Q9GL65 · TLR4_BOVIN

  • Protein
    Toll-like receptor 4
  • Gene
    TLR4
  • Status
    UniProtKB reviewed (Swiss-Prot)
  • Amino acids
  • Protein existence
    Evidence at protein level
  • Annotation score
    5/5

Function

function

Transmembrane receptor that functions as a pattern recognition receptor recognizing pathogen- and damage-associated molecular patterns (PAMPs and DAMPs) to induce innate immune responses via downstream signaling pathways. At the plasma membrane, cooperates with LY96 to mediate the innate immune response to bacterial lipopolysaccharide (LPS) (PubMed:17559944).
Also involved in LPS-independent inflammatory responses triggered by free fatty acids, such as palmitate, and Ni2+. Mechanistically, acts via MYD88, TIRAP and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response. Alternatively, CD14-mediated TLR4 internalization via endocytosis is associated with the initiation of a MYD88-independent signaling via the TICAM1-TBK1-IRF3 axis leading to type I interferon production. In addition to the secretion of proinflammatory cytokines, initiates the activation of NLRP3 inflammasome and formation of a positive feedback loop between autophagy and NF-kappa-B signaling cascade. In complex with TLR6, promotes inflammation in monocytes/macrophages by associating with TLR6 and the receptor CD86. Upon ligand binding, such as oxLDL or amyloid-beta 42, the TLR4:TLR6 complex is internalized and triggers inflammatory response, leading to NF-kappa-B-dependent production of CXCL1, CXCL2 and CCL9 cytokines, via MYD88 signaling pathway, and CCL5 cytokine, via TICAM1 signaling pathway. In myeloid dendritic cells, vesicular stomatitis virus glycoprotein G but not LPS promotes the activation of IRF7, leading to type I IFN production in a CD14-dependent manner (By similarity).

Caution

In some plant proteins and in human SARM1, the TIR domain has NAD+ hydrolase (NADase) activity (By similarity).
However, despite the presence of the catalytic Asp residue, the isolated TIR domain of human TLR4 lacks NADase activity (By similarity).
Based on this, it is unlikely that Toll-like receptors have NADase activity

GO annotations

AspectTerm
Cellular Componentearly endosome
Cellular Componentlipopolysaccharide receptor complex
Cellular Componentplasma membrane
Cellular Componentruffle
Molecular Functionlipopolysaccharide binding
Molecular Functionlipopolysaccharide immune receptor activity
Molecular FunctionNAD+ nucleotidase, cyclic ADP-ribose generating
Molecular Functiontransmembrane signaling receptor activity
Biological Processdefense response to Gram-negative bacterium
Biological Processdetection of lipopolysaccharide
Biological Processinflammatory response
Biological Processinnate immune response
Biological Processmacrophage activation
Biological ProcessMyD88-dependent toll-like receptor signaling pathway
Biological Processpositive regulation of interleukin-1 beta production
Biological Processpositive regulation of NLRP3 inflammasome complex assembly
Biological Processtoll-like receptor 4 signaling pathway

Keywords

Names & Taxonomy

Protein names

  • Recommended name
    Toll-like receptor 4
  • CD Antigen Name
    • CD284

Gene names

    • Name
      TLR4

Organism names

  • Taxonomic identifier
  • Taxonomic lineage
    Eukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Laurasiatheria > Artiodactyla > Ruminantia > Pecora > Bovidae > Bovinae > Bos

Accessions

  • Primary accession
    Q9GL65
  • Secondary accessions
    • Q0MW16
    • Q6GV19

Proteomes

Subcellular Location

Cell membrane
; Single-pass type I membrane protein
Early endosome
Note: Upon complex formation with CD36 and TLR6, internalized through dynamin-dependent endocytosis. Colocalizes with RFTN1 at cell membrane and then together with RFTN1 moves to endosomes, upon lipopolysaccharide stimulation.

Features

Showing features for topological domain, transmembrane.

TypeIDPosition(s)Description
Topological domain24-632Extracellular
Transmembrane633-653Helical
Topological domain654-841Cytoplasmic

Keywords

PTM/Processing

Features

Showing features for signal, chain, disulfide bond, glycosylation.

TypeIDPosition(s)Description
Signal1-23
ChainPRO_000003471724-841Toll-like receptor 4
Disulfide bond29↔40
Glycosylation35N-linked (GlcNAc...) asparagine
Glycosylation73N-linked (GlcNAc...) asparagine
Glycosylation205N-linked (GlcNAc...) asparagine
Glycosylation238N-linked (GlcNAc...) asparagine
Disulfide bond281↔306
Glycosylation282N-linked (GlcNAc...) asparagine
Glycosylation309N-linked (GlcNAc...) asparagine
Disulfide bond390↔391
Glycosylation497N-linked (GlcNAc...) asparagine
Glycosylation526N-linked (GlcNAc...) asparagine
Glycosylation575N-linked (GlcNAc...) asparagine
Disulfide bond583↔609
Disulfide bond585↔628
Glycosylation625N-linked (GlcNAc...) asparagine

Post-translational modification

Phosphorylated on tyrosine residues by LYN after binding lipopolysaccharide.

Keywords

Proteomic databases

PTM databases

Interaction

Subunit

Belongs to the lipopolysaccharide (LPS) receptor, a multi-protein complex containing at least CD14, LY96 and TLR4 (PubMed:17559944).
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 TICAM2. Interacts with NOX4. Interacts with CNPY3 and HSP90B1; this interaction is required for proper folding in the endoplasmic reticulum. Interacts with MAP3K21; this interaction leads to negative regulation of TLR4 signaling. Interacts with CD36, following CD36 stimulation by oxLDL or amyloid-beta 42, and forms a heterodimer with TLR6. 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 (By similarity).
Interacts with WDFY1 in response to LPS. 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).
Interacts with RFTN1; the interaction occurs in response to lipopolysaccharide stimulation (By similarity).
Interacts with SCIMP; the interaction occurs in response to lipopolysaccharide stimulation and is enhanced by phosphorylation of SCIMP by LYN (By similarity).
This interaction facilitates the phosphorylation of TLR4 by LYN which elicits a selective cytokine response in macrophages (By similarity).
Interacts with TRAF3IP3 (By similarity).
Interacts with TREM1; this interaction enhances TLR4-mediated inflammatory response (By similarity).
Interacts with ZG16B/PAUF (By similarity).
Interacts with CD82; this interaction inhibits TLR4-mediated signaling pathway (By similarity).

Protein-protein interaction databases

Structure

Family & Domains

Features

Showing features for repeat, domain, region, compositional bias.

TypeIDPosition(s)Description
Repeat55-76LRR 1
Repeat79-100LRR 2
Repeat103-124LRR 3
Repeat127-148LRR 4
Repeat151-172LRR 5
Repeat176-197LRR 6
Repeat205-225LRR 7
Repeat352-373LRR 8
Repeat374-394LRR 9
Repeat400-422LRR 10
Repeat423-444LRR 11
Repeat448-469LRR 12
Repeat472-495LRR 13
Repeat497-518LRR 14
Repeat521-542LRR 15
Repeat545-568LRR 16
Domain579-630LRRCT
Domain673-816TIR
Region820-841Disordered
Compositional bias826-841Polar residues

Domain

The TIR domain mediates interaction with NOX4.

Sequence similarities

Belongs to the Toll-like receptor family.

Keywords

Phylogenomic databases

Family and domain databases

Sequence

  • Sequence status
    Complete
  • Sequence processing
    The displayed sequence is further processed into a mature form.
  • Length
    841
  • Mass (Da)
    96,027
  • Last updated
    2002-02-11 v2
  • Checksum
    C5E17CB9C798CD16
MMARARLAAALIPATAILSCLRTESWDPCVQVVPNISYQCMELNLYKIPDNIPISTKMLDLSFNYLRHLGSHNFSSFPELQVLDLSRCEIKIIEDDTFQGLNHLSTLILTGNPIQSLAWGAFSGLSSLQKLVAVETNLVSLNDFPIGHLKNLKELNVAHNFIHSFKLPEYFSNLPNLEHLDLSNNKIQNIYYEDVKVLHQMPLLNLSLDLSLNPLDFIEPGTFKEIKLNGLTLRSNFNSSHVMKTCIQGLAGLKTNRLVLGEFKNERKLQRFDRSFLEGLCNLTIEQFRIAYLDKFSGDDTDLFNCLANVSVISLLSISLGSLQALLKDFRWQHLEIINCDFDKFPALKLSSLKKFVFTDNKDISTFTEFQLPSLQYLDLKRNHLSFKGCCSHTDFGTTNLKHLDLSFNDVITLGSNFMGLEQLEHLDFQHSTLKQINAFSAFLSLRNLRYLDISYTNIRIVFHGIFTGLVSLQTLKMAGNSFQNNLLPDIFTELTNLTVLDLSKCQLEQVAQTAFHSLSSLQVLNMSHNKLLSLDTFLYEPLHSLRILDCSFNRIMASKEQELQNLPRSLTWLNLTQNAFACVCEHQSFLQWVKDQRQLLVGAEQMMCAEPLDMEDMPVLSFRNATCQLSKTIISVSVVTVLLVSVVGVLVYKFYFHLMLLAGCKKYGRGESIYDAFVIYSSQDEDWVRNELVKNLEEGVPPFQLCLHYRDFIPGVAIAANIIQEGFHKSRKVIVVVSQHFIQSRWCIFEYEIAQTWQFLSSRAGIIFIVLQKLEKSLLRQQVELYRLLSRNTYLEWEDSVLGRHVFWRRLRKALLAGKPQSPEGTADAETNPQEATTST

Features

Showing features for compositional bias.

TypeIDPosition(s)Description
Compositional bias826-841Polar residues

Keywords

Sequence databases

Nucleotide SequenceProtein SequenceMolecule TypeStatus
AF310952
EMBL· GenBank· DDBJ
AAG32061.2
EMBL· GenBank· DDBJ
mRNA
AY634630
EMBL· GenBank· DDBJ
AAT48488.1
EMBL· GenBank· DDBJ
mRNA
DQ839566
EMBL· GenBank· DDBJ
ABH09759.1
EMBL· GenBank· DDBJ
mRNA

Genome annotation databases

Similar Proteins

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