ID TLR4_FELCA Reviewed; 833 AA.
AC P58727;
DT 11-FEB-2002, integrated into UniProtKB/Swiss-Prot.
DT 11-FEB-2002, sequence version 1.
DT 27-MAR-2024, entry version 126.
DE RecName: Full=Toll-like receptor 4;
DE AltName: CD_antigen=CD284;
DE Flags: Precursor;
GN Name=TLR4;
OS Felis catus (Cat) (Felis silvestris catus).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Carnivora; Feliformia; Felidae; Felinae; Felis.
OX NCBI_TaxID=9685;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Yoshioka N., Kano R.;
RT "Felis catus Toll like receptor 4.";
RL Submitted (APR-2001) to the EMBL/GenBank/DDBJ databases.
CC -!- FUNCTION: Transmembrane receptor that functions as a pattern
CC recognition receptor recognizing pathogen- and damage-associated
CC molecular patterns (PAMPs and DAMPs) to induce innate immune responses
CC via downstream signaling pathways. At the plasma membrane, cooperates
CC with LY96 to mediate the innate immune response to bacterial
CC lipopolysaccharide (LPS). Also involved in LPS-independent inflammatory
CC responses triggered by free fatty acids, such as palmitate, and Ni(2+).
CC Mechanistically, acts via MYD88, TIRAP and TRAF6, leading to NF-kappa-B
CC activation, cytokine secretion and the inflammatory response.
CC Alternatively, CD14-mediated TLR4 internalization via endocytosis is
CC associated with the initiation of a MYD88-independent signaling via the
CC TICAM1-TBK1-IRF3 axis leading to type I interferon production. In
CC addition to the secretion of proinflammatory cytokines, initiates the
CC activation of NLRP3 inflammasome and formation of a positive feedback
CC loop between autophagy and NF-kappa-B signaling cascade. In complex
CC with TLR6, promotes inflammation in monocytes/macrophages by
CC associating with TLR6 and the receptor CD86. Upon ligand binding, such
CC as oxLDL or amyloid-beta 42, the TLR4:TLR6 complex is internalized and
CC triggers inflammatory response, leading to NF-kappa-B-dependent
CC production of CXCL1, CXCL2 and CCL9 cytokines, via MYD88 signaling
CC pathway, and CCL5 cytokine, via TICAM1 signaling pathway. In myeloid
CC dendritic cells, vesicular stomatitis virus glycoprotein G but not LPS
CC promotes the activation of IRF7, leading to type I IFN production in a
CC CD14-dependent manner. {ECO:0000250|UniProtKB:O00206}.
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 TICAM2. Interacts with NOX4.
CC Interacts with CNPY3 and HSP90B1; this interaction is required for
CC proper folding in the endoplasmic reticulum. Interacts with MAP3K21;
CC this interaction leads to negative regulation of TLR4 signaling.
CC Interacts with CD36, following CD36 stimulation by oxLDL or amyloid-
CC beta 42, and forms a heterodimer with TLR6. The trimeric complex is
CC internalized and triggers inflammatory response. LYN kinase activity
CC facilitates TLR4-TLR6 heterodimerization and signal initiation.
CC Interacts with TICAM1 in response to LPS in a WDFY1-dependent manner.
CC Interacts with WDFY1 in response to LPS. Interacts with SMPDL3B.
CC Interacts with CEACAM1; upon lipopolysaccharide stimulation, forms a
CC complex including TLR4 and the phosphorylated form of SYK and CEACAM1,
CC which in turn, recruits PTPN6 that dephosphorylates SYK, reducing the
CC production of reactive oxygen species (ROS) and lysosome disruption,
CC which in turn, reduces the activity of the inflammasome. Interacts with
CC RFTN1; the interaction occurs in response to lipopolysaccharide
CC stimulation. Interacts with SCIMP; the interaction occurs in response
CC to lipopolysaccharide stimulation and is enhanced by phosphorylation of
CC SCIMP by LYN (By similarity). This interaction facilitates the
CC phosphorylation of TLR4 by LYN which elicits a selective cytokine
CC response in macrophages (By similarity). Interacts with TRAF3IP3 (By
CC similarity). Interacts with TREM1; this interaction enhances TLR4-
CC mediated inflammatory response (By similarity). Interacts with
CC ZG16B/PAUF (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.
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; AB060687; BAB43947.1; -; mRNA.
DR RefSeq; NP_001009223.1; NM_001009223.1.
DR AlphaFoldDB; P58727; -.
DR SMR; P58727; -.
DR STRING; 9685.ENSFCAP00000023731; -.
DR GlyCosmos; P58727; 10 sites, No reported glycans.
DR PaxDb; 9685-ENSFCAP00000023731; -.
DR GeneID; 493698; -.
DR KEGG; fca:493698; -.
DR eggNOG; KOG4641; Eukaryota.
DR InParanoid; P58727; -.
DR OrthoDB; 1207361at2759; -.
DR Proteomes; UP000011712; 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; 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: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:0002755; P:MyD88-dependent toll-like receptor signaling pathway; IBA:GO_Central.
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:0034142; P:toll-like receptor 4 signaling pathway; IBA:GO_Central.
DR Gene3D; 3.80.10.10; Ribonuclease Inhibitor; 1.
DR Gene3D; 3.40.50.10140; Toll/interleukin-1 receptor homology (TIR) domain; 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; TOLL-LIKE RECEPTOR; 1.
DR PANTHER; PTHR24365:SF521; TOLL-LIKE RECEPTOR 4; 1.
DR Pfam; PF00560; LRR_1; 1.
DR Pfam; PF13855; LRR_8; 3.
DR Pfam; PF01582; TIR; 1.
DR PIRSF; PIRSF037595; Toll-like_receptor; 1.
DR PRINTS; PR00019; LEURICHRPT.
DR SMART; SM00365; LRR_SD22; 7.
DR SMART; SM00369; LRR_TYP; 9.
DR SMART; SM00082; LRRCT; 1.
DR SMART; SM00255; TIR; 1.
DR SUPFAM; SSF52075; Outer arm dynein light chain 1; 1.
DR SUPFAM; SSF52047; RNI-like; 1.
DR SUPFAM; SSF52200; Toll/Interleukin receptor TIR domain; 1.
DR PROSITE; PS51450; LRR; 13.
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..833
FT /note="Toll-like receptor 4"
FT /id="PRO_0000034719"
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..833
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..236
FT /note="LRR 8"
FT REPEAT 352..373
FT /note="LRR 9"
FT REPEAT 374..394
FT /note="LRR 10"
FT REPEAT 400..420
FT /note="LRR 11"
FT REPEAT 423..444
FT /note="LRR 12"
FT REPEAT 448..456
FT /note="LRR 13"
FT REPEAT 472..495
FT /note="LRR 14"
FT REPEAT 497..518
FT /note="LRR 15"
FT REPEAT 521..542
FT /note="LRR 16"
FT REPEAT 545..565
FT /note="LRR 17"
FT DOMAIN 579..630
FT /note="LRRCT"
FT DOMAIN 673..816
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 238
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 570
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 833 AA; 95592 MW; 3E3A84F2BEBA55EA CRC64;
MMPPTRLAGT LIPAMAFLSC LRPESWDPCV EVVPNITYQC MDLNLHKIPD NIPSSTKDLD
MSFNPLRNLG SHSFSNFPEL QVLDLSRCEI QIIEDDAYQG LNHLSILILT GNPIQRLFPG
AFSGLSSLQT LVAVETNIAS LEDFPIGHLK TLKELNVAHN LIHSFKLPEY FSNMSNLEYL
DLSNNKIQNI YHKDLQVLHQ KPLLNLSLDL SLNPLDFIQP GAFKEVKLRE LTLRSNFNST
DVMKASIQGL AGLQIHQLVL GEFKNERNLG RFDKSILEGL CNLIIEKFRI AYFDKFSEDA
IDSFNCLANV STISLVHLYF KGLKQLPKNL GWQRLELVNC EFEQFPTWKL DPLKELVFSA
NEVRNAFTQV KLESLEFLDL SRNDFSLKSC CSERDLGTTR LKHLDLSFNN IITISSNFLG
LEQLEYLDFQ HSSLKQVSDF SVFLPLKNLR YLDISYTHTQ VAFHGIFNGL ISLQILKMAG
NSFQDNFLPN IFMELTNLTI LDLSDCQLEQ VSQVAFNSLP KLQLLNMSHN HLLSLDTLPY
EPLHSLQTLD CSFNRIVASK EQELRHFPSN LSSLNLTRND FACVCEHQSF LQWVKDQRQL
LVEVEQMVCA KPLDMQGMPM LNFRNATCQV RKTIITGSVF TVLLVFLVVV LVYKFYFHLM
LLAGCKKYSR GESTYDAFVI YSSQDEDWVR NELVKNLEEG VPPFQLCLHY RDFIPGVAIA
ANIIQEGFHK SRKVIVVVSQ HFIQSRWCIF EYGIAQTWQF LSSRAGIIFI VLQKLEKSLL
RQQVELYRLL NRNTYLEWED SVLGRHIFWR RLRKALLDGK PRCPEGMADA EGS
//