Gene/Proteome Database (LMPD)

LMPD ID
LMP002771
Gene ID
7099
Species
Homo sapiens (Human)
Gene Name
toll-like receptor 4
Gene Symbol
TLR4
Synonyms
ARMD10; CD284; TLR-4; TOLL
Alternate Names
toll-like receptor 4; hToll; homolog of Drosophila toll
Chromosome
9
Map Location
9q33.1
Summary
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]
Orthologs
View orthologs and multiple alignments for TLR4

Proteins

toll-like receptor 4 isoform A precursor
Refseq ID NP_612564
Protein GI 19924149
UniProt ID O00206
mRNA ID NM_138554
Length 839
RefSeq Status REVIEWED
MMSASRLAGTLIPAMAFLSCVRPESWEPCVEVVPNITYQCMELNFYKIPDNLPFSTKNLDLSFNPLRHLGSYSFFSFPELQVLDLSRCEIQTIEDGAYQSLSHLSTLILTGNPIQSLALGAFSGLSSLQKLVAVETNLASLENFPIGHLKTLKELNVAHNLIQSFKLPEYFSNLTNLEHLDLSSNKIQSIYCTDLRVLHQMPLLNLSLDLSLNPMNFIQPGAFKEIRLHKLTLRNNFDSLNVMKTCIQGLAGLEVHRLVLGEFRNEGNLEKFDKSALEGLCNLTIEEFRLAYLDYYLDDIIDLFNCLTNVSSFSLVSVTIERVKDFSYNFGWQHLELVNCKFGQFPTLKLKSLKRLTFTSNKGGNAFSEVDLPSLEFLDLSRNGLSFKGCCSQSDFGTTSLKYLDLSFNGVITMSSNFLGLEQLEHLDFQHSNLKQMSEFSVFLSLRNLIYLDISHTHTRVAFNGIFNGLSSLEVLKMAGNSFQENFLPDIFTELRNLTFLDLSQCQLEQLSPTAFNSLSSLQVLNMSHNNFFSLDTFPYKCLNSLQVLDYSLNHIMTSKKQELQHFPSSLAFLNLTQNDFACTCEHQSFLQWIKDQRQLLVEVERMECATPSDKQGMPVLSLNITCQMNKTIIGVSVLSVLVVSVVAVLVYKFYFHLMLLAGCIKYGRGENIYDAFVIYSSQDEDWVRNELVKNLEEGVPPFQLCLHYRDFIPGVAIAANIIHEGFHKSRKVIVVVSQHFIQSRWCIFEYEIAQTWQFLSSRAGIIFIVLQKVEKTLLRQQVELYRLLSRNTYLEWEDSVLGRHIFWRRLRKALLDGKSWNPEGTVGTGCNWQEATSI
toll-like receptor 4 isoform C
Refseq ID NP_003257
Protein GI 4507533
UniProt ID O00206
mRNA ID NM_003266
Length 799
RefSeq Status REVIEWED
MELNFYKIPDNLPFSTKNLDLSFNPLRHLGSYSFFSFPELQVLDLSRCEIQTIEDGAYQSLSHLSTLILTGNPIQSLALGAFSGLSSLQKLVAVETNLASLENFPIGHLKTLKELNVAHNLIQSFKLPEYFSNLTNLEHLDLSSNKIQSIYCTDLRVLHQMPLLNLSLDLSLNPMNFIQPGAFKEIRLHKLTLRNNFDSLNVMKTCIQGLAGLEVHRLVLGEFRNEGNLEKFDKSALEGLCNLTIEEFRLAYLDYYLDDIIDLFNCLTNVSSFSLVSVTIERVKDFSYNFGWQHLELVNCKFGQFPTLKLKSLKRLTFTSNKGGNAFSEVDLPSLEFLDLSRNGLSFKGCCSQSDFGTTSLKYLDLSFNGVITMSSNFLGLEQLEHLDFQHSNLKQMSEFSVFLSLRNLIYLDISHTHTRVAFNGIFNGLSSLEVLKMAGNSFQENFLPDIFTELRNLTFLDLSQCQLEQLSPTAFNSLSSLQVLNMSHNNFFSLDTFPYKCLNSLQVLDYSLNHIMTSKKQELQHFPSSLAFLNLTQNDFACTCEHQSFLQWIKDQRQLLVEVERMECATPSDKQGMPVLSLNITCQMNKTIIGVSVLSVLVVSVVAVLVYKFYFHLMLLAGCIKYGRGENIYDAFVIYSSQDEDWVRNELVKNLEEGVPPFQLCLHYRDFIPGVAIAANIIHEGFHKSRKVIVVVSQHFIQSRWCIFEYEIAQTWQFLSSRAGIIFIVLQKVEKTLLRQQVELYRLLSRNTYLEWEDSVLGRHIFWRRLRKALLDGKSWNPEGTVGTGCNWQEATSI
toll-like receptor 4 isoform D
Refseq ID NP_612567
Protein GI 19924153
UniProt ID O00206
mRNA ID NM_138557
Length 639
RefSeq Status REVIEWED
MPLLNLSLDLSLNPMNFIQPGAFKEIRLHKLTLRNNFDSLNVMKTCIQGLAGLEVHRLVLGEFRNEGNLEKFDKSALEGLCNLTIEEFRLAYLDYYLDDIIDLFNCLTNVSSFSLVSVTIERVKDFSYNFGWQHLELVNCKFGQFPTLKLKSLKRLTFTSNKGGNAFSEVDLPSLEFLDLSRNGLSFKGCCSQSDFGTTSLKYLDLSFNGVITMSSNFLGLEQLEHLDFQHSNLKQMSEFSVFLSLRNLIYLDISHTHTRVAFNGIFNGLSSLEVLKMAGNSFQENFLPDIFTELRNLTFLDLSQCQLEQLSPTAFNSLSSLQVLNMSHNNFFSLDTFPYKCLNSLQVLDYSLNHIMTSKKQELQHFPSSLAFLNLTQNDFACTCEHQSFLQWIKDQRQLLVEVERMECATPSDKQGMPVLSLNITCQMNKTIIGVSVLSVLVVSVVAVLVYKFYFHLMLLAGCIKYGRGENIYDAFVIYSSQDEDWVRNELVKNLEEGVPPFQLCLHYRDFIPGVAIAANIIHEGFHKSRKVIVVVSQHFIQSRWCIFEYEIAQTWQFLSSRAGIIFIVLQKVEKTLLRQQVELYRLLSRNTYLEWEDSVLGRHIFWRRLRKALLDGKSWNPEGTVGTGCNWQEATSI
sig_peptide: 1..23 inference: COORDINATES: ab initio prediction:SignalP:4.0 calculated_mol_wt: 2424 peptide sequence: MMSASRLAGTLIPAMAFLSCVRP mat_peptide: 24..839 product: Toll-like receptor 4 experiment: experimental evidence, no additional details recorded note: propagated from UniProtKB/Swiss-Prot (O00206.2) calculated_mol_wt: 93275 peptide sequence: ESWEPCVEVVPNITYQCMELNFYKIPDNLPFSTKNLDLSFNPLRHLGSYSFFSFPELQVLDLSRCEIQTIEDGAYQSLSHLSTLILTGNPIQSLALGAFSGLSSLQKLVAVETNLASLENFPIGHLKTLKELNVAHNLIQSFKLPEYFSNLTNLEHLDLSSNKIQSIYCTDLRVLHQMPLLNLSLDLSLNPMNFIQPGAFKEIRLHKLTLRNNFDSLNVMKTCIQGLAGLEVHRLVLGEFRNEGNLEKFDKSALEGLCNLTIEEFRLAYLDYYLDDIIDLFNCLTNVSSFSLVSVTIERVKDFSYNFGWQHLELVNCKFGQFPTLKLKSLKRLTFTSNKGGNAFSEVDLPSLEFLDLSRNGLSFKGCCSQSDFGTTSLKYLDLSFNGVITMSSNFLGLEQLEHLDFQHSNLKQMSEFSVFLSLRNLIYLDISHTHTRVAFNGIFNGLSSLEVLKMAGNSFQENFLPDIFTELRNLTFLDLSQCQLEQLSPTAFNSLSSLQVLNMSHNNFFSLDTFPYKCLNSLQVLDYSLNHIMTSKKQELQHFPSSLAFLNLTQNDFACTCEHQSFLQWIKDQRQLLVEVERMECATPSDKQGMPVLSLNITCQMNKTIIGVSVLSVLVVSVVAVLVYKFYFHLMLLAGCIKYGRGENIYDAFVIYSSQDEDWVRNELVKNLEEGVPPFQLCLHYRDFIPGVAIAANIIHEGFHKSRKVIVVVSQHFIQSRWCIFEYEIAQTWQFLSSRAGIIFIVLQKVEKTLLRQQVELYRLLSRNTYLEWEDSVLGRHIFWRRLRKALLDGKSWNPEGTVGTGCNWQEATSI

Gene Information

Entrez Gene ID
7099
Gene Name
toll-like receptor 4
Gene Symbol
TLR4
Species
Homo sapiens

Gene Ontology (GO Annotations)

GO ID Source Type Description
GO:0005737 IDA:BHF-UCL C cytoplasm
GO:0010008 TAS:Reactome C endosome membrane
GO:0009897 IDA:BHF-UCL C external side of plasma membrane
GO:0005887 IDA:UniProtKB C integral component of plasma membrane
GO:0046696 IDA:UniProtKB C lipopolysaccharide receptor complex
GO:0048471 IDA:UniProtKB C perinuclear region of cytoplasm
GO:0005886 IDA:BHF-UCL C plasma membrane
GO:0001530 NAS:UniProtKB F lipopolysaccharide binding
GO:0001875 IDA:UniProtKB F lipopolysaccharide receptor activity
GO:0004872 TAS:ProtInc F receptor activity
GO:0004888 NAS:UniProtKB F transmembrane signaling receptor activity
GO:0000187 ISS:BHF-UCL P activation of MAPK activity
GO:0002322 IEA:Ensembl P B cell proliferation involved in immune response
GO:0071222 ISS:BHF-UCL P cellular response to lipopolysaccharide
GO:0071223 IEA:Ensembl P cellular response to lipoteichoic acid
GO:0071260 IEP:UniProtKB P cellular response to mechanical stimulus
GO:0042742 TAS:UniProtKB P defense response to bacterium
GO:0050829 IC:BHF-UCL P defense response to Gram-negative bacterium
GO:0016046 NAS:UniProtKB P detection of fungus
GO:0032497 IDA:UniProtKB P detection of lipopolysaccharide
GO:0007249 TAS:Reactome P I-kappaB kinase/NF-kappaB signaling
GO:0007252 IDA:BHF-UCL P I-kappaB phosphorylation
GO:0006955 TAS:ProtInc P immune response
GO:0045087 TAS:BHF-UCL P innate immune response
GO:0032609 IEA:Ensembl P interferon-gamma production
GO:0060729 ISS:BHF-UCL P intestinal epithelial structure maintenance
GO:0031663 IGI:MGI P lipopolysaccharide-mediated signaling pathway
GO:0042116 IMP:UniProtKB P macrophage activation
GO:0002755 TAS:Reactome P MyD88-dependent toll-like receptor signaling pathway
GO:0002756 TAS:Reactome P MyD88-independent toll-like receptor signaling pathway
GO:0070373 ISS:BHF-UCL P negative regulation of ERK1 and ERK2 cascade
GO:0032689 ISS:BHF-UCL P negative regulation of interferon-gamma production
GO:0032700 ISS:BHF-UCL P negative regulation of interleukin-17 production
GO:0032707 ISS:BHF-UCL P negative regulation of interleukin-23 production
GO:0032715 ISS:BHF-UCL P negative regulation of interleukin-6 production
GO:0045671 NAS:UniProtKB P negative regulation of osteoclast differentiation
GO:0032720 ISS:BHF-UCL P negative regulation of tumor necrosis factor production
GO:0002537 IEA:Ensembl P nitric oxide production involved in inflammatory response
GO:0030890 IEA:Ensembl P positive regulation of B cell proliferation
GO:0032722 IDA:BHF-UCL P positive regulation of chemokine production
GO:0070374 IEA:Ensembl P positive regulation of ERK1 and ERK2 cascade
GO:0043123 IEA:Ensembl P positive regulation of I-kappaB kinase/NF-kappaB signaling
GO:0050729 IC:BHF-UCL P positive regulation of inflammatory response
GO:0032727 ISS:BHF-UCL P positive regulation of interferon-alpha production
GO:0045359 IEA:Ensembl P positive regulation of interferon-beta biosynthetic process
GO:0032728 ISS:BHF-UCL P positive regulation of interferon-beta production
GO:0032729 ISS:BHF-UCL P positive regulation of interferon-gamma production
GO:0032733 ISS:BHF-UCL P positive regulation of interleukin-10 production
GO:0045084 IDA:UniProtKB P positive regulation of interleukin-12 biosynthetic process
GO:0032735 ISS:BHF-UCL P positive regulation of interleukin-12 production
GO:0032732 ISS:BHF-UCL P positive regulation of interleukin-1 production
GO:0032755 IDA:BHF-UCL P positive regulation of interleukin-6 production
GO:0045416 IDA:UniProtKB P positive regulation of interleukin-8 biosynthetic process
GO:0032757 IDA:BHF-UCL P positive regulation of interleukin-8 production
GO:0046330 IEA:Ensembl P positive regulation of JNK cascade
GO:0060907 IEA:Ensembl P positive regulation of macrophage cytokine production
GO:0045348 IEA:Ensembl P positive regulation of MHC class II biosynthetic process
GO:0042346 IDA:BHF-UCL P positive regulation of NF-kappaB import into nucleus
GO:0051092 IDA:MGI P positive regulation of NF-kappaB transcription factor activity
GO:0045429 IEA:Ensembl P positive regulation of nitric oxide biosynthetic process
GO:0051770 ISS:BHF-UCL P positive regulation of nitric-oxide synthase biosynthetic process
GO:0070430 IEA:Ensembl P positive regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway
GO:0070434 IEA:Ensembl P positive regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway
GO:0010572 ISS:BHF-UCL P positive regulation of platelet activation
GO:0045944 ISS:BHF-UCL P positive regulation of transcription from RNA polymerase II promoter
GO:0042535 IDA:UniProtKB P positive regulation of tumor necrosis factor biosynthetic process
GO:0032760 ISS:BHF-UCL P positive regulation of tumor necrosis factor production
GO:0050707 IEA:InterPro P regulation of cytokine secretion
GO:0032496 IC:BHF-UCL P response to lipopolysaccharide
GO:0042088 NAS:UniProtKB P T-helper 1 type immune response
GO:0034134 TAS:Reactome P toll-like receptor 2 signaling pathway
GO:0034138 TAS:Reactome P toll-like receptor 3 signaling pathway
GO:0034142 TAS:Reactome P toll-like receptor 4 signaling pathway
GO:0002224 TAS:Reactome P toll-like receptor signaling pathway
GO:0038123 TAS:Reactome P toll-like receptor TLR1:TLR2 signaling pathway
GO:0038124 TAS:Reactome P toll-like receptor TLR6:TLR2 signaling pathway
GO:0035666 TAS:Reactome P TRIF-dependent toll-like receptor signaling pathway

KEGG Pathway Links

KEGG Pathway ID Description
hsa04066 HIF-1 signaling pathway
hsa05321 Inflammatory bowel disease (IBD)
hsa05205 Proteoglycans in cancer

Domain Information

InterPro Annotations

Accession Description
IPR000483 Cysteine-rich flanking region, C-terminal
IPR001611 Leucine-rich repeat
IPR025875 Leucine rich repeat 4
IPR003591 Leucine-rich repeat, typical subtype
IPR000157 Toll/interleukin-1 receptor homology (TIR) domain
IPR017241 Toll-like receptor
IPR027168 Toll-like receptor 4

UniProt Annotations

Entry Information

Gene Name
toll-like receptor 4
Protein Entry
TLR4_HUMAN
UniProt ID
O00206
Species
Human

Comments

Comment Type Description
Alternative Products Event=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.;
Disease Macular degeneration, age-related, 10 (ARMD10) [MIM
Domain The TIR domain mediates interaction with NOX4.
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 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
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;
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.
Polymorphism Allele TLR4*B (Gly-299, Ile-399) is associated with a blunted response to inhaled LPS.
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. {ECO
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. {ECO
Subcellular Location Cell membrane; Single-pass type I membrane protein. Note=Upon complex formation with CD36 and TLR6, internalized through dynamin-dependent endocytosis.
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. 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
Tissue Specificity Highly expressed in placenta, spleen and peripheral blood leukocytes. Detected in monocytes, macrophages, dendritic cells and several types of T-cells.
Web Resource Name=Protein Spotlight; Note=Zips, necklaces and mobile telephones - Issue 134 of December 2011; URL="http://web.expasy.org/spotlight/back_issues/134";

Identical and Related Proteins

Unique RefSeq proteins for LMP002771 (as displayed in Record Overview)

Protein GI Database Accession Length Protein Name
19924149 RefSeq NP_612564 839 toll-like receptor 4 isoform A precursor
4507533 RefSeq NP_003257 799 toll-like receptor 4 isoform C
19924153 RefSeq NP_612567 639 toll-like receptor 4 isoform D

Identical Sequences to LMP002771 proteins

Reference Database Accession Length Protein Name
GI:19924153 GenBank EAW87449.1 639 hCG27399, isoform CRA_b [Homo sapiens]
GI:19924153 GenBank ADM02932.1 639 Sequence 27 from patent US 7727725
GI:4507533 GenBank ADR96887.1 799 Sequence 222 from patent US 7749695
GI:4507533 GenBank ADS18303.1 799 Sequence 90 from patent US 7763425
GI:4507533 GenBank ADS87502.1 799 Sequence 378 from patent US 7820380
GI:19924153 GenBank ADS87503.1 639 Sequence 379 from patent US 7820380
GI:4507533 GenBank AEW40497.1 799 Sequence 378 from patent US 8071302
GI:19924153 GenBank AEW40498.1 639 Sequence 379 from patent US 8071302
GI:4507533 GenBank AFO15258.1 799 Sequence 26 from patent US 8211638
GI:19924153 GenBank AFO15259.1 639 Sequence 27 from patent US 8211638
GI:19924149 GenBank AFT61331.1 839 Sequence 2 from patent US 8273541
GI:19924149 GenBank AGA52229.1 839 Sequence 2 from patent US 8329420
GI:4507533 GenBank AGJ47802.1 799 Sequence 4 from patent US 8414887
GI:19924149 GenBank AGV80311.1 839 Sequence 8 from patent US 8501925
GI:19924149 GenBank AGY18310.1 839 Sequence 43 from patent US 8546539
GI:19924149 GenBank AGY24886.1 839 Sequence 2 from patent US 8557517
GI:19924149 GenBank AHD69684.1 839 Sequence 698 from patent US 8586006

Related Sequences to LMP002771 proteins

Reference Database Accession Length Protein Name
GI:4507533 DBBJ BAF85757.1 839 unnamed protein product [Homo sapiens]
GI:19924153 EMBL CAD36115.1 799 unnamed protein product [Homo sapiens]
GI:4507533 GenBank AAF05316.1 839 toll-like receptor 4 [Homo sapiens]
GI:4507533 GenBank AAF89753.1 839 toll-like receptor 4 [Homo sapiens]
GI:19924149 GenBank AAY82267.1 839 toll-like receptor 4 [Homo sapiens]
GI:19924149 GenBank AAY82270.1 839 toll-like receptor 4 [Homo sapiens]
GI:4507533 GenBank ABH65774.1 839 Sequence 2 from patent US 7029861
GI:19924153 GenBank EAW87450.1 782 hCG27399, isoform CRA_c [Homo sapiens]
GI:19924153 GenBank ADM02933.1 782 Sequence 28 from patent US 7727725
GI:19924153 GenBank ADS87504.1 782 Sequence 380 from patent US 7820380
GI:4507533 GenBank AEQ77503.1 839 Sequence 61 from patent US 8029794
GI:4507533 GenBank AEQ83413.1 839 Sequence 28 from patent US 8039212
GI:19924153 GenBank AEW40499.1 782 Sequence 380 from patent US 8071302
GI:19924153 GenBank AFO15260.1 782 Sequence 28 from patent US 8211638
GI:19924149 GenBank JAA05262.1 839 toll-like receptor 4 [Pan troglodytes]
GI:19924149 GenBank JAA17562.1 839 toll-like receptor 4 [Pan troglodytes]
GI:19924149 GenBank JAA25841.1 839 toll-like receptor 4 [Pan troglodytes]
GI:19924149 GenBank JAA42756.1 839 toll-like receptor 4 [Pan troglodytes]