TLR4_PANPA
ID TLR4_PANPA Reviewed; 839 AA.
AC Q9TTN0;
DT 11-FEB-2002, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-2000, sequence version 1.
DT 25-MAY-2022, entry version 122.
DE RecName: Full=Toll-like receptor 4;
DE AltName: CD_antigen=CD284;
DE Flags: Precursor;
GN Name=TLR4;
OS Pan paniscus (Pygmy chimpanzee) (Bonobo).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Pan.
OX NCBI_TaxID=9597;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=11104518; DOI=10.1186/gb-2000-1-1-research002;
RA Smirnova I., Poltorak A., Chan E.K.L., McBride C., Beutler B.;
RT "Phylogenetic variation and polymorphism at the Toll-like receptor 4 locus
RT (TLR4).";
RL Genome Biol. 1:RESEARCH002.1-RESEARCH002.10(2000).
CC -!- FUNCTION: Cooperates with LY96 and CD14 to mediate the innate immune
CC response to bacterial lipopolysaccharide (LPS). Acts via MYD88, TIRAP
CC and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the
CC inflammatory response (By similarity). Also involved in LPS-independent
CC inflammatory responses triggered by free fatty acids, such as
CC palmitate. In complex with TLR6, promotes sterile inflammation in
CC monocytes/macrophages in response to oxidized low-density lipoprotein
CC (oxLDL) or amyloid-beta 42. In this context, the initial signal is
CC provided by oxLDL- or amyloid-beta 42-binding to CD36. This event
CC induces the formation of a heterodimer of TLR4 and TLR6, which is
CC rapidly internalized and triggers inflammatory response, leading to the
CC NF-kappa-B-dependent production of CXCL1, CXCL2 and CCL9 cytokines, via
CC MYD88 signaling pathway, and CCL5 cytokine, via TICAM1 signaling
CC pathway, as well as IL1B secretion. Binds electronegative LDL (LDL(-))
CC and mediates the cytokine release induced by LDL(-) (By similarity).
CC Activated by the signaling pathway regulator NMI which acts as damage-
CC associated molecular patterns (DAMPs) in response to cell injury or
CC pathogen invasion, therefore promoting nuclear factor NF-kappa-B
CC activation (By similarity). {ECO:0000250|UniProtKB:O00206,
CC ECO:0000250|UniProtKB:Q9QUK6}.
CC -!- SUBUNIT: Belongs to the lipopolysaccharide (LPS) receptor, a multi-
CC protein complex containing at least CD14, LY96 and TLR4. Binding to
CC bacterial LPS leads to homodimerization. Interacts with LY96 via the
CC extracellular domain. Interacts with MYD88 and TIRAP via their
CC respective TIR domains. Interacts with NOX4. Interacts with CNPY3 and
CC HSP90B1; this interaction is required for proper folding in the
CC endoplasmic reticulum. Interacts with MAP3K21; this interaction leads
CC to negative regulation of TLR4 signaling. Interacts with CD36,
CC following CD36 stimulation by oxLDL or amyloid-beta 42, and forms a
CC heterodimer with TLR6. The trimeric complex is internalized and
CC triggers inflammatory response. LYN kinase activity facilitates TLR4-
CC TLR6 heterodimerization and signal initiation. Interacts with TICAM1 in
CC response to LPS in a WDFY1-dependent manner. Interacts with WDFY1 in
CC response to LPS. Interacts with SMPDL3B. Interacts with CEACAM1; upon
CC lipopolysaccharide stimulation, forms a complex including TLR4 and the
CC phosphorylated form of SYK and CEACAM1, which in turn, recruits PTPN6
CC that dephosphorylates SYK, reducing the production of reactive oxygen
CC species (ROS) and lysosome disruption, which in turn, reduces the
CC activity of the inflammasome. Interacts with RFTN1; the interaction
CC occurs in response to lipopolysaccharide stimulation. Interacts with
CC SCIMP; the interaction occurs in response to lipopolysaccharide
CC stimulation and is enhanced by phosphorylation of SCIMP by LYN (By
CC similarity). This interaction facilitates the phosphorylation of TLR4
CC by LYN which elicits a selective cytokine response in macrophages (By
CC similarity). Interacts with TRAF3IP3 (By similarity). Interacts with
CC TREM1; this interaction enhances TLR4-mediated inflammatory response
CC (By similarity). {ECO:0000250|UniProtKB:O00206,
CC ECO:0000250|UniProtKB:Q9QUK6}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:O00206};
CC Single-pass type I membrane protein {ECO:0000250|UniProtKB:O00206}.
CC Early endosome {ECO:0000250|UniProtKB:O00206}. Cell projection, ruffle
CC {ECO:0000250|UniProtKB:Q9QUK6}. Note=Upon complex formation with CD36
CC and TLR6, internalized through dynamin-dependent endocytosis.
CC Colocalizes with RFTN1 at cell membrane and then together with RFTN1
CC moves to endosomes, upon lipopolysaccharide stimulation.
CC {ECO:0000250|UniProtKB:O00206}.
CC -!- DOMAIN: The TIR domain mediates interaction with NOX4. {ECO:0000250}.
CC -!- PTM: Phosphorylated on tyrosine residues by LYN after binding
CC lipopolysaccharide. {ECO:0000250|UniProtKB:Q9QUK6}.
CC -!- SIMILARITY: Belongs to the Toll-like receptor family. {ECO:0000305}.
CC -!- CAUTION: In some plant proteins and in human SARM1, the TIR domain has
CC NAD(+) hydrolase (NADase) activity (By similarity). However, despite
CC the presence of the catalytic Asp residue, the isolated TIR domain of
CC human TLR4 lacks NADase activity (By similarity). Based on this, it is
CC unlikely that Toll-like receptors have NADase activity.
CC {ECO:0000250|UniProtKB:O00206, ECO:0000305}.
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DR EMBL; AF179220; AAF05320.1; -; Genomic_DNA.
DR EMBL; AF179218; AAF05320.1; JOINED; Genomic_DNA.
DR EMBL; AF179219; AAF05320.1; JOINED; Genomic_DNA.
DR AlphaFoldDB; Q9TTN0; -.
DR SMR; Q9TTN0; -.
DR STRING; 9597.NP_001266152.1; -.
DR eggNOG; KOG4641; Eukaryota.
DR Proteomes; UP000240080; Unplaced.
DR GO; GO:0005769; C:early endosome; IEA:UniProtKB-SubCell.
DR GO; GO:0046696; C:lipopolysaccharide receptor complex; ISS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0001726; C:ruffle; IEA:UniProtKB-SubCell.
DR GO; GO:0001875; F:lipopolysaccharide immune receptor activity; ISS:UniProtKB.
DR GO; GO:0050135; F:NAD(P)+ nucleosidase activity; IEA:UniProtKB-EC.
DR GO; GO:0061809; F:NAD+ nucleotidase, cyclic ADP-ribose generating; IEA:UniProtKB-EC.
DR GO; GO:0004888; F:transmembrane signaling receptor activity; IEA:InterPro.
DR GO; GO:0032497; P:detection of lipopolysaccharide; ISS:UniProtKB.
DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0042116; P:macrophage activation; ISS:UniProtKB.
DR GO; GO:0032731; P:positive regulation of interleukin-1 beta production; ISS:UniProtKB.
DR GO; GO:1900227; P:positive regulation of NLRP3 inflammasome complex assembly; ISS:UniProtKB.
DR GO; GO:0002224; P:toll-like receptor signaling pathway; IEA:InterPro.
DR Gene3D; 3.40.50.10140; -; 1.
DR Gene3D; 3.80.10.10; -; 1.
DR InterPro; IPR000483; Cys-rich_flank_reg_C.
DR InterPro; IPR001611; Leu-rich_rpt.
DR InterPro; IPR003591; Leu-rich_rpt_typical-subtyp.
DR InterPro; IPR032675; LRR_dom_sf.
DR InterPro; IPR000157; TIR_dom.
DR InterPro; IPR017241; Toll-like_receptor.
DR InterPro; IPR035897; Toll_tir_struct_dom_sf.
DR PANTHER; PTHR24365; PTHR24365; 1.
DR Pfam; PF13855; LRR_8; 3.
DR Pfam; PF01582; TIR; 1.
DR PIRSF; PIRSF037595; Toll-like_receptor; 1.
DR SMART; SM00369; LRR_TYP; 11.
DR SMART; SM00082; LRRCT; 1.
DR SMART; SM00255; TIR; 1.
DR SUPFAM; SSF52200; SSF52200; 1.
DR PROSITE; PS51450; LRR; 11.
DR PROSITE; PS50104; TIR; 1.
PE 3: Inferred from homology;
KW Cell membrane; Cell projection; Disulfide bond; Endosome; Glycoprotein;
KW Immunity; Inflammatory response; Innate immunity; Leucine-rich repeat;
KW Membrane; NAD; Receptor; Reference proteome; Repeat; Signal; Transmembrane;
KW Transmembrane helix.
FT SIGNAL 1..23
FT /evidence="ECO:0000255"
FT CHAIN 24..839
FT /note="Toll-like receptor 4"
FT /id="PRO_0000034724"
FT TOPO_DOM 24..631
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 632..652
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 653..839
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT REPEAT 55..76
FT /note="LRR 1"
FT REPEAT 79..100
FT /note="LRR 2"
FT REPEAT 103..124
FT /note="LRR 3"
FT REPEAT 127..148
FT /note="LRR 4"
FT REPEAT 151..172
FT /note="LRR 5"
FT REPEAT 176..199
FT /note="LRR 6"
FT REPEAT 205..225
FT /note="LRR 7"
FT REPEAT 227..247
FT /note="LRR 8"
FT REPEAT 331..351
FT /note="LRR 9"
FT REPEAT 352..373
FT /note="LRR 10"
FT REPEAT 374..394
FT /note="LRR 11"
FT REPEAT 400..422
FT /note="LRR 12"
FT REPEAT 423..444
FT /note="LRR 13"
FT REPEAT 448..456
FT /note="LRR 14"
FT REPEAT 472..495
FT /note="LRR 15"
FT REPEAT 497..518
FT /note="LRR 16"
FT REPEAT 521..542
FT /note="LRR 17"
FT REPEAT 545..565
FT /note="LRR 18"
FT DOMAIN 579..629
FT /note="LRRCT"
FT DOMAIN 672..815
FT /note="TIR"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00204"
FT CARBOHYD 35
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 173
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 205
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 282
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 309
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 497
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 526
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 575
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 624
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 630
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 29..40
FT /evidence="ECO:0000250"
FT DISULFID 281..306
FT /evidence="ECO:0000250"
FT DISULFID 390..391
FT /evidence="ECO:0000250"
FT DISULFID 583..609
FT /evidence="ECO:0000250"
FT DISULFID 585..627
FT /evidence="ECO:0000250"
SQ SEQUENCE 839 AA; 95638 MW; 3B328C5682127D37 CRC64;
MMSASRLAGT LIPAMAFLSC VRPESWEPCV EVVPNITYQC MELNFYKIPD NLPFSTKNLD
LSFNPLRHLG SYSFFSFPEL QVLDLSRCEI QTIEDGAYQS LSHLSTLILT GNPIQSLALG
AFSGLSSLQK LVAVETNLAS LENFPIGHLK TLKELNVAHN LIQSFKLPEY FSNLTNLEHL
DLSSNKIQSI YCTDLRVLHQ MPLLNLSLDL SLNPMNFIQP GAFKEIRLHK LTLRNNFDSL
NVMKTCIQGL AGLEVHRLVL GEFRNEGNLE KFDKSALEGL CNLTIEEFRL AYLDYYLDDI
IDLFNCLTNV SSFSLVSVTI KSVKDFSYNF GWQHLELVNC KFGQFPTLKL KSLKRLTFTS
NKGGNAFSEV DLPSLEFLDL SRNGLSFKGC CSQSDFGTTS LKYLDLSFNG VITMSSNFLG
LEQLEHLDFQ HSNLKQMSEF SVFLSLRNLI YLDISHTHTR VAFNGIFNGL SSLEVLKMAG
NSFQENFLPD IFTELRNLTF LDLSQCQLEQ LSPTAFNSLS SLQVLNMSHN NFFSLDTFPY
KCLNSLQVLD YSLNHIMTSK KQELQHFPSS LAFLNLTQND FACTCEHQSF LQWIKDQRQL
LVEVERMECA TPSDKQGMPV LSLNITCQMN KTIIGVSVLS VLVVSVVAVL VYKFYFHLML
LAGCIKYGRG ENIYDAFVIY SSQDEDWVRN ELVKNLEEGV PPFQLCLHYR DFIPGVAIAA
NIIHEGFHKS RKVIVVVSQH FIQSRWCIFE YEIAQTWQFL SSRAGIIFIV LQKVEKTLLR
RQVELYRLLS RNTYLEWEDS VLGRHIFWRR LRKALLDGKS WNPEGTVGTG CNWQEATSI
