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Protein

Toll-like receptor 4

Gene

TLR4

Organism
Pan paniscus (Pygmy chimpanzee) (Bonobo)
Status
Reviewed-Annotation score: Annotation score: 4 out of 5-Protein inferred from homologyi

Functioni

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. 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 similarity

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
OrganismiPan paniscus (Pygmy chimpanzee) (Bonobo)
Taxonomic identifieri9597 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaePan

Subcellular locationi

  • Cell membrane By similarity; 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 – 631ExtracellularSequence analysisAdd BLAST608
Transmembranei632 – 652HelicalSequence analysisAdd BLAST21
Topological domaini653 – 839CytoplasmicSequence analysisAdd BLAST187

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_000003472424 – 839Toll-like receptor 4Add BLAST816

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi29 ↔ 40By similarity
Glycosylationi35N-linked (GlcNAc...)Sequence analysis1
Glycosylationi173N-linked (GlcNAc...)Sequence analysis1
Glycosylationi205N-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 ↔ 627By similarity
Glycosylationi624N-linked (GlcNAc...)Sequence analysis1
Glycosylationi630N-linked (GlcNAc...)Sequence analysis1

Keywords - PTMi

Disulfide bond, Glycoprotein

Interactioni

Subunit structurei

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 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. Interacts with WDFY1 in response to LPS. Interacts with SMPDL3B. 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 similarity

Structurei

3D structure databases

ProteinModelPortaliQ9TTN0.
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 – 199LRR 6Add BLAST24
Repeati205 – 225LRR 7Add BLAST21
Repeati227 – 247LRR 8Add BLAST21
Repeati331 – 351LRR 9Add BLAST21
Repeati352 – 373LRR 10Add BLAST22
Repeati374 – 394LRR 11Add BLAST21
Repeati400 – 422LRR 12Add BLAST23
Repeati423 – 444LRR 13Add BLAST22
Repeati448 – 456LRR 149
Repeati472 – 495LRR 15Add BLAST24
Repeati497 – 518LRR 16Add BLAST22
Repeati521 – 542LRR 17Add BLAST22
Repeati545 – 565LRR 18Add BLAST21
Domaini579 – 629LRRCTAdd BLAST51
Domaini672 – 818TIRPROSITE-ProRule annotationAdd BLAST147

Domaini

The TIR domain mediates interaction with NOX4.By similarity

Sequence similaritiesi

Belongs to the Toll-like receptor family.Curated
Contains 18 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

HOVERGENiHBG018823.

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. 3 hits.
PF01582. TIR. 1 hit.
[Graphical view]
SMARTiSM00369. LRR_TYP. 11 hits.
SM00082. LRRCT. 1 hit.
SM00255. TIR. 1 hit.
[Graphical view]
SUPFAMiSSF52058. SSF52058. 2 hits.
SSF52200. SSF52200. 1 hit.
PROSITEiPS51450. LRR. 11 hits.
PS50104. TIR. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

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

Q9TTN0-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MMSASRLAGT LIPAMAFLSC VRPESWEPCV EVVPNITYQC MELNFYKIPD
60 70 80 90 100
NLPFSTKNLD LSFNPLRHLG SYSFFSFPEL QVLDLSRCEI QTIEDGAYQS
110 120 130 140 150
LSHLSTLILT GNPIQSLALG AFSGLSSLQK LVAVETNLAS LENFPIGHLK
160 170 180 190 200
TLKELNVAHN LIQSFKLPEY FSNLTNLEHL DLSSNKIQSI YCTDLRVLHQ
210 220 230 240 250
MPLLNLSLDL SLNPMNFIQP GAFKEIRLHK LTLRNNFDSL NVMKTCIQGL
260 270 280 290 300
AGLEVHRLVL GEFRNEGNLE KFDKSALEGL CNLTIEEFRL AYLDYYLDDI
310 320 330 340 350
IDLFNCLTNV SSFSLVSVTI KSVKDFSYNF GWQHLELVNC KFGQFPTLKL
360 370 380 390 400
KSLKRLTFTS NKGGNAFSEV DLPSLEFLDL SRNGLSFKGC CSQSDFGTTS
410 420 430 440 450
LKYLDLSFNG VITMSSNFLG LEQLEHLDFQ HSNLKQMSEF SVFLSLRNLI
460 470 480 490 500
YLDISHTHTR VAFNGIFNGL SSLEVLKMAG NSFQENFLPD IFTELRNLTF
510 520 530 540 550
LDLSQCQLEQ LSPTAFNSLS SLQVLNMSHN NFFSLDTFPY KCLNSLQVLD
560 570 580 590 600
YSLNHIMTSK KQELQHFPSS LAFLNLTQND FACTCEHQSF LQWIKDQRQL
610 620 630 640 650
LVEVERMECA TPSDKQGMPV LSLNITCQMN KTIIGVSVLS VLVVSVVAVL
660 670 680 690 700
VYKFYFHLML LAGCIKYGRG ENIYDAFVIY SSQDEDWVRN ELVKNLEEGV
710 720 730 740 750
PPFQLCLHYR DFIPGVAIAA NIIHEGFHKS RKVIVVVSQH FIQSRWCIFE
760 770 780 790 800
YEIAQTWQFL SSRAGIIFIV LQKVEKTLLR RQVELYRLLS RNTYLEWEDS
810 820 830
VLGRHIFWRR LRKALLDGKS WNPEGTVGTG CNWQEATSI
Length:839
Mass (Da):95,638
Last modified:May 1, 2000 - v1
Checksum:i3B328C5682127D37
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF179220, AF179218, AF179219 Genomic DNA. Translation: AAF05320.1.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF179220, AF179218, AF179219 Genomic DNA. Translation: AAF05320.1.

3D structure databases

ProteinModelPortaliQ9TTN0.
ModBaseiSearch...
MobiDBiSearch...

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Phylogenomic databases

HOVERGENiHBG018823.

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. 3 hits.
PF01582. TIR. 1 hit.
[Graphical view]
SMARTiSM00369. LRR_TYP. 11 hits.
SM00082. LRRCT. 1 hit.
SM00255. TIR. 1 hit.
[Graphical view]
SUPFAMiSSF52058. SSF52058. 2 hits.
SSF52200. SSF52200. 1 hit.
PROSITEiPS51450. LRR. 11 hits.
PS50104. TIR. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiTLR4_PANPA
AccessioniPrimary (citable) accession number: Q9TTN0
Entry historyi
Integrated into UniProtKB/Swiss-Prot: February 11, 2002
Last sequence update: May 1, 2000
Last modified: October 5, 2016
This is version 98 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

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.