Description: Homo sapiens toll-like receptor 4 (TLR4), transcript variant 1, mRNA. RefSeq Summary (NM_138554): The protein encoded by this gene is a member of the Toll-like receptor (TLR) family which plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. This receptor has been implicated in signal transduction events induced by lipopolysaccharide (LPS) found in most gram-negative bacteria. Mutations in this gene have been associated with differences in LPS responsiveness. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]. Transcript (Including UTRs) Position: hg19 chr9:120,466,453-120,479,769 Size: 13,317 Total Exon Count: 3 Strand: + Coding Region Position: hg19 chr9:120,466,751-120,476,926 Size: 10,176 Coding Exon Count: 3
ID:TLR4_HUMAN DESCRIPTION: RecName: Full=Toll-like receptor 4; AltName: Full=hToll; AltName: CD_antigen=CD284; Flags: Precursor; 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 Ni(2+). These responses require non-conserved histidines and are, therefore, species-specific. SUBUNIT: 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. INTERACTION: O76552:- (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; 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. 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. POLYMORPHISM: Allele TLR4*B (Gly-299, Ile-399) is associated with a blunted response to inhaled LPS. DISEASE: Genetic variation in TLR4 is associated with age-related macular degeneration type 10 (ARMD10) [MIM:611488]. ARMD is 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. 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. SIMILARITY: Belongs to the Toll-like receptor family. SIMILARITY: Contains 18 LRR (leucine-rich) repeats. SIMILARITY: Contains 1 LRRCT domain. SIMILARITY: Contains 1 TIR domain. WEB RESOURCE: Name=Protein Spotlight; Note=Zips, necklaces and mobile telephones - Issue 134 of December 2011; URL="http://www.expasy.org/spotlight/back_issues/sptlt134.shtml";
acute coronary syndrome Ameziane, N. et al. 2003, Association of the Toll-like receptor 4 gene Asp299Gly polymorphism with acute coronary events., Arteriosclerosis, thrombosis, and vascular biology. 2003 Dec;23(12):e61-4.
[PubMed 14563652]
These results, which must be confirmed by a prospective longitudinal study, provide evidence of an association between the Asp299Gly polymorphism of the human TLR4 receptor and acute coronary syndromes. They confirm the previously reported involvement of TLR4 in carotid and femoral artery atherosclerosis.
acute pancreatitis Yasuhiko Takagi , et al. Human immunology 2009 Jan, Microsatellite polymorphism in intron 2 of human Toll-like receptor 2 gene is associated with susceptibility to acute pancreatitis in Japan., Human immunology 2009 Jan.
[PubMed 19480862]
microsatellite polymorphism in intron 2 of the TLR2 gene was associated with susceptibility to AP and its severity in Japan.
Arthritis, Rheumatoid|Rheumatoid Arthritis|Anti-TNF Response Potter C et al. 2010, Association between anti-tumour necrosis factor treatment response and genetic variants within the TLR and NF{kappa}B signalling pathways., Annals of the rheumatic diseases 69(7) : 1315-20 2010.
[PubMed 20448286]
Several SNPs mapping to the TLR and NFkappaB signalling systems demonstrated association with anti-TNF response as a whole and, in particular, with response to etanercept. Validation of these findings in an independent cohort is now warranted.
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on O00206
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Biological Process: GO:0000187 activation of MAPK activity GO:0002224 toll-like receptor signaling pathway GO:0002376 immune system process GO:0002755 MyD88-dependent toll-like receptor signaling pathway GO:0002756 MyD88-independent toll-like receptor signaling pathway GO:0006954 inflammatory response GO:0006955 immune response GO:0007165 signal transduction GO:0007249 I-kappaB kinase/NF-kappaB signaling GO:0007252 I-kappaB phosphorylation GO:0010572 positive regulation of platelet activation GO:0010628 positive regulation of gene expression GO:0016046 detection of fungus GO:0031663 lipopolysaccharide-mediated signaling pathway GO:0032496 response to lipopolysaccharide GO:0032497 detection of lipopolysaccharide GO:0032689 negative regulation of interferon-gamma production GO:0032700 negative regulation of interleukin-17 production GO:0032707 negative regulation of interleukin-23 production GO:0032715 negative regulation of interleukin-6 production GO:0032720 negative regulation of tumor necrosis factor production GO:0032722 positive regulation of chemokine production GO:0032727 positive regulation of interferon-alpha production GO:0032728 positive regulation of interferon-beta production GO:0032729 positive regulation of interferon-gamma production GO:0032732 positive regulation of interleukin-1 production GO:0032733 positive regulation of interleukin-10 production GO:0032735 positive regulation of interleukin-12 production GO:0032755 positive regulation of interleukin-6 production GO:0032757 positive regulation of interleukin-8 production GO:0032760 positive regulation of tumor necrosis factor production GO:0034128 negative regulation of MyD88-independent toll-like receptor signaling pathway GO:0034142 toll-like receptor 4 signaling pathway GO:0035666 TRIF-dependent toll-like receptor signaling pathway GO:0042088 T-helper 1 type immune response GO:0042116 macrophage activation GO:0042535 positive regulation of tumor necrosis factor biosynthetic process GO:0042742 defense response to bacterium GO:0043032 positive regulation of macrophage activation GO:0045084 positive regulation of interleukin-12 biosynthetic process GO:0045087 innate immune response GO:0045416 positive regulation of interleukin-8 biosynthetic process GO:0045429 positive regulation of nitric oxide biosynthetic process GO:0045671 negative regulation of osteoclast differentiation GO:0045944 positive regulation of transcription from RNA polymerase II promoter GO:0050702 interleukin-1 beta secretion GO:0050707 regulation of cytokine secretion GO:0050718 positive regulation of interleukin-1 beta secretion GO:0050729 positive regulation of inflammatory response GO:0050829 defense response to Gram-negative bacterium GO:0051092 positive regulation of NF-kappaB transcription factor activity GO:0051770 positive regulation of nitric-oxide synthase biosynthetic process GO:0060729 intestinal epithelial structure maintenance GO:0070266 necroptotic process GO:0070373 negative regulation of ERK1 and ERK2 cascade GO:0071222 cellular response to lipopolysaccharide GO:0071260 cellular response to mechanical stimulus GO:0071346 cellular response to interferon-gamma GO:0097190 apoptotic signaling pathway GO:1900017 positive regulation of cytokine production involved in inflammatory response GO:1900227 positive regulation of NLRP3 inflammasome complex assembly GO:1901224 positive regulation of NIK/NF-kappaB signaling GO:1903223 positive regulation of oxidative stress-induced neuron death GO:1903428 positive regulation of reactive oxygen species biosynthetic process GO:1903974 positive regulation of cellular response to macrophage colony-stimulating factor stimulus GO:1904646 cellular response to beta-amyloid
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