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Protein

Toll-like receptor 4

Gene

TLR4

Organism
Bos taurus (Bovine)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Cooperates with LY96 and CD14 to mediate the innate immune response to bacterial lipopolysaccharide (LPS) (PubMed:17559944). 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. 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. Binds electronegative LDL (LDL-) and mediates the cytokine release induced by LDL- (By similarity).By similarity1 Publication

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Receptor

Keywords - Biological processi

Immunity, Inflammatory response, Innate immunity

Names & Taxonomyi

Protein namesi
Recommended name:
Toll-like receptor 4
Alternative name(s):
CD_antigen: CD284
Gene namesi
Name:TLR4
OrganismiBos taurus (Bovine)
Taxonomic identifieri9913 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaLaurasiatheriaCetartiodactylaRuminantiaPecoraBovidaeBovinaeBos
Proteomesi
  • UP000009136 Componenti: Unplaced

Subcellular locationi

  • Cell membrane By similarity1 Publication; Single-pass type I membrane protein By similarity

  • Note: Upon complex formation with CD36 and TLR6, internalized through dynamin-dependent endocytosis.By similarity

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini24 – 632ExtracellularSequence analysisAdd BLAST609
Transmembranei633 – 653HelicalSequence analysisAdd BLAST21
Topological domaini654 – 841CytoplasmicSequence analysisAdd BLAST188

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Membrane

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 23Sequence analysisAdd BLAST23
ChainiPRO_000003471724 – 841Toll-like receptor 4Add BLAST818

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi29 ↔ 40By similarity
Glycosylationi35N-linked (GlcNAc...)Sequence analysis1
Glycosylationi73N-linked (GlcNAc...)Sequence analysis1
Glycosylationi205N-linked (GlcNAc...)Sequence analysis1
Glycosylationi238N-linked (GlcNAc...)Sequence analysis1
Disulfide bondi281 ↔ 306By similarity
Glycosylationi282N-linked (GlcNAc...)Sequence analysis1
Glycosylationi309N-linked (GlcNAc...)Sequence analysis1
Disulfide bondi390 ↔ 391By similarity
Glycosylationi497N-linked (GlcNAc...)Sequence analysis1
Glycosylationi526N-linked (GlcNAc...)Sequence analysis1
Glycosylationi575N-linked (GlcNAc...)Sequence analysis1
Disulfide bondi583 ↔ 609By similarity
Disulfide bondi585 ↔ 628By similarity
Glycosylationi625N-linked (GlcNAc...)Sequence analysis1

Keywords - PTMi

Disulfide bond, Glycoprotein

Proteomic databases

PaxDbiQ9GL65.

Interactioni

Subunit structurei

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 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. 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).By similarity1 Publication

Protein-protein interaction databases

STRINGi9913.ENSBTAP00000008190.

Structurei

3D structure databases

ProteinModelPortaliQ9GL65.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Repeati55 – 76LRR 1Add BLAST22
Repeati79 – 100LRR 2Add BLAST22
Repeati103 – 124LRR 3Add BLAST22
Repeati127 – 148LRR 4Add BLAST22
Repeati151 – 172LRR 5Add BLAST22
Repeati176 – 197LRR 6Add BLAST22
Repeati205 – 225LRR 7Add BLAST21
Repeati352 – 373LRR 8Add BLAST22
Repeati374 – 394LRR 9Add BLAST21
Repeati400 – 422LRR 10Add BLAST23
Repeati423 – 444LRR 11Add BLAST22
Repeati448 – 469LRR 12Add BLAST22
Repeati472 – 495LRR 13Add BLAST24
Repeati497 – 518LRR 14Add BLAST22
Repeati521 – 542LRR 15Add BLAST22
Repeati545 – 568LRR 16Add BLAST24
Domaini579 – 630LRRCTAdd BLAST52
Domaini673 – 819TIRPROSITE-ProRule annotationAdd BLAST147

Domaini

The TIR domain mediates interaction with NOX4.By similarity

Sequence similaritiesi

Belongs to the Toll-like receptor family.Curated
Contains 16 LRR (leucine-rich) repeats.Curated
Contains 1 LRRCT domain.Curated
Contains 1 TIR domain.PROSITE-ProRule annotation

Keywords - Domaini

Leucine-rich repeat, Repeat, Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG4641. Eukaryota.
COG4886. LUCA.
HOGENOMiHOG000037951.
HOVERGENiHBG018823.
InParanoidiQ9GL65.
KOiK10160.

Family and domain databases

Gene3Di3.40.50.10140. 1 hit.
3.80.10.10. 4 hits.
InterProiIPR000483. Cys-rich_flank_reg_C.
IPR032675. L_dom-like.
IPR001611. Leu-rich_rpt.
IPR003591. Leu-rich_rpt_typical-subtyp.
IPR000157. TIR_dom.
IPR027168. TLR4.
[Graphical view]
PANTHERiPTHR24365:SF230. PTHR24365:SF230. 2 hits.
PfamiPF13516. LRR_6. 1 hit.
PF13855. LRR_8. 4 hits.
PF01582. TIR. 1 hit.
[Graphical view]
SMARTiSM00369. LRR_TYP. 13 hits.
SM00082. LRRCT. 1 hit.
SM00255. TIR. 1 hit.
[Graphical view]
SUPFAMiSSF52200. SSF52200. 1 hit.
PROSITEiPS51450. LRR. 13 hits.
PS50104. TIR. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

Q9GL65-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MMARARLAAA LIPATAILSC LRTESWDPCV QVVPNISYQC MELNLYKIPD
60 70 80 90 100
NIPISTKMLD LSFNYLRHLG SHNFSSFPEL QVLDLSRCEI KIIEDDTFQG
110 120 130 140 150
LNHLSTLILT GNPIQSLAWG AFSGLSSLQK LVAVETNLVS LNDFPIGHLK
160 170 180 190 200
NLKELNVAHN FIHSFKLPEY FSNLPNLEHL DLSNNKIQNI YYEDVKVLHQ
210 220 230 240 250
MPLLNLSLDL SLNPLDFIEP GTFKEIKLNG LTLRSNFNSS HVMKTCIQGL
260 270 280 290 300
AGLKTNRLVL GEFKNERKLQ RFDRSFLEGL CNLTIEQFRI AYLDKFSGDD
310 320 330 340 350
TDLFNCLANV SVISLLSISL GSLQALLKDF RWQHLEIINC DFDKFPALKL
360 370 380 390 400
SSLKKFVFTD NKDISTFTEF QLPSLQYLDL KRNHLSFKGC CSHTDFGTTN
410 420 430 440 450
LKHLDLSFND VITLGSNFMG LEQLEHLDFQ HSTLKQINAF SAFLSLRNLR
460 470 480 490 500
YLDISYTNIR IVFHGIFTGL VSLQTLKMAG NSFQNNLLPD IFTELTNLTV
510 520 530 540 550
LDLSKCQLEQ VAQTAFHSLS SLQVLNMSHN KLLSLDTFLY EPLHSLRILD
560 570 580 590 600
CSFNRIMASK EQELQNLPRS LTWLNLTQNA FACVCEHQSF LQWVKDQRQL
610 620 630 640 650
LVGAEQMMCA EPLDMEDMPV LSFRNATCQL SKTIISVSVV TVLLVSVVGV
660 670 680 690 700
LVYKFYFHLM LLAGCKKYGR GESIYDAFVI YSSQDEDWVR NELVKNLEEG
710 720 730 740 750
VPPFQLCLHY RDFIPGVAIA ANIIQEGFHK SRKVIVVVSQ HFIQSRWCIF
760 770 780 790 800
EYEIAQTWQF LSSRAGIIFI VLQKLEKSLL RQQVELYRLL SRNTYLEWED
810 820 830 840
SVLGRHVFWR RLRKALLAGK PQSPEGTADA ETNPQEATTS T
Length:841
Mass (Da):96,027
Last modified:February 11, 2002 - v2
Checksum:iC5E17CB9C798CD16
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF310952 mRNA. Translation: AAG32061.2.
AY634630 mRNA. Translation: AAT48488.1.
DQ839566 mRNA. Translation: ABH09759.1.
RefSeqiNP_776623.5. NM_174198.6.
UniGeneiBt.9030.

Genome annotation databases

GeneIDi281536.
KEGGibta:281536.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF310952 mRNA. Translation: AAG32061.2.
AY634630 mRNA. Translation: AAT48488.1.
DQ839566 mRNA. Translation: ABH09759.1.
RefSeqiNP_776623.5. NM_174198.6.
UniGeneiBt.9030.

3D structure databases

ProteinModelPortaliQ9GL65.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

STRINGi9913.ENSBTAP00000008190.

Proteomic databases

PaxDbiQ9GL65.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

GeneIDi281536.
KEGGibta:281536.

Organism-specific databases

CTDi7099.

Phylogenomic databases

eggNOGiKOG4641. Eukaryota.
COG4886. LUCA.
HOGENOMiHOG000037951.
HOVERGENiHBG018823.
InParanoidiQ9GL65.
KOiK10160.

Family and domain databases

Gene3Di3.40.50.10140. 1 hit.
3.80.10.10. 4 hits.
InterProiIPR000483. Cys-rich_flank_reg_C.
IPR032675. L_dom-like.
IPR001611. Leu-rich_rpt.
IPR003591. Leu-rich_rpt_typical-subtyp.
IPR000157. TIR_dom.
IPR027168. TLR4.
[Graphical view]
PANTHERiPTHR24365:SF230. PTHR24365:SF230. 2 hits.
PfamiPF13516. LRR_6. 1 hit.
PF13855. LRR_8. 4 hits.
PF01582. TIR. 1 hit.
[Graphical view]
SMARTiSM00369. LRR_TYP. 13 hits.
SM00082. LRRCT. 1 hit.
SM00255. TIR. 1 hit.
[Graphical view]
SUPFAMiSSF52200. SSF52200. 1 hit.
PROSITEiPS51450. LRR. 13 hits.
PS50104. TIR. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiTLR4_BOVIN
AccessioniPrimary (citable) accession number: Q9GL65
Secondary accession number(s): Q0MW16, Q6GV19
Entry historyi
Integrated into UniProtKB/Swiss-Prot: February 11, 2002
Last sequence update: February 11, 2002
Last modified: October 5, 2016
This is version 113 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.