TLR4_PONPY
ID TLR4_PONPY Reviewed; 828 AA.
AC Q8SPE9;
DT 07-JUN-2004, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-2002, sequence version 1.
DT 25-MAY-2022, entry version 111.
DE RecName: Full=Toll-like receptor 4;
DE AltName: CD_antigen=CD284;
DE Flags: Precursor;
GN Name=TLR4;
OS Pongo pygmaeus (Bornean orangutan).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Pongo.
OX NCBI_TaxID=9600;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=11514453; DOI=10.1093/genetics/158.4.1657;
RA Smirnova I., Hamblin M.T., McBride C., Beutler B., Di Rienzo A.;
RT "Excess of rare amino acid polymorphisms in the Toll-like receptor 4 in
RT humans.";
RL Genetics 158:1657-1664(2001).
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; AF497562; AAM18616.1; -; Genomic_DNA.
DR EMBL; AF497560; AAM18616.1; JOINED; Genomic_DNA.
DR EMBL; AF497561; AAM18616.1; JOINED; Genomic_DNA.
DR AlphaFoldDB; Q8SPE9; -.
DR SMR; Q8SPE9; -.
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; 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; Repeat; Signal; Transmembrane;
KW Transmembrane helix.
FT SIGNAL 1..23
FT /evidence="ECO:0000255"
FT CHAIN 24..828
FT /note="Toll-like receptor 4"
FT /id="PRO_0000034727"
FT TOPO_DOM 24..629
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 630..650
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 651..828
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT REPEAT 53..74
FT /note="LRR 1"
FT REPEAT 77..98
FT /note="LRR 2"
FT REPEAT 101..122
FT /note="LRR 3"
FT REPEAT 125..146
FT /note="LRR 4"
FT REPEAT 149..170
FT /note="LRR 5"
FT REPEAT 174..195
FT /note="LRR 6"
FT REPEAT 203..223
FT /note="LRR 7"
FT REPEAT 225..245
FT /note="LRR 8"
FT REPEAT 372..392
FT /note="LRR 9"
FT REPEAT 398..420
FT /note="LRR 10"
FT REPEAT 421..442
FT /note="LRR 11"
FT REPEAT 446..454
FT /note="LRR 12"
FT REPEAT 470..493
FT /note="LRR 13"
FT REPEAT 495..516
FT /note="LRR 14"
FT REPEAT 519..540
FT /note="LRR 15"
FT REPEAT 543..563
FT /note="LRR 16"
FT DOMAIN 577..627
FT /note="LRRCT"
FT DOMAIN 670..813
FT /note="TIR"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00204"
FT CARBOHYD 33
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 171
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 203
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 280
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 307
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 495
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 524
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 573
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 622
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 628
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 29..38
FT /evidence="ECO:0000250|UniProtKB:O00206"
FT DISULFID 279..304
FT /evidence="ECO:0000250|UniProtKB:O00206"
FT DISULFID 388..389
FT /evidence="ECO:0000250|UniProtKB:O00206"
FT DISULFID 581..607
FT /evidence="ECO:0000250|UniProtKB:O00206"
FT DISULFID 583..625
FT /evidence="ECO:0000250|UniProtKB:O00206"
SQ SEQUENCE 828 AA; 94341 MW; 51AC0984E5970FDF CRC64;
MMSASRLAGT LIPAMAFLSC VRPESWEPCV VPNITYQCME LNFYKIPDNL PFSTKNLDLS
FNPLRHLGSY SFFSFPELQV LDLSRCEIQT IEDGAYQSLS HLSTLILTGN PIQNLALGAF
SGLSSLQKLV AVETNLASLE NFPIGHLKTL KELNVAHNLI QSFKLPEYFS NLTNLEHLDL
SSNKIQSIYC KDLQVLHQMP LLNLSLDLSL NAMNFIQPGA FKEIRLHKLT LRNSFDSLNV
MKTCIQGLAG LEVHHLVLGE FRNEKNLEKF DTSALEGLCN LTIEEFRLAY LDYYLDDIID
LFNCLANVSS FSLVSVTIKS VKDFSYNFGW QHLELVNCKF GQFPTLELKS LKRLTFTANK
GGNAFSEVDL PSLEFLDLSR NGLSFKGCCS QSDFGTTSLK YLDLSFNDVI TMGSNFLGLE
QLEHLDFQHS NLKQMSEFSV FLSLRNLIYL DISHTHTRVA FNGIFNGLSS LKVLKMAGNS
FQENFLPDIF TELRNLTFLD LSQCQLEQLS PTAFNSLSSL QVLNMSHNNF FSLDTFPYKC
LNSLQVLDYS LNHIMTSKKQ ELQHFPSSLA FLNLTQNDFA CTCEHQSFLQ WIKDQRQLLV
EVERMECATP SDKQGMPVLS LNITCQMNKT VIGVSVFSVL VVSVVAVLVY KFYFHLMLLA
GCIKYGRGEN TYDAFVIYSS QDEDWVRNEL VKNLEEGVPT FQLCLHYRDF IPGVAIAANI
IHEGFHKSRK VIVVVSQHFI QSRWCIFEYE IAQTWQFLSS RAGIIFIVLQ KVEKTLLRQQ
VELYRLLSRN TYLEWEDSVL GRHIFWRRLR KALLDGKSWN PEGTVGTG
