TLR4_FELCA
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 25-MAY-2022, entry version 119.
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: 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 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).
CC {ECO:0000250|UniProtKB:O00206, 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 GeneID; 493698; -.
DR KEGG; fca:493698; -.
DR CTD; 7099; -.
DR eggNOG; KOG4641; Eukaryota.
DR InParanoid; P58727; -.
DR OrthoDB; 282372at2759; -.
DR Proteomes; UP000011712; Unplaced.
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; PF00560; LRR_1; 1.
DR Pfam; PF13855; LRR_8; 3.
DR Pfam; PF01582; TIR; 1.
DR PIRSF; PIRSF037595; Toll-like_receptor; 1.
DR SMART; SM00369; LRR_TYP; 9.
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 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
