Q9GL65 · TLR4_BOVIN
- ProteinToll-like receptor 4
- GeneTLR4
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids841 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
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).
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).
GO annotations
Aspect | Term | |
---|---|---|
Cellular Component | early endosome | |
Cellular Component | lipopolysaccharide receptor complex | |
Cellular Component | plasma membrane | |
Cellular Component | ruffle | |
Molecular Function | lipopolysaccharide binding | |
Molecular Function | lipopolysaccharide immune receptor activity | |
Molecular Function | NAD+ nucleotidase, cyclic ADP-ribose generating | |
Molecular Function | transmembrane signaling receptor activity | |
Biological Process | defense response to Gram-negative bacterium | |
Biological Process | detection of lipopolysaccharide | |
Biological Process | inflammatory response | |
Biological Process | innate immune response | |
Biological Process | macrophage activation | |
Biological Process | MyD88-dependent toll-like receptor signaling pathway | |
Biological Process | positive regulation of interleukin-1 beta production | |
Biological Process | positive regulation of NLRP3 inflammasome complex assembly | |
Biological Process | toll-like receptor 4 signaling pathway |
Keywords
- Molecular function
- Biological process
- Ligand
Names & Taxonomy
Protein names
- Recommended nameToll-like receptor 4
- CD Antigen Name
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Laurasiatheria > Artiodactyla > Ruminantia > Pecora > Bovidae > Bovinae > Bos
Accessions
- Primary accessionQ9GL65
- Secondary accessions
Proteomes
Subcellular Location
UniProt Annotation
GO Annotation
Cell membrane ; Single-pass type I membrane protein
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.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Topological domain | 24-632 | Extracellular | ||||
Sequence: ESWDPCVQVVPNISYQCMELNLYKIPDNIPISTKMLDLSFNYLRHLGSHNFSSFPELQVLDLSRCEIKIIEDDTFQGLNHLSTLILTGNPIQSLAWGAFSGLSSLQKLVAVETNLVSLNDFPIGHLKNLKELNVAHNFIHSFKLPEYFSNLPNLEHLDLSNNKIQNIYYEDVKVLHQMPLLNLSLDLSLNPLDFIEPGTFKEIKLNGLTLRSNFNSSHVMKTCIQGLAGLKTNRLVLGEFKNERKLQRFDRSFLEGLCNLTIEQFRIAYLDKFSGDDTDLFNCLANVSVISLLSISLGSLQALLKDFRWQHLEIINCDFDKFPALKLSSLKKFVFTDNKDISTFTEFQLPSLQYLDLKRNHLSFKGCCSHTDFGTTNLKHLDLSFNDVITLGSNFMGLEQLEHLDFQHSTLKQINAFSAFLSLRNLRYLDISYTNIRIVFHGIFTGLVSLQTLKMAGNSFQNNLLPDIFTELTNLTVLDLSKCQLEQVAQTAFHSLSSLQVLNMSHNKLLSLDTFLYEPLHSLRILDCSFNRIMASKEQELQNLPRSLTWLNLTQNAFACVCEHQSFLQWVKDQRQLLVGAEQMMCAEPLDMEDMPVLSFRNATCQLSK | ||||||
Transmembrane | 633-653 | Helical | ||||
Sequence: TIISVSVVTVLLVSVVGVLVY | ||||||
Topological domain | 654-841 | Cytoplasmic | ||||
Sequence: KFYFHLMLLAGCKKYGRGESIYDAFVIYSSQDEDWVRNELVKNLEEGVPPFQLCLHYRDFIPGVAIAANIIQEGFHKSRKVIVVVSQHFIQSRWCIFEYEIAQTWQFLSSRAGIIFIVLQKLEKSLLRQQVELYRLLSRNTYLEWEDSVLGRHVFWRRLRKALLAGKPQSPEGTADAETNPQEATTST |
Keywords
- Cellular component
PTM/Processing
Features
Showing features for signal, chain, disulfide bond, glycosylation.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Signal | 1-23 | |||||
Sequence: MMARARLAAALIPATAILSCLRT | ||||||
Chain | PRO_0000034717 | 24-841 | Toll-like receptor 4 | |||
Sequence: ESWDPCVQVVPNISYQCMELNLYKIPDNIPISTKMLDLSFNYLRHLGSHNFSSFPELQVLDLSRCEIKIIEDDTFQGLNHLSTLILTGNPIQSLAWGAFSGLSSLQKLVAVETNLVSLNDFPIGHLKNLKELNVAHNFIHSFKLPEYFSNLPNLEHLDLSNNKIQNIYYEDVKVLHQMPLLNLSLDLSLNPLDFIEPGTFKEIKLNGLTLRSNFNSSHVMKTCIQGLAGLKTNRLVLGEFKNERKLQRFDRSFLEGLCNLTIEQFRIAYLDKFSGDDTDLFNCLANVSVISLLSISLGSLQALLKDFRWQHLEIINCDFDKFPALKLSSLKKFVFTDNKDISTFTEFQLPSLQYLDLKRNHLSFKGCCSHTDFGTTNLKHLDLSFNDVITLGSNFMGLEQLEHLDFQHSTLKQINAFSAFLSLRNLRYLDISYTNIRIVFHGIFTGLVSLQTLKMAGNSFQNNLLPDIFTELTNLTVLDLSKCQLEQVAQTAFHSLSSLQVLNMSHNKLLSLDTFLYEPLHSLRILDCSFNRIMASKEQELQNLPRSLTWLNLTQNAFACVCEHQSFLQWVKDQRQLLVGAEQMMCAEPLDMEDMPVLSFRNATCQLSKTIISVSVVTVLLVSVVGVLVYKFYFHLMLLAGCKKYGRGESIYDAFVIYSSQDEDWVRNELVKNLEEGVPPFQLCLHYRDFIPGVAIAANIIQEGFHKSRKVIVVVSQHFIQSRWCIFEYEIAQTWQFLSSRAGIIFIVLQKLEKSLLRQQVELYRLLSRNTYLEWEDSVLGRHVFWRRLRKALLAGKPQSPEGTADAETNPQEATTST | ||||||
Disulfide bond | 29↔40 | |||||
Sequence: CVQVVPNISYQC | ||||||
Glycosylation | 35 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Glycosylation | 73 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Glycosylation | 205 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Glycosylation | 238 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Disulfide bond | 281↔306 | |||||
Sequence: CNLTIEQFRIAYLDKFSGDDTDLFNC | ||||||
Glycosylation | 282 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Glycosylation | 309 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Disulfide bond | 390↔391 | |||||
Sequence: CC | ||||||
Glycosylation | 497 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Glycosylation | 526 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Glycosylation | 575 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Disulfide bond | 583↔609 | |||||
Sequence: CVCEHQSFLQWVKDQRQLLVGAEQMMC | ||||||
Disulfide bond | 585↔628 | |||||
Sequence: CEHQSFLQWVKDQRQLLVGAEQMMCAEPLDMEDMPVLSFRNATC | ||||||
Glycosylation | 625 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N |
Post-translational modification
Phosphorylated on tyrosine residues by LYN after binding lipopolysaccharide.
Keywords
- PTM
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).
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.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Repeat | 55-76 | LRR 1 | ||||
Sequence: STKMLDLSFNYLRHLGSHNFSS | ||||||
Repeat | 79-100 | LRR 2 | ||||
Sequence: ELQVLDLSRCEIKIIEDDTFQG | ||||||
Repeat | 103-124 | LRR 3 | ||||
Sequence: HLSTLILTGNPIQSLAWGAFSG | ||||||
Repeat | 127-148 | LRR 4 | ||||
Sequence: SLQKLVAVETNLVSLNDFPIGH | ||||||
Repeat | 151-172 | LRR 5 | ||||
Sequence: NLKELNVAHNFIHSFKLPEYFS | ||||||
Repeat | 176-197 | LRR 6 | ||||
Sequence: NLEHLDLSNNKIQNIYYEDVKV | ||||||
Repeat | 205-225 | LRR 7 | ||||
Sequence: NLSLDLSLNPLDFIEPGTFKE | ||||||
Repeat | 352-373 | LRR 8 | ||||
Sequence: SLKKFVFTDNKDISTFTEFQLP | ||||||
Repeat | 374-394 | LRR 9 | ||||
Sequence: SLQYLDLKRNHLSFKGCCSHT | ||||||
Repeat | 400-422 | LRR 10 | ||||
Sequence: NLKHLDLSFNDVITLGSNFMGLE | ||||||
Repeat | 423-444 | LRR 11 | ||||
Sequence: QLEHLDFQHSTLKQINAFSAFL | ||||||
Repeat | 448-469 | LRR 12 | ||||
Sequence: NLRYLDISYTNIRIVFHGIFTG | ||||||
Repeat | 472-495 | LRR 13 | ||||
Sequence: SLQTLKMAGNSFQNNLLPDIFTEL | ||||||
Repeat | 497-518 | LRR 14 | ||||
Sequence: NLTVLDLSKCQLEQVAQTAFHS | ||||||
Repeat | 521-542 | LRR 15 | ||||
Sequence: SLQVLNMSHNKLLSLDTFLYEP | ||||||
Repeat | 545-568 | LRR 16 | ||||
Sequence: SLRILDCSFNRIMASKEQELQNLP | ||||||
Domain | 579-630 | LRRCT | ||||
Sequence: NAFACVCEHQSFLQWVKDQRQLLVGAEQMMCAEPLDMEDMPVLSFRNATCQL | ||||||
Domain | 673-816 | TIR | ||||
Sequence: SIYDAFVIYSSQDEDWVRNELVKNLEEGVPPFQLCLHYRDFIPGVAIAANIIQEGFHKSRKVIVVVSQHFIQSRWCIFEYEIAQTWQFLSSRAGIIFIVLQKLEKSLLRQQVELYRLLSRNTYLEWEDSVLGRHVFWRRLRKAL | ||||||
Region | 820-841 | Disordered | ||||
Sequence: KPQSPEGTADAETNPQEATTST | ||||||
Compositional bias | 826-841 | Polar residues | ||||
Sequence: GTADAETNPQEATTST |
Domain
The TIR domain mediates interaction with NOX4.
Sequence similarities
Belongs to the Toll-like receptor family.
Keywords
- Domain
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Sequence processingThe displayed sequence is further processed into a mature form.
- Length841
- Mass (Da)96,027
- Last updated2002-02-11 v2
- ChecksumC5E17CB9C798CD16
Features
Showing features for compositional bias.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Compositional bias | 826-841 | Polar residues | ||||
Sequence: GTADAETNPQEATTST |
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
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 |