.
GO; GO:0002756; P:MyD88-independent toll-like receptor signaling pathway; TAS:Reactome.
GO; GO:0070266; P:necroptotic process; TAS:Reactome.
GO; GO:0070373; P:negative regulation of ERK1 and ERK2 cascade; ISS:BHF-UCL.
GO; GO:0032689; P:negative regulation of interferon-gamma production; ISS:BHF-UCL.
GO; GO:0032700; P:negative regulation of interleukin-17 production; ISS:BHF-UCL.
GO; GO:0032707; P:negative regulation of interleukin-23 production; ISS:BHF-UCL.
GO; GO:0032715; P:negative regulation of interleukin-6 production; ISS:BHF-UCL.
GO; GO:0034128; P:negative regulation of MyD88-independent toll-like receptor signaling pathway; TAS:Reactome.
GO; GO:0045671; P:negative regulation of osteoclast differentiation; NAS:UniProtKB.
GO; GO:0032720; P:negative regulation of tumor necrosis factor production; ISS:BHF-UCL.
GO; GO:0002537; P:nitric oxide production involved in inflammatory response; IEA:Ensembl.
GO; GO:0030890; P:positive regulation of B cell proliferation; IEA:Ensembl.
GO; GO:0032722; P:positive regulation of chemokine production; IDA:BHF-UCL.
GO; GO:1900017; P:positive regulation of cytokine production involved in inflammatory response; ISS:ARUK-UCL.
GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IEA:Ensembl.
GO; GO:0010628; P:positive regulation of gene expression; IMP:UniProtKB.
GO; GO:0050729; P:positive regulation of inflammatory response; IC:BHF-UCL.
GO; GO:0032727; P:positive regulation of interferon-alpha production; ISS:BHF-UCL.
GO; GO:0045359; P:positive regulation of interferon-beta biosynthetic process; IEA:Ensembl.
GO; GO:0032728; P:positive regulation of interferon-beta production; ISS:BHF-UCL.
GO; GO:0032729; P:positive regulation of interferon-gamma production; ISS:BHF-UCL.
GO; GO:0050718; P:positive regulation of interleukin-1 beta secretion; IDA:UniProtKB.
GO; GO:0032732; P:positive regulation of interleukin-1 production; ISS:BHF-UCL.
GO; GO:0032733; P:positive regulation of interleukin-10 production; ISS:BHF-UCL.
GO; GO:0045084; P:positive regulation of interleukin-12 biosynthetic process; IDA:UniProtKB.
GO; GO:0032735; P:positive regulation of interleukin-12 production; ISS:BHF-UCL.
GO; GO:0032755; P:positive regulation of interleukin-6 production; IDA:BHF-UCL.
GO; GO:0045416; P:positive regulation of interleukin-8 biosynthetic process; IDA:UniProtKB.
GO; GO:0032757; P:positive regulation of interleukin-8 production; IDA:BHF-UCL.
GO; GO:0046330; P:positive regulation of JNK cascade; IEA:Ensembl.
GO; GO:0043032; P:positive regulation of macrophage activation; ISS:ARUK-UCL.
GO; GO:0060907; P:positive regulation of macrophage cytokine production; IEA:Ensembl.
GO; GO:0045348; P:positive regulation of MHC class II biosynthetic process; IEA:Ensembl.
GO; GO:0042346; P:positive regulation of NF-kappaB import into nucleus; IDA:BHF-UCL.
GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IDA:MGI.
GO; GO:0045429; P:positive regulation of nitric oxide biosynthetic process; ISS:ARUK-UCL.
GO; GO:0051770; P:positive regulation of nitric-oxide synthase biosynthetic process; ISS:BHF-UCL.
GO; GO:1900227; P:positive regulation of NLRP3 inflammasome complex assembly; ISS:UniProtKB.
GO; GO:0070430; P:positive regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway; IEA:Ensembl.
GO; GO:0070434; P:positive regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway; IEA:Ensembl.
GO; GO:1903223; P:positive regulation of oxidative stress-induced neuron death; ISS:ARUK-UCL.
GO; GO:0010572; P:positive regulation of platelet activation; ISS:BHF-UCL.
GO; GO:1903428; P:positive regulation of reactive oxygen species biosynthetic process; ISS:ARUK-UCL.
GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; ISS:BHF-UCL.
GO; GO:0042535; P:positive regulation of tumor necrosis factor biosynthetic process; IDA:UniProtKB.
GO; GO:0032760; P:positive regulation of tumor necrosis factor production; ISS:BHF-UCL.
GO; GO:0002730; P:regulation of dendritic cell cytokine production; IEA:Ensembl.
GO; GO:0032496; P:response to lipopolysaccharide; IDA:MGI.
GO; GO:0042088; P:T-helper 1 type immune response; NAS:UniProtKB.
GO; GO:0034142; P:toll-like receptor 4 signaling pathway; TAS:Reactome.
GO; GO:0002224; P:toll-like receptor signaling pathway; IBA:GO_Central.
GO; GO:0035666; P:TRIF-dependent toll-like receptor signaling pathway; ISS:ARUK-UCL.
Gene3D; 3.40.50.10140; -; 1.
Gene3D; 3.80.10.10; -; 3.
InterPro; IPR000483; Cys-rich_flank_reg_C.
InterPro; IPR032675; L_dom-like.
InterPro; IPR001611; Leu-rich_rpt.
InterPro; IPR003591; Leu-rich_rpt_typical-subtyp.
InterPro; IPR000157; TIR_dom.
InterPro; IPR027168; TLR4.
PANTHER; PTHR24365:SF494; PTHR24365:SF494; 1.
Pfam; PF13516; LRR_6; 1.
Pfam; PF13855; LRR_8; 3.
Pfam; PF01582; TIR; 1.
SMART; SM00369; LRR_TYP; 11.
SMART; SM00082; LRRCT; 1.
SMART; SM00255; TIR; 1.
SUPFAM; SSF52200; SSF52200; 1.
PROSITE; PS51450; LRR; 11.
PROSITE; PS50104; TIR; 1.
1: Evidence at protein level;
3D-structure; Age-related macular degeneration; Alternative splicing;
Cell membrane; Complete proteome; Direct protein sequencing;
Disulfide bond; Glycoprotein; Immunity; Inflammatory response;
Innate immunity; Leucine-rich repeat; Membrane; Polymorphism;
Receptor; Reference proteome; Repeat; Signal; Transmembrane;
Transmembrane helix.
SIGNAL 1 23 {ECO:0000269|PubMed:15340161}.
CHAIN 24 839 Toll-like receptor 4.
/FTId=PRO_0000034722.
TOPO_DOM 24 631 Extracellular. {ECO:0000255}.
TRANSMEM 632 652 Helical. {ECO:0000255}.
TOPO_DOM 653 839 Cytoplasmic. {ECO:0000255}.
REPEAT 55 76 LRR 1.
REPEAT 79 100 LRR 2.
REPEAT 103 124 LRR 3.
REPEAT 127 148 LRR 4.
REPEAT 151 172 LRR 5.
REPEAT 176 199 LRR 6.
REPEAT 205 225 LRR 7.
REPEAT 227 247 LRR 8.
REPEAT 331 351 LRR 9.
REPEAT 352 373 LRR 10.
REPEAT 374 394 LRR 11.
REPEAT 400 422 LRR 12.
REPEAT 423 444 LRR 13.
REPEAT 448 456 LRR 14.
REPEAT 472 495 LRR 15.
REPEAT 497 518 LRR 16.
REPEAT 521 542 LRR 17.
REPEAT 545 565 LRR 18.
DOMAIN 579 629 LRRCT.
DOMAIN 672 818 TIR. {ECO:0000255|PROSITE-
ProRule:PRU00204}.
CARBOHYD 35 35 N-linked (GlcNAc...) asparagine.
{ECO:0000269|PubMed:11706042,
ECO:0000269|PubMed:17803912,
ECO:0000269|PubMed:22363519}.
CARBOHYD 173 173 N-linked (GlcNAc...) asparagine.
{ECO:0000269|PubMed:11706042,
ECO:0000269|PubMed:17803912,
ECO:0000269|PubMed:19252480,
ECO:0000269|PubMed:22363519}.
CARBOHYD 205 205 N-linked (GlcNAc...) asparagine.
{ECO:0000269|PubMed:11706042,
ECO:0000269|PubMed:17803912,
ECO:0000269|PubMed:19252480}.
CARBOHYD 282 282 N-linked (GlcNAc...) asparagine.
{ECO:0000269|PubMed:11706042}.
CARBOHYD 309 309 N-linked (GlcNAc...) asparagine.
{ECO:0000269|PubMed:11706042}.
CARBOHYD 497 497 N-linked (GlcNAc...) asparagine.
{ECO:0000269|PubMed:11706042,
ECO:0000269|PubMed:19252480}.
CARBOHYD 526 526 N-linked (GlcNAc...) asparagine.
{ECO:0000269|PubMed:11706042,
ECO:0000269|PubMed:19252480}.
CARBOHYD 575 575 N-linked (GlcNAc...) asparagine.
{ECO:0000269|PubMed:11706042,
ECO:0000269|PubMed:19252480}.
CARBOHYD 624 624 N-linked (GlcNAc...) asparagine.
{ECO:0000269|PubMed:11706042}.
CARBOHYD 630 630 N-linked (GlcNAc...) asparagine.
{ECO:0000255}.
DISULFID 29 40 {ECO:0000269|PubMed:17803912,
ECO:0000269|PubMed:19252480}.
DISULFID 281 306 {ECO:0000269|PubMed:19252480}.
DISULFID 390 391 {ECO:0000269|PubMed:19252480}.
DISULFID 583 609 {ECO:0000269|PubMed:19252480}.
DISULFID 585 627 {ECO:0000269|PubMed:19252480}.
VAR_SEQ 1 200 Missing (in isoform 3).
{ECO:0000303|PubMed:14702039}.
/FTId=VSP_035793.
VAR_SEQ 1 40 Missing (in isoform 2).
{ECO:0000303|PubMed:14702039,
ECO:0000303|PubMed:9435236}.
/FTId=VSP_035794.
VARIANT 175 175 T -> A (in dbSNP:rs16906079).
/FTId=VAR_021977.
VARIANT 188 188 Q -> R (in dbSNP:rs5030713).
{ECO:0000269|PubMed:11514453}.
/FTId=VAR_018729.
VARIANT 246 246 C -> S (in dbSNP:rs5030714).
{ECO:0000269|PubMed:11514453}.
/FTId=VAR_018730.
VARIANT 287 287 E -> D. {ECO:0000269|PubMed:25787250}.
/FTId=VAR_074187.
VARIANT 299 299 D -> G (in allele TLR4*B; reduced LPS-
response; associated with an increased
risk for age-related macular degeneration
in Caucasian carriers; dbSNP:rs4986790).
{ECO:0000269|PubMed:10835634,
ECO:0000269|PubMed:11104518,
ECO:0000269|PubMed:11514453,
ECO:0000269|PubMed:15829498,
ECO:0000269|PubMed:19924287}.
/FTId=VAR_012739.
VARIANT 306 306 C -> W (in dbSNP:rs2770145).
/FTId=VAR_047563.
VARIANT 310 310 V -> G (in dbSNP:rs2770144).
/FTId=VAR_047564.
VARIANT 329 329 N -> S (in dbSNP:rs5030715).
{ECO:0000269|PubMed:11514453}.
/FTId=VAR_018731.
VARIANT 342 342 F -> Y (in dbSNP:rs5031050).
/FTId=VAR_020334.
VARIANT 385 385 L -> F (in dbSNP:rs11536884).
/FTId=VAR_037668.
VARIANT 399 399 T -> I (in allele TLR4*B; reduced LPS-
response; dbSNP:rs4986791).
{ECO:0000269|PubMed:10835634,
ECO:0000269|PubMed:11104518,
ECO:0000269|PubMed:11514453,
ECO:0000269|PubMed:19924287}.
/FTId=VAR_012740.
VARIANT 400 400 S -> N (in dbSNP:rs4987233).
/FTId=VAR_020335.
VARIANT 443 443 F -> L (in dbSNP:rs5030716).
{ECO:0000269|PubMed:11514453}.
/FTId=VAR_018732.
VARIANT 474 474 E -> K (in dbSNP:rs5030718).
{ECO:0000269|PubMed:11514453}.
/FTId=VAR_018733.
VARIANT 510 510 Q -> H (in dbSNP:rs5030719).
{ECO:0000269|PubMed:11514453}.
/FTId=VAR_018734.
VARIANT 694 694 K -> R (in dbSNP:rs5030722).
{ECO:0000269|PubMed:11514453}.
/FTId=VAR_018735.
VARIANT 763 763 R -> H (in dbSNP:rs5030723).
{ECO:0000269|PubMed:11514453}.
/FTId=VAR_018736.
VARIANT 834 834 Q -> H. {ECO:0000269|PubMed:11514453}.
/FTId=VAR_018737.
MUTAGEN 431 431 H->A: Partially diminishes NF-kappa-B
activation induced by Ni(2+). Strongly
reduces NF-kappa-B activation induced by
Ni(2+); when associated with A-456 or A-
458. {ECO:0000269|PubMed:20711192}.
MUTAGEN 456 456 H->A: Partially diminishes NF-kappa-B
activation induced by Ni(2+). Strongly
reduces NF-kappa-B activation induced by
Ni(2+); when associated with A-431.
Suppresses NF-kappa-B activation induced
by Ni(2+); when associated with A-458.
{ECO:0000269|PubMed:20711192}.
MUTAGEN 458 458 H->A: Partially diminishes NF-kappa-B
activation induced by Ni(2+). Strongly
reduces NF-kappa-B activation induced by
Ni(2+); when associated with A-431.
Suppresses NF-kappa-B activation induced
by Ni(2+); when associated with A-456.
{ECO:0000269|PubMed:20711192}.
MUTAGEN 526 526 N->A: Abolishes LPS-response and prevents
the cell surface expression.
{ECO:0000269|PubMed:11706042}.
MUTAGEN 575 575 N->A: Abolishes LPS-response and prevents
the cell surface expression.
{ECO:0000269|PubMed:11706042}.
MUTAGEN 697 697 E->R: Abolishes LPS-response.
{ECO:0000269|PubMed:11081518}.
MUTAGEN 710 710 R->E: Abolishes LPS-response.
{ECO:0000269|PubMed:11081518}.
MUTAGEN 711 711 D->K: Abolishes LPS-response.
{ECO:0000269|PubMed:11081518}.
MUTAGEN 714 714 P->H,R,E: Abolishes MYD88-binding and
LPS-response.
{ECO:0000269|PubMed:11081518}.
CONFLICT 73 73 S -> R (in Ref. 11; ABU41664).
{ECO:0000305}.
CONFLICT 400 400 S -> C (in Ref. 7; BAF82742).
{ECO:0000305}.
CONFLICT 581 581 F -> S (in Ref. 7; BAG64706).
{ECO:0000305}.
STRAND 29 33 {ECO:0000244|PDB:2Z62}.
TURN 34 36 {ECO:0000244|PDB:2Z62}.
STRAND 37 39 {ECO:0000244|PDB:2Z62}.
STRAND 50 52 {ECO:0000244|PDB:2Z62}.
STRAND 58 60 {ECO:0000244|PDB:2Z62}.
TURN 71 76 {ECO:0000244|PDB:2Z62}.
STRAND 81 84 {ECO:0000244|PDB:2Z62}.
TURN 95 100 {ECO:0000244|PDB:2Z62}.
STRAND 106 108 {ECO:0000244|PDB:2Z62}.
STRAND 115 117 {ECO:0000244|PDB:3UL9}.
TURN 119 124 {ECO:0000244|PDB:2Z62}.
STRAND 130 132 {ECO:0000244|PDB:2Z62}.
HELIX 141 143 {ECO:0000244|PDB:3UL8}.
TURN 145 148 {ECO:0000244|PDB:3FXI}.
STRAND 154 156 {ECO:0000244|PDB:2Z62}.
HELIX 169 173 {ECO:0000244|PDB:2Z62}.
STRAND 179 181 {ECO:0000244|PDB:2Z62}.
HELIX 192 195 {ECO:0000244|PDB:2Z62}.
HELIX 196 199 {ECO:0000244|PDB:2Z62}.
STRAND 206 209 {ECO:0000244|PDB:2Z62}.
TURN 220 225 {ECO:0000244|PDB:2Z63}.
STRAND 228 232 {ECO:0000244|PDB:2Z62}.
HELIX 242 248 {ECO:0000244|PDB:2Z63}.
TURN 249 252 {ECO:0000244|PDB:2Z63}.
STRAND 254 262 {ECO:0000244|PDB:2Z63}.
TURN 274 277 {ECO:0000244|PDB:2Z63}.
HELIX 278 282 {ECO:0000244|PDB:2Z63}.
STRAND 283 292 {ECO:0000244|PDB:2Z63}.
STRAND 295 298 {ECO:0000244|PDB:2Z63}.
TURN 301 304 {ECO:0000244|PDB:2Z63}.
HELIX 305 307 {ECO:0000244|PDB:2Z63}.
STRAND 311 317 {ECO:0000244|PDB:2Z63}.
STRAND 319 322 {ECO:0000244|PDB:4G8A}.
HELIX 324 327 {ECO:0000244|PDB:4G8A}.
STRAND 333 339 {ECO:0000244|PDB:2Z63}.
STRAND 341 344 {ECO:0000244|PDB:4G8A}.
STRAND 355 357 {ECO:0000244|PDB:2Z66}.
TURN 368 371 {ECO:0000244|PDB:2Z66}.
STRAND 376 379 {ECO:0000244|PDB:2Z66}.
STRAND 387 392 {ECO:0000244|PDB:2Z66}.
HELIX 393 396 {ECO:0000244|PDB:2Z66}.
STRAND 403 405 {ECO:0000244|PDB:2Z66}.
STRAND 410 419 {ECO:0000244|PDB:2Z66}.
STRAND 426 428 {ECO:0000244|PDB:2Z66}.
STRAND 432 437 {ECO:0000244|PDB:2Z66}.
TURN 438 445 {ECO:0000244|PDB:2Z66}.
STRAND 451 453 {ECO:0000244|PDB:2Z66}.
TURN 464 469 {ECO:0000244|PDB:2Z66}.
STRAND 475 477 {ECO:0000244|PDB:2Z66}.
HELIX 484 486 {ECO:0000244|PDB:2Z66}.
STRAND 500 502 {ECO:0000244|PDB:2Z66}.
TURN 513 518 {ECO:0000244|PDB:2Z66}.
STRAND 524 526 {ECO:0000244|PDB:2Z66}.
HELIX 538 540 {ECO:0000244|PDB:2Z66}.
STRAND 548 550 {ECO:0000244|PDB:2Z66}.
STRAND 560 563 {ECO:0000244|PDB:2Z66}.
STRAND 573 575 {ECO:0000244|PDB:2Z66}.
HELIX 585 587 {ECO:0000244|PDB:2Z66}.
HELIX 588 596 {ECO:0000244|PDB:2Z66}.
HELIX 597 600 {ECO:0000244|PDB:2Z66}.
HELIX 604 606 {ECO:0000244|PDB:2Z66}.
STRAND 608 612 {ECO:0000244|PDB:2Z66}.
HELIX 613 615 {ECO:0000244|PDB:2Z66}.
STRAND 617 619 {ECO:0000244|PDB:3FXI}.
HELIX 620 622 {ECO:0000244|PDB:2Z66}.
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


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