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MGP003151

UniProt Annotations

Entry Information
Gene Nametoll-like receptor 4
Protein EntryTLR4_HUMAN
UniProt IDO00206
SpeciesHuman
Comments
Comment typeDescription
Alternative ProductsEvent=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.;
DiseaseMacular 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.
DomainThe TIR domain mediates interaction with NOX4.
FunctionCooperates 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 free fatty acids, such as palmitate, and Ni(2+). Responses triggered by Ni(2+) require non-conserved histidines and are, therefore, species- specific. 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. {ECO:0000269|PubMed:17478729, ECO:0000269|PubMed:20037584, ECO:0000269|PubMed:20711192}.
InteractionO76552:- (xeno); NbExp=3; IntAct=EBI-528701, EBI-3870694; Q9Y6Y9:LY96; NbExp=3; IntAct=EBI-528701, EBI-1539247; P58753:TIRAP; NbExp=2; IntAct=EBI-528701, EBI-528644;
MiscellaneousHis-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.
PolymorphismAllele TLR4*B (Gly-299, Ile-399) is associated with a blunted response to inhaled LPS.
PtmN-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}.
SimilarityBelongs to the Toll-like receptor family. {ECO:0000305}.
SimilarityContains 18 LRR (leucine-rich) repeats. {ECO:0000305}.
SimilarityContains 1 LRRCT domain. {ECO:0000305}.
SimilarityContains 1 TIR domain. {ECO:0000255|PROSITE- ProRule:PRU00204}.
Subcellular LocationCell membrane; Single-pass type I membrane protein. Note=Upon complex formation with CD36 and TLR6, internalized through dynamin-dependent endocytosis. {ECO:0000269|PubMed:20037584}.
SubunitBelongs 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. 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. {ECO:0000250, ECO:0000269|PubMed:15356101, ECO:0000269|PubMed:19252480, ECO:0000269|PubMed:20037584, ECO:0000269|PubMed:20865800, ECO:0000269|PubMed:21602844}.
Tissue SpecificityHighly expressed in placenta, spleen and peripheral blood leukocytes. Detected in monocytes, macrophages, dendritic cells and several types of T-cells.
Web ResourceName=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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