TLR4_BOVIN
ID TLR4_BOVIN Reviewed; 841 AA.
AC Q9GL65; Q0MW16; Q6GV19;
DT 11-FEB-2002, integrated into UniProtKB/Swiss-Prot.
DT 11-FEB-2002, sequence version 2.
DT 25-MAY-2022, entry version 137.
DE RecName: Full=Toll-like receptor 4;
DE AltName: CD_antigen=CD284;
DE Flags: Precursor;
GN Name=TLR4;
OS Bos taurus (Bovine).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae;
OC Bovinae; Bos.
OX NCBI_TaxID=9913;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Guionaud C.T., Dubey C., Jungi T.W.;
RT "Bovine Toll-like receptor 4 (TLR4).";
RL Submitted (NOV-2001) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Werling D., McGuire K., Glass E.;
RT "Role of bovine TLRs in antigen presentation.";
RL Submitted (MAY-2004) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Mammary gland;
RA Wang X.P., Xu S.Z., Gao X., Ma T.H., Ren H.Y., Chen J.B.;
RT "cDNA cloning and sequence analysis of signalling molecules on bovine toll-
RT like receptors.";
RL Submitted (JUL-2006) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP FUNCTION, SUBCELLULAR LOCATION, AND SUBUNIT.
RX PubMed=17559944; DOI=10.1016/j.vetimm.2007.04.017;
RA Sauter K.S., Brcic M., Franchini M., Jungi T.W.;
RT "Stable transduction of bovine TLR4 and bovine MD-2 into LPS-nonresponsive
RT cells and soluble CD14 promote the ability to respond to LPS.";
RL Vet. Immunol. Immunopathol. 118:92-104(2007).
CC -!- FUNCTION: Cooperates with LY96 and CD14 to mediate the innate immune
CC response to bacterial lipopolysaccharide (LPS) (PubMed:17559944). Acts
CC via MYD88, TIRAP and TRAF6, leading to NF-kappa-B activation, cytokine
CC secretion and the inflammatory response. Also involved in LPS-
CC independent inflammatory responses triggered by free fatty acids, such
CC as 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:0000269|PubMed:17559944}.
CC -!- SUBUNIT: Belongs to the lipopolysaccharide (LPS) receptor, a multi-
CC protein complex containing at least CD14, LY96 and TLR4
CC (PubMed:17559944). Binding to bacterial LPS leads to homodimerization.
CC Interacts with LY96 via the extracellular domain. Interacts with MYD88
CC and TIRAP via their respective TIR domains. Interacts with TICAM2.
CC Interacts with NOX4. Interacts with CNPY3 and HSP90B1; this interaction
CC is required for proper folding in the endoplasmic reticulum. Interacts
CC with MAP3K21; this interaction leads to negative regulation of TLR4
CC signaling. Interacts with CD36, following CD36 stimulation by oxLDL or
CC amyloid-beta 42, and forms a heterodimer with TLR6. The trimeric
CC complex is internalized and triggers inflammatory response. LYN kinase
CC activity facilitates TLR4-TLR6 heterodimerization and signal
CC initiation. Interacts with TICAM1 in response to LPS in a WDFY1-
CC dependent manner (By similarity). Interacts with WDFY1 in response to
CC LPS. Interacts with SMPDL3B (By similarity). Interacts with CEACAM1;
CC upon lipopolysaccharide stimulation, forms a complex including TLR4 and
CC the phosphorylated form of SYK and CEACAM1, which in turn, recruits
CC PTPN6 that dephosphorylates SYK, reducing the production of reactive
CC oxygen species (ROS) and lysosome disruption, which in turn, reduces
CC the activity of the inflammasome (By similarity). Interacts with RFTN1;
CC the interaction occurs in response to lipopolysaccharide stimulation
CC (By similarity). Interacts with SCIMP; the interaction occurs in
CC response to lipopolysaccharide stimulation and is enhanced by
CC phosphorylation of SCIMP by LYN (By similarity). This interaction
CC facilitates the phosphorylation of TLR4 by LYN which elicits a
CC selective cytokine response in macrophages (By similarity). Interacts
CC with TRAF3IP3 (By similarity). Interacts with TREM1; this interaction
CC enhances TLR4-mediated inflammatory response (By similarity).
CC {ECO:0000250|UniProtKB:O00206, ECO:0000250|UniProtKB:Q9QUK6,
CC ECO:0000305|PubMed:17559944}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:O00206,
CC ECO:0000269|PubMed:17559944}; Single-pass type I membrane protein
CC {ECO:0000250|UniProtKB:O00206}. 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.
CC {ECO:0000250|UniProtKB:O00206}.
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; AF310952; AAG32061.2; -; mRNA.
DR EMBL; AY634630; AAT48488.1; -; mRNA.
DR EMBL; DQ839566; ABH09759.1; -; mRNA.
DR RefSeq; NP_776623.5; NM_174198.6.
DR AlphaFoldDB; Q9GL65; -.
DR SMR; Q9GL65; -.
DR STRING; 9913.ENSBTAP00000008190; -.
DR PaxDb; Q9GL65; -.
DR GeneID; 281536; -.
DR KEGG; bta:281536; -.
DR CTD; 7099; -.
DR eggNOG; KOG4641; Eukaryota.
DR InParanoid; Q9GL65; -.
DR OrthoDB; 282372at2759; -.
DR Proteomes; UP000009136; 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; PF13516; LRR_6; 1.
DR Pfam; PF13855; LRR_8; 4.
DR Pfam; PF01582; TIR; 1.
DR PIRSF; PIRSF037595; Toll-like_receptor; 1.
DR SMART; SM00369; LRR_TYP; 13.
DR SMART; SM00082; LRRCT; 1.
DR SMART; SM00255; TIR; 1.
DR SUPFAM; SSF52200; SSF52200; 1.
DR PROSITE; PS51450; LRR; 13.
DR PROSITE; PS50104; TIR; 1.
PE 1: Evidence at protein 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..841
FT /note="Toll-like receptor 4"
FT /id="PRO_0000034717"
FT TOPO_DOM 24..632
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 633..653
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 654..841
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..197
FT /note="LRR 6"
FT REPEAT 205..225
FT /note="LRR 7"
FT REPEAT 352..373
FT /note="LRR 8"
FT REPEAT 374..394
FT /note="LRR 9"
FT REPEAT 400..422
FT /note="LRR 10"
FT REPEAT 423..444
FT /note="LRR 11"
FT REPEAT 448..469
FT /note="LRR 12"
FT REPEAT 472..495
FT /note="LRR 13"
FT REPEAT 497..518
FT /note="LRR 14"
FT REPEAT 521..542
FT /note="LRR 15"
FT REPEAT 545..568
FT /note="LRR 16"
FT DOMAIN 579..630
FT /note="LRRCT"
FT DOMAIN 673..816
FT /note="TIR"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00204"
FT REGION 820..841
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 826..841
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT CARBOHYD 35
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 73
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 238
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 625
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 29..40
FT /evidence="ECO:0000250|UniProtKB:O00206"
FT DISULFID 281..306
FT /evidence="ECO:0000250|UniProtKB:O00206"
FT DISULFID 390..391
FT /evidence="ECO:0000250|UniProtKB:O00206"
FT DISULFID 583..609
FT /evidence="ECO:0000250|UniProtKB:O00206"
FT DISULFID 585..628
FT /evidence="ECO:0000250|UniProtKB:O00206"
SQ SEQUENCE 841 AA; 96027 MW; C5E17CB9C798CD16 CRC64;
MMARARLAAA LIPATAILSC LRTESWDPCV QVVPNISYQC MELNLYKIPD NIPISTKMLD
LSFNYLRHLG SHNFSSFPEL QVLDLSRCEI KIIEDDTFQG LNHLSTLILT GNPIQSLAWG
AFSGLSSLQK LVAVETNLVS LNDFPIGHLK NLKELNVAHN FIHSFKLPEY FSNLPNLEHL
DLSNNKIQNI YYEDVKVLHQ MPLLNLSLDL SLNPLDFIEP GTFKEIKLNG LTLRSNFNSS
HVMKTCIQGL AGLKTNRLVL GEFKNERKLQ RFDRSFLEGL CNLTIEQFRI AYLDKFSGDD
TDLFNCLANV SVISLLSISL GSLQALLKDF RWQHLEIINC DFDKFPALKL SSLKKFVFTD
NKDISTFTEF QLPSLQYLDL KRNHLSFKGC CSHTDFGTTN LKHLDLSFND VITLGSNFMG
LEQLEHLDFQ HSTLKQINAF SAFLSLRNLR YLDISYTNIR IVFHGIFTGL VSLQTLKMAG
NSFQNNLLPD IFTELTNLTV LDLSKCQLEQ VAQTAFHSLS SLQVLNMSHN KLLSLDTFLY
EPLHSLRILD CSFNRIMASK EQELQNLPRS LTWLNLTQNA FACVCEHQSF LQWVKDQRQL
LVGAEQMMCA EPLDMEDMPV LSFRNATCQL SKTIISVSVV TVLLVSVVGV LVYKFYFHLM
LLAGCKKYGR GESIYDAFVI YSSQDEDWVR NELVKNLEEG VPPFQLCLHY RDFIPGVAIA
ANIIQEGFHK SRKVIVVVSQ HFIQSRWCIF EYEIAQTWQF LSSRAGIIFI VLQKLEKSLL
RQQVELYRLL SRNTYLEWED SVLGRHVFWR RLRKALLAGK PQSPEGTADA ETNPQEATTS
T