TLR4_HORSE
ID TLR4_HORSE Reviewed; 843 AA.
AC Q9MYW3;
DT 11-FEB-2002, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-2000, sequence version 1.
DT 03-AUG-2022, entry version 138.
DE RecName: Full=Toll-like receptor 4;
DE AltName: CD_antigen=CD284;
DE Flags: Precursor;
GN Name=TLR4;
OS Equus caballus (Horse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Perissodactyla; Equidae; Equus.
OX NCBI_TaxID=9796;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Vandenplas M.L., McNeill B.W., Barton M.H., Moore J.N.;
RT "Cloning and sequencing of equine Toll-like receptor 4 (TLR4).";
RL Submitted (JUL-2000) to the EMBL/GenBank/DDBJ databases.
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}. Early endosome
CC {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}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; AY005808; AAF91076.1; -; mRNA.
DR RefSeq; NP_001093239.2; NM_001099769.2.
DR AlphaFoldDB; Q9MYW3; -.
DR SMR; Q9MYW3; -.
DR STRING; 9796.ENSECAP00000008292; -.
DR PaxDb; Q9MYW3; -.
DR Ensembl; ENSECAT00000010707; ENSECAP00000008292; ENSECAG00000010339.
DR Ensembl; ENSECAT00000044702; ENSECAP00000033420; ENSECAG00000033740.
DR GeneID; 100066890; -.
DR KEGG; ecb:100066890; -.
DR CTD; 7099; -.
DR VGNC; VGNC:56909; TLR4.
DR GeneTree; ENSGT00940000160778; -.
DR InParanoid; Q9MYW3; -.
DR OrthoDB; 282372at2759; -.
DR Proteomes; UP000002281; Chromosome 25.
DR Bgee; ENSECAG00000010339; Expressed in chorionic villus and 19 other tissues.
DR GO; GO:0005769; C:early endosome; IEA:UniProtKB-SubCell.
DR GO; GO:0005887; C:integral component of plasma membrane; IBA:GO_Central.
DR GO; GO:0046696; C:lipopolysaccharide receptor complex; ISS:UniProtKB.
DR GO; GO:0001726; C:ruffle; IEA:UniProtKB-SubCell.
DR GO; GO:0001530; F:lipopolysaccharide binding; IBA:GO_Central.
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:0038023; F:signaling receptor activity; IBA:GO_Central.
DR GO; GO:0004888; F:transmembrane signaling receptor activity; IEA:InterPro.
DR GO; GO:0050829; P:defense response to Gram-negative bacterium; IBA:GO_Central.
DR GO; GO:0032497; P:detection of lipopolysaccharide; ISS:UniProtKB.
DR GO; GO:0006954; P:inflammatory response; IBA:GO_Central.
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; IBA:GO_Central.
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; PF13516; LRR_6; 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; 12.
DR PROSITE; PS50104; TIR; 1.
PE 2: Evidence at transcript level;
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..843
FT /note="Toll-like receptor 4"
FT /id="PRO_0000034721"
FT TOPO_DOM 24..633
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 634..654
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 655..843
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 24..54
FT /note="LRRNT"
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..197
FT /note="LRR 6"
FT REPEAT 205..225
FT /note="LRR 7"
FT REPEAT 227..247
FT /note="LRR 8"
FT REPEAT 353..374
FT /note="LRR 9"
FT REPEAT 375..398
FT /note="LRR 10"
FT REPEAT 401..423
FT /note="LRR 11"
FT REPEAT 424..445
FT /note="LRR 12"
FT REPEAT 449..459
FT /note="LRR 13"
FT REPEAT 473..496
FT /note="LRR 14"
FT REPEAT 498..519
FT /note="LRR 15"
FT REPEAT 522..543
FT /note="LRR 16"
FT REPEAT 546..569
FT /note="LRR 17"
FT DOMAIN 580..631
FT /note="LRRCT"
FT DOMAIN 674..817
FT /note="TIR"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00204"
FT REGION 824..843
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT CARBOHYD 35
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 189
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 295
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 498
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 527
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 576
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 626
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 29..40
FT /evidence="ECO:0000250"
FT DISULFID 391..392
FT /evidence="ECO:0000250"
FT DISULFID 584..610
FT /evidence="ECO:0000250"
FT DISULFID 586..629
FT /evidence="ECO:0000250"
SQ SEQUENCE 843 AA; 96496 MW; B5976898AD6F7A69 CRC64;
MMPPTRLAGT LIPAMAFLSC LRPESWDPCV QVVPNTTYQC MDLNLYKIPE NIPTSTKELD
LSFNPLKELG SHSFSNFPEL QVLDLSRCEI EMIEDDAYQG LNHLSTLILT GNPIRSLALG
AFSGLSSLQT LVAVETKLSS LEKFPIGHLK TLKELNVAHN LIHSFKLPEY FSKMPNLEHL
DLSNNKIQNI SHEDLRVLHQ MPLLNLSLDL SLNPLEFIQP DAFKEIKLHK LTLRSNFDSI
DVMKSCIQGL AGLKVNRLVL GEFKNERKLE RFDTSALRGL HNLTIEEFRL AYIDNYSSKD
SIDLLNCLAD ISKISLVSLD LGNLKDFPKG FGWQDFELVN CRIEGFPTLE LTSLKRLVFT
SNKDMKSFNE VKLPSLEFLD LSRNRLSFKS CCSEADLKTT RLKHLDLSFN DVISMSSNFM
GLEQLEHLDF QHSTLKQASD FPVFLSLKNL RYLDISYTNT RVVFHGIFDG LVSLQVLKMA
GNSFKDNFLP NIFREMTNLT TLDLSKCNLE QVSQEAFCLL PRLRVLNMSH NNLLFLDMLP
YKPLHSLQIL DCSFNRIVAF KWQELQHFPS SLASLNLTQN DFACVCEYQS FLQWVKDQRQ
LLVEVEHLVC AIPLQMRGMP VLGFNNATCQ ISKTIVGGSV FSILMVSVIA VLVYKFYFHL
MLLAGCKKYG RGESIYDAFV IYSSQDEDWV RNELVKNLEE GVPPFQLCLH YRDFIPGVAI
AANIIQEGFH KSRKVIVVVS QHFIQSRWCI FEYEIAQTWQ FLSSRAGIIF IVLHKLEKSL
LRQQVELYRL LNRNTYLEWE DSVLGRHIFW RRLRKALLDG KPWSPAGTAD AAESRQHDAE
TST
