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O00206 (TLR4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 152. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (8) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Toll-like receptor 4
Alternative name(s):
hToll
CD_antigen=CD284
Gene names
Name:TLR4
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length839 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

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. Also involved in LPS-independent inflammatory responses triggered by Ni2+. These responses require non-conserved histidines and are, therefore, species-specific. Ref.18

Subunit structure

Belongs to the lipopolysaccharide (LPS) receptor, a multi-protein complex containing at least CD14, LY96 and TLR4. Binding to bacterial LPS leads to homodimerization. Interacts with LY96 via the extracellular domain. Interacts with MYD88 and TIRAP via their respective TIR domains. Interacts with NOX4. 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 MLK4; this interaction leads to negative regulation of TLR4 signaling. Ref.15 Ref.16 Ref.19

Subcellular location

Membrane; Single-pass type I membrane protein.

Tissue specificity

Highly expressed in placenta, spleen and peripheral blood leukocytes. Detected in monocytes, macrophages, dendritic cells and several types of T-cells.

Domain

The TIR domain mediates interaction with NOX4.

Post-translational modification

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. Ref.14 Ref.20 Ref.21 Ref.22

Polymorphism

Allele TLR4*B (Gly-299, Ile-399) is associated with a blunted response to inhaled LPS.

Involvement in disease

Macular degeneration, age-related, 10 (ARMD10) [MIM:611488]: A form of age-related macular degeneration, a multifactorial eye disease and the most common cause of irreversible vision loss in the developed world. In most patients, the disease is manifest as ophthalmoscopically visible yellowish accumulations of protein and lipid that lie beneath the retinal pigment epithelium and within an elastin-containing structure known as Bruch membrane.
Note: Disease susceptibility is associated with variations affecting the gene represented in this entry.

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 (Ni2+). Ni2+ 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 Ni2+. A mouse model of contact allergy to Ni2+ in which TLR4-deficient mice expresses human TLR4 has been proposed.

Sequence similarities

Belongs to the Toll-like receptor family.

Contains 18 LRR (leucine-rich) repeats.

Contains 1 LRRCT domain.

Contains 1 TIR domain.

Ontologies

Keywords
   Biological processImmunity
Inflammatory response
Innate immunity
   Cellular componentMembrane
   Coding sequence diversityAlternative splicing
Polymorphism
   DiseaseAge-related macular degeneration
   DomainLeucine-rich repeat
Repeat
Signal
Transmembrane
Transmembrane helix
   Molecular functionReceptor
   PTMDisulfide bond
Glycoprotein
   Technical term3D-structure
Complete proteome
Direct protein sequencing
Reference proteome
Gene Ontology (GO)
   Biological_processB cell proliferation involved in immune response

Inferred from electronic annotation. Source: Ensembl

I-kappaB kinase/NF-kappaB signaling

Traceable author statement. Source: Reactome

I-kappaB phosphorylation

Inferred from direct assay PubMed 19740627. Source: BHF-UCL

MyD88-dependent toll-like receptor signaling pathway

Traceable author statement. Source: Reactome

MyD88-independent toll-like receptor signaling pathway

Traceable author statement. Source: Reactome

T-helper 1 type immune response

Non-traceable author statement PubMed 11970998. Source: UniProtKB

TRIF-dependent toll-like receptor signaling pathway

Traceable author statement. Source: Reactome

activation of MAPK activity

Inferred from sequence or structural similarity. Source: BHF-UCL

cellular response to lipopolysaccharide

Inferred from sequence or structural similarity. Source: BHF-UCL

cellular response to lipoteichoic acid

Inferred from electronic annotation. Source: Ensembl

cellular response to mechanical stimulus

Inferred from expression pattern PubMed 19593445. Source: UniProtKB

defense response to Gram-negative bacterium

Inferred by curator PubMed 16514062. Source: BHF-UCL

defense response to bacterium

Traceable author statement PubMed 10426995. Source: UniProtKB

detection of fungus

Non-traceable author statement PubMed 11254600. Source: UniProtKB

detection of lipopolysaccharide

Inferred from direct assay Ref.21. Source: UniProtKB

immune response

Traceable author statement PubMed 10426995. Source: ProtInc

innate immune response

Traceable author statement PubMed 15356140. Source: BHF-UCL

interferon-gamma production

Inferred from electronic annotation. Source: Ensembl

intestinal epithelial structure maintenance

Inferred from sequence or structural similarity. Source: BHF-UCL

lipopolysaccharide-mediated signaling pathway

Inferred from genetic interaction PubMed 10880523. Source: MGI

macrophage activation

Inferred from mutant phenotype Ref.4. Source: UniProtKB

negative regulation of ERK1 and ERK2 cascade

Inferred from sequence or structural similarity. Source: BHF-UCL

negative regulation of interferon-gamma production

Inferred from sequence or structural similarity. Source: BHF-UCL

negative regulation of interleukin-17 production

Inferred from sequence or structural similarity. Source: BHF-UCL

negative regulation of interleukin-23 production

Inferred from sequence or structural similarity. Source: BHF-UCL

negative regulation of interleukin-6 production

Inferred from sequence or structural similarity. Source: BHF-UCL

negative regulation of osteoclast differentiation

Non-traceable author statement PubMed 12133979. Source: UniProtKB

negative regulation of tumor necrosis factor production

Inferred from sequence or structural similarity. Source: BHF-UCL

nitric oxide production involved in inflammatory response

Inferred from electronic annotation. Source: Ensembl

positive regulation of B cell proliferation

Inferred from electronic annotation. Source: Ensembl

positive regulation of ERK1 and ERK2 cascade

Inferred from electronic annotation. Source: Ensembl

positive regulation of I-kappaB kinase/NF-kappaB signaling

Inferred from electronic annotation. Source: Ensembl

positive regulation of JNK cascade

Inferred from electronic annotation. Source: Ensembl

positive regulation of MHC class II biosynthetic process

Inferred from electronic annotation. Source: Ensembl

positive regulation of NF-kappaB import into nucleus

Inferred from direct assay PubMed 19740627. Source: BHF-UCL

positive regulation of NF-kappaB transcription factor activity

Inferred from direct assay PubMed 12594207. Source: MGI

positive regulation of chemokine production

Inferred from direct assay PubMed 19740627. Source: BHF-UCL

positive regulation of inflammatory response

Inferred by curator PubMed 19740627. Source: BHF-UCL

positive regulation of interferon-alpha production

Inferred from sequence or structural similarity. Source: BHF-UCL

positive regulation of interferon-beta biosynthetic process

Inferred from electronic annotation. Source: Ensembl

positive regulation of interferon-beta production

Inferred from sequence or structural similarity. Source: BHF-UCL

positive regulation of interferon-gamma production

Inferred from sequence or structural similarity. Source: BHF-UCL

positive regulation of interleukin-1 production

Inferred from sequence or structural similarity. Source: BHF-UCL

positive regulation of interleukin-10 production

Inferred from sequence or structural similarity. Source: BHF-UCL

positive regulation of interleukin-12 biosynthetic process

Inferred from direct assay PubMed 15027902. Source: UniProtKB

positive regulation of interleukin-12 production

Inferred from sequence or structural similarity. Source: BHF-UCL

positive regulation of interleukin-6 production

Inferred from direct assay PubMed 19740627. Source: BHF-UCL

positive regulation of interleukin-8 biosynthetic process

Inferred from direct assay PubMed 17951129. Source: UniProtKB

positive regulation of interleukin-8 production

Inferred from direct assay PubMed 19740627. Source: BHF-UCL

positive regulation of macrophage cytokine production

Inferred from electronic annotation. Source: Ensembl

positive regulation of nitric oxide biosynthetic process

Inferred from electronic annotation. Source: Ensembl

positive regulation of nitric-oxide synthase biosynthetic process

Inferred from sequence or structural similarity. Source: BHF-UCL

positive regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway

Inferred from electronic annotation. Source: Ensembl

positive regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway

Inferred from electronic annotation. Source: Ensembl

positive regulation of platelet activation

Inferred from sequence or structural similarity PubMed 16514062. Source: BHF-UCL

positive regulation of transcription from RNA polymerase II promoter

Inferred from sequence or structural similarity. Source: BHF-UCL

positive regulation of tumor necrosis factor biosynthetic process

Inferred from direct assay PubMed 17951129. Source: UniProtKB

positive regulation of tumor necrosis factor production

Inferred from sequence or structural similarity. Source: BHF-UCL

response to lipopolysaccharide

Inferred by curator PubMed 16514062. Source: BHF-UCL

toll-like receptor 2 signaling pathway

Traceable author statement. Source: Reactome

toll-like receptor 3 signaling pathway

Traceable author statement. Source: Reactome

toll-like receptor 4 signaling pathway

Traceable author statement. Source: Reactome

toll-like receptor TLR1:TLR2 signaling pathway

Traceable author statement. Source: Reactome

toll-like receptor TLR6:TLR2 signaling pathway

Traceable author statement. Source: Reactome

toll-like receptor signaling pathway

Traceable author statement. Source: Reactome

   Cellular_componentcytoplasm

Inferred from direct assay PubMed 19740627. Source: BHF-UCL

endosome membrane

Traceable author statement. Source: Reactome

external side of plasma membrane

Inferred from direct assay PubMed 16514062. Source: BHF-UCL

integral component of plasma membrane

Inferred from direct assay PubMed 15027902. Source: UniProtKB

lipopolysaccharide receptor complex

Inferred from direct assay Ref.21. Source: UniProtKB

perinuclear region of cytoplasm

Inferred from direct assay PubMed 15027902. Source: UniProtKB

plasma membrane

Inferred from direct assay PubMed 19740627. Source: BHF-UCL

   Molecular_functionlipopolysaccharide binding

Non-traceable author statement Ref.4. Source: UniProtKB

lipopolysaccharide receptor activity

Inferred from direct assay Ref.21. Source: UniProtKB

protein binding

Inferred from physical interaction PubMed 11441107Ref.21. Source: UniProtKB

receptor activity

Traceable author statement PubMed 10426995. Source: ProtInc

transmembrane signaling receptor activity

Non-traceable author statement PubMed 11970998. Source: UniProtKB

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

O765523EBI-528701,EBI-3870694From a different organism.
LY96Q9Y6Y93EBI-528701,EBI-1539247
TIRAPP587532EBI-528701,EBI-528644

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: O00206-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 2 (identifier: O00206-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-40: Missing.
Isoform 3 (identifier: O00206-3)

The sequence of this isoform differs from the canonical sequence as follows:
     1-200: Missing.
Note: No experimental confirmation available.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 2323 Ref.12
Chain24 – 839816Toll-like receptor 4
PRO_0000034722

Regions

Topological domain24 – 631608Extracellular Potential
Transmembrane632 – 65221Helical; Potential
Topological domain653 – 839187Cytoplasmic Potential
Repeat55 – 7622LRR 1
Repeat79 – 10022LRR 2
Repeat103 – 12422LRR 3
Repeat127 – 14822LRR 4
Repeat151 – 17222LRR 5
Repeat176 – 19924LRR 6
Repeat205 – 22521LRR 7
Repeat227 – 24721LRR 8
Repeat331 – 35121LRR 9
Repeat352 – 37322LRR 10
Repeat374 – 39421LRR 11
Repeat400 – 42223LRR 12
Repeat423 – 44422LRR 13
Repeat448 – 4569LRR 14
Repeat472 – 49524LRR 15
Repeat497 – 51822LRR 16
Repeat521 – 54222LRR 17
Repeat545 – 56521LRR 18
Domain579 – 62951LRRCT
Domain672 – 818147TIR

Amino acid modifications

Glycosylation351N-linked (GlcNAc...) Ref.14 Ref.20 Ref.22
Glycosylation1731N-linked (GlcNAc...) Ref.14 Ref.20 Ref.21 Ref.22
Glycosylation2051N-linked (GlcNAc...) Ref.14 Ref.20 Ref.21
Glycosylation2821N-linked (GlcNAc...) Ref.14
Glycosylation3091N-linked (GlcNAc...) Ref.14
Glycosylation4971N-linked (GlcNAc...) Ref.14 Ref.21
Glycosylation5261N-linked (GlcNAc...) Ref.14 Ref.21
Glycosylation5751N-linked (GlcNAc...) Ref.14 Ref.21
Glycosylation6241N-linked (GlcNAc...) Ref.14
Glycosylation6301N-linked (GlcNAc...) Potential
Disulfide bond29 ↔ 40 Ref.20 Ref.21 Ref.22
Disulfide bond281 ↔ 306 Ref.20 Ref.21 Ref.22
Disulfide bond390 ↔ 391 Ref.20 Ref.21 Ref.22
Disulfide bond583 ↔ 609 Ref.20 Ref.21 Ref.22
Disulfide bond585 ↔ 627 Ref.20 Ref.21 Ref.22

Natural variations

Alternative sequence1 – 200200Missing in isoform 3.
VSP_035793
Alternative sequence1 – 4040Missing in isoform 2.
VSP_035794
Natural variant1751T → A.
Corresponds to variant rs16906079 [ dbSNP | Ensembl ].
VAR_021977
Natural variant1881Q → R. Ref.23
Corresponds to variant rs5030713 [ dbSNP | Ensembl ].
VAR_018729
Natural variant2461C → S. Ref.23
Corresponds to variant rs5030714 [ dbSNP | Ensembl ].
VAR_018730
Natural variant2991D → G in allele TLR4*B; reduced LPS-response; associated with an increased risk for ARMD10 in Caucasian patients carriers. Ref.3 Ref.4 Ref.6 Ref.23 Ref.24
Corresponds to variant rs4986790 [ dbSNP | Ensembl ].
VAR_012739
Natural variant3061C → W.
Corresponds to variant rs2770145 [ dbSNP | Ensembl ].
VAR_047563
Natural variant3101V → G.
Corresponds to variant rs2770144 [ dbSNP | Ensembl ].
VAR_047564
Natural variant3291N → S. Ref.23
Corresponds to variant rs5030715 [ dbSNP | Ensembl ].
VAR_018731
Natural variant3421F → Y.
Corresponds to variant rs5031050 [ dbSNP | Ensembl ].
VAR_020334
Natural variant3851L → F.
Corresponds to variant rs11536884 [ dbSNP | Ensembl ].
VAR_037668
Natural variant3991T → I in allele TLR4*B; reduced LPS-response. Ref.3 Ref.4 Ref.6 Ref.23
Corresponds to variant rs4986791 [ dbSNP | Ensembl ].
VAR_012740
Natural variant4001S → N.
Corresponds to variant rs4987233 [ dbSNP | Ensembl ].
VAR_020335
Natural variant4431F → L. Ref.23
Corresponds to variant rs5030716 [ dbSNP | Ensembl ].
VAR_018732
Natural variant4741E → K. Ref.23
Corresponds to variant rs5030718 [ dbSNP | Ensembl ].
VAR_018733
Natural variant5101Q → H. Ref.23
Corresponds to variant rs5030719 [ dbSNP | Ensembl ].
VAR_018734
Natural variant6941K → R. Ref.23
Corresponds to variant rs5030722 [ dbSNP | Ensembl ].
VAR_018735
Natural variant7631R → H. Ref.23
Corresponds to variant rs5030723 [ dbSNP | Ensembl ].
VAR_018736
Natural variant8341Q → H. Ref.23
VAR_018737

Experimental info

Mutagenesis4311H → 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. Ref.18
Mutagenesis4561H → 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. Ref.18
Mutagenesis4581H → 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. Ref.18
Mutagenesis5261N → A: Abolishes LPS-response and prevents the cell surface expression. Ref.14
Mutagenesis5751N → A: Abolishes LPS-response and prevents the cell surface expression. Ref.14
Mutagenesis6971E → R: Abolishes LPS-response. Ref.13
Mutagenesis7101R → E: Abolishes LPS-response. Ref.13
Mutagenesis7111D → K: Abolishes LPS-response. Ref.13
Mutagenesis7141P → H, R or E: Abolishes MYD88-binding and LPS-response. Ref.13
Sequence conflict731S → R in ABU41664. Ref.11
Sequence conflict4001S → C in BAF82742. Ref.7
Sequence conflict5811F → S in BAG64706. Ref.7

Secondary structure

.................................................................................................................... 839
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified January 1, 1998. Version 2.
Checksum: 92C48F55821133E8

FASTA83995,680
        10         20         30         40         50         60 
MMSASRLAGT LIPAMAFLSC VRPESWEPCV EVVPNITYQC MELNFYKIPD NLPFSTKNLD 

        70         80         90        100        110        120 
LSFNPLRHLG SYSFFSFPEL QVLDLSRCEI QTIEDGAYQS LSHLSTLILT GNPIQSLALG 

       130        140        150        160        170        180 
AFSGLSSLQK LVAVETNLAS LENFPIGHLK TLKELNVAHN LIQSFKLPEY FSNLTNLEHL 

       190        200        210        220        230        240 
DLSSNKIQSI YCTDLRVLHQ MPLLNLSLDL SLNPMNFIQP GAFKEIRLHK LTLRNNFDSL 

       250        260        270        280        290        300 
NVMKTCIQGL AGLEVHRLVL GEFRNEGNLE KFDKSALEGL CNLTIEEFRL AYLDYYLDDI 

       310        320        330        340        350        360 
IDLFNCLTNV SSFSLVSVTI ERVKDFSYNF GWQHLELVNC KFGQFPTLKL KSLKRLTFTS 

       370        380        390        400        410        420 
NKGGNAFSEV DLPSLEFLDL SRNGLSFKGC CSQSDFGTTS LKYLDLSFNG VITMSSNFLG 

       430        440        450        460        470        480 
LEQLEHLDFQ HSNLKQMSEF SVFLSLRNLI YLDISHTHTR VAFNGIFNGL SSLEVLKMAG 

       490        500        510        520        530        540 
NSFQENFLPD IFTELRNLTF LDLSQCQLEQ LSPTAFNSLS SLQVLNMSHN NFFSLDTFPY 

       550        560        570        580        590        600 
KCLNSLQVLD YSLNHIMTSK KQELQHFPSS LAFLNLTQND FACTCEHQSF LQWIKDQRQL 

       610        620        630        640        650        660 
LVEVERMECA TPSDKQGMPV LSLNITCQMN KTIIGVSVLS VLVVSVVAVL VYKFYFHLML 

       670        680        690        700        710        720 
LAGCIKYGRG ENIYDAFVIY SSQDEDWVRN ELVKNLEEGV PPFQLCLHYR DFIPGVAIAA 

       730        740        750        760        770        780 
NIIHEGFHKS RKVIVVVSQH FIQSRWCIFE YEIAQTWQFL SSRAGIIFIV LQKVEKTLLR 

       790        800        810        820        830 
QQVELYRLLS RNTYLEWEDS VLGRHIFWRR LRKALLDGKS WNPEGTVGTG CNWQEATSI 

« Hide

Isoform 2 [UniParc].

Checksum: 82F70995E7F2AF9D
Show »

FASTA79991,296
Isoform 3 [UniParc].

Checksum: 23C1406CE32427EC
Show »

FASTA63973,301

References

« Hide 'large scale' references
[1]"A human homologue of the Drosophila Toll protein signals activation of adaptive immunity."
Medzhitov R., Preston-Hurlburt P., Janeway C.A. Jr.
Nature 388:394-397(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
Tissue: Spleen.
[2]"A family of human receptors structurally related to Drosophila Toll."
Rock F.L., Hardiman G., Timans J.C., Kastelein R.A., Bazan J.F.
Proc. Natl. Acad. Sci. U.S.A. 95:588-593(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
Tissue: Fetal liver, Lung and Placenta.
[3]"Phylogenetic variation and polymorphism at the Toll-like receptor 4 locus (TLR4)."
Smirnova I., Poltorak A., Chan E.K.L., McBride C., Beutler B.
Genome Biol. 1:RESEARCH002.1-RESEARCH002.10(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS GLY-299 AND ILE-399.
[4]"TLR4 mutations are associated with endotoxin hyporesponsiveness in humans."
Arbour N.C., Lorenz E., Schutte B.C., Zabner J., Kline J.N., Jones M., Frees K., Watt J.L., Schwartz D.A.
Nat. Genet. 25:187-191(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS GLY-299 AND ILE-399.
[5]"Natural selection in the TLR-related genes in the course of primate evolution."
Nakajima T., Ohtani H., Satta Y., Uno Y., Akari H., Ishida T., Kimura A.
Immunogenetics 60:727-735(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[6]"The heterogeneous allelic repertoire of human Toll-Like receptor (TLR) genes."
Georgel P., Macquin C., Bahram S.
PLoS ONE 4:E7803-E7803(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS GLY-299 AND ILE-399.
[7]"Complete sequencing and characterization of 21,243 full-length human cDNAs."
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. expand/collapse author list , 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.
Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 2 AND 3).
Tissue: Hippocampus, Kidney and Uterus.
[8]"DNA sequence and analysis of human chromosome 9."
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. expand/collapse author list , 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.
Nature 429:369-374(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[9]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. expand/collapse author list , 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
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[10]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Cerebellum.
[11]Liu Z., Li N., Wang J., Xiao W.
Submitted (MAR-2007) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-86.
[12]"Signal peptide prediction based on analysis of experimentally verified cleavage sites."
Zhang Z., Henzel W.J.
Protein Sci. 13:2819-2824(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEIN SEQUENCE OF 24-38.
[13]"Structural basis for signal transduction by the Toll/interleukin-1 receptor domains."
Xu Y., Tao X., Shen B., Horng T., Medzhitov R., Manley J.L., Tong L.
Nature 408:111-115(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: MUTAGENESIS OF GLU-697; ARG-710; ASP-711 AND PRO-714.
[14]"MD-2 and TLR4 N-linked glycosylations are important for a functional lipopolysaccharide receptor."
da Silva Correia J., Ulevitch R.J.
J. Biol. Chem. 277:1845-1854(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: GLYCOSYLATION AT ASN-35; ASN-173; ASN-205; ASN-282; ASN-309; ASN-497; ASN-526; ASN-575 AND ASN-624, MUTAGENESIS OF ASN-526 AND ASN-575.
[15]"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."
Park H.S., Jung H.Y., Park E.Y., Kim J., Lee W.J., Bae Y.S.
J. Immunol. 173:3589-3593(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH NOX4.
[16]"Folding of Toll-like receptors by the HSP90 paralogue gp96 requires a substrate-specific cochaperone."
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. 1:79-79(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH HSP90B1.
[17]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)
[18]"Crucial role for human Toll-like receptor 4 in the development of contact allergy to nickel."
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.
Nat. Immunol. 11:814-819(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, MUTAGENESIS OF HIS-431; HIS-456 AND HIS-458, INVOLVEMENT IN CONTACT ALLERGY TO NICKEL.
[19]"MLK4 has negative effect on TLR4 signaling."
Seit-Nebi A., Cheng W., Xu H., Han J.
Cell. Mol. Immunol. 9:27-33(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH MLK4.
[20]"Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist Eritoran."
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.
Cell 130:906-917(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 27-228, DISULFIDE BONDS, GLYCOSYLATION AT ASN-35; ASN-173 AND ASN-205.
[21]"The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex."
Park B.S., Song D.H., Kim H.M., Choi B.-S., Lee H., Lee J.-O.
Nature 458:1191-1195(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (3.1 ANGSTROMS) OF 27-631 IN COMPLEX WITH LY96 AND LIPOPOLYSACCHARIDE, DISULFIDE BONDS, GLYCOSYLATION AT ASN-173; ASN-205; ASN-497 AND ASN-526 AND ASN-575.
[22]"Structure-based rational design of a Toll-like receptor 4 (TLR4) decoy receptor with high binding affinity for a target protein."
Han J., Kim H.J., Lee S.C., Hong S., Park K., Jeon Y.H., Kim D., Cheong H.K., Kim H.S.
PLoS ONE 7:E30929-E30929(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.37 ANGSTROMS) OF 28-228, GLYCOSYLATION AT ASN-35 AND ASN-173, DISULFIDE BONDS.
[23]"Excess of rare amino acid polymorphisms in the Toll-like receptor 4 in humans."
Smirnova I., Hamblin M.T., McBride C., Beutler B., Di Rienzo A.
Genetics 158:1657-1664(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS ARG-188; SER-246; GLY-299; SER-329; ILE-399; LEU-443; LYS-474; HIS-510; ARG-694; HIS-763 AND HIS-834.
[24]"Toll-like receptor 4 variant D299G is associated with susceptibility to age-related macular degeneration."
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.
Hum. Mol. Genet. 14:1449-1455(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT GLY-299, ASSOCIATION WITH ARMD SUSCEPTIBILITY.
+Additional computationally mapped references.

Web resources

Protein Spotlight

Zips, necklaces and mobile telephones - Issue 134 of December 2011

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
U93091 mRNA. Translation: AAC80227.1.
AB445638 mRNA. Translation: BAG55035.1.
DQ018107 Genomic DNA. Translation: AAY82267.1.
DQ018108 Genomic DNA. Translation: AAY82268.1.
DQ018109 Genomic DNA. Translation: AAY82269.1.
AK290053 mRNA. Translation: BAF82742.1.
AK293068 mRNA. Translation: BAF85757.1.
AK303730 mRNA. Translation: BAG64706.1.
AL160272 Genomic DNA. Translation: CAH72618.1.
AL160272 Genomic DNA. Translation: CAH72619.1.
CH471090 Genomic DNA. Translation: EAW87448.1.
CH471090 Genomic DNA. Translation: EAW87451.1.
BC117422 mRNA. Translation: AAI17423.1.
EF535831 Genomic DNA. Translation: ABU41662.1.
EF535832 Genomic DNA. Translation: ABU41663.1.
EF535833 Genomic DNA. Translation: ABU41664.1.
AF177765 Genomic DNA. Translation: AAF05316.1.
AF177766 Genomic DNA. Translation: AAF07823.1.
AF172171, AF172169, AF172170 Genomic DNA. Translation: AAF89753.1.
U88880 mRNA. Translation: AAC34135.1.
CCDSCCDS6818.1. [O00206-1]
RefSeqNP_003257.1. NM_003266.3. [O00206-2]
NP_612564.1. NM_138554.4. [O00206-1]
NP_612567.1. NM_138557.2. [O00206-3]
UniGeneHs.174312.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
2Z62X-ray1.70A27-228[»]
2Z63X-ray2.00A27-527[»]
2Z65X-ray2.70A/B27-228[»]
2Z66X-ray1.90A/B/C/D381-627[»]
3FXIX-ray3.10A/B27-631[»]
3UL7X-ray2.37A28-226[»]
3UL8X-ray2.50A27-228[»]
3UL9X-ray2.45A28-228[»]
3ULAX-ray3.60A/C27-228[»]
4G8AX-ray2.40A/B23-629[»]
ProteinModelPortalO00206.
SMRO00206. Positions 23-816.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid112954. 30 interactions.
DIPDIP-34769N.
IntActO00206. 13 interactions.
MINTMINT-3981856.

Chemistry

BindingDBO00206.
ChEMBLCHEMBL3038512.
GuidetoPHARMACOLOGY1754.

PTM databases

PhosphoSiteO00206.

Proteomic databases

PaxDbO00206.
PRIDEO00206.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000355622; ENSP00000363089; ENSG00000136869. [O00206-1]
ENST00000394487; ENSP00000377997; ENSG00000136869. [O00206-2]
GeneID7099.
KEGGhsa:7099.
UCSCuc004bjz.4. human. [O00206-1]

Organism-specific databases

CTD7099.
GeneCardsGC09P120466.
HGNCHGNC:11850. TLR4.
HPACAB004025.
MIM603030. gene+phenotype.
611488. phenotype.
neXtProtNX_O00206.
Orphanet117. Behcet disease.
PharmGKBPA36552.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG249751.
HOVERGENHBG018823.
InParanoidO00206.
KOK10160.
OMAPESWDPC.
OrthoDBEOG7ZKS9G.
PhylomeDBO00206.
TreeFamTF351113.

Enzyme and pathway databases

ReactomeREACT_6900. Immune System.
SignaLinkO00206.

Gene expression databases

ArrayExpressO00206.
BgeeO00206.
GenevestigatorO00206.

Family and domain databases

Gene3D3.40.50.10140. 1 hit.
InterProIPR000483. Cys-rich_flank_reg_C.
IPR001611. Leu-rich_rpt.
IPR025875. Leu-rich_rpt_4.
IPR003591. Leu-rich_rpt_typical-subtyp.
IPR000157. TIR_dom.
IPR027168. TLR4.
IPR017241. Toll-like_receptor.
[Graphical view]
PANTHERPTHR24365:SF230. PTHR24365:SF230. 1 hit.
PfamPF12799. LRR_4. 1 hit.
PF13855. LRR_8. 2 hits.
PF01582. TIR. 1 hit.
[Graphical view]
PIRSFPIRSF037595. Toll-like_receptor. 1 hit.
SMARTSM00369. LRR_TYP. 2 hits.
SM00082. LRRCT. 1 hit.
SM00255. TIR. 1 hit.
[Graphical view]
SUPFAMSSF52200. SSF52200. 1 hit.
PROSITEPS51450. LRR. 11 hits.
PS50104. TIR. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceO00206.
GeneWikiTLR_4.
GenomeRNAi7099.
NextBio27773.
PROO00206.
SOURCESearch...

Entry information

Entry nameTLR4_HUMAN
AccessionPrimary (citable) accession number: O00206
Secondary accession number(s): A8K1Y8 expand/collapse secondary AC list , A9XLP9, A9XLQ0, A9XLQ1, B4E194, D1CS52, D1CS53, Q5VZI8, Q5VZI9, Q9UK78, Q9UM57
Entry history
Integrated into UniProtKB/Swiss-Prot: February 11, 2002
Last sequence update: January 1, 1998
Last modified: July 9, 2014
This is version 152 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

Protein Spotlight

Protein Spotlight articles and cited UniProtKB/Swiss-Prot entries

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 9

Human chromosome 9: entries, gene names and cross-references to MIM

Human cell differentiation molecules

CD nomenclature of surface proteins of human leucocytes and list of entries