TLR4_CRIGR
ID TLR4_CRIGR Reviewed; 838 AA.
AC Q9WV82;
DT 11-FEB-2002, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1999, sequence version 1.
DT 03-AUG-2022, entry version 140.
DE RecName: Full=Toll-like receptor 4;
DE AltName: CD_antigen=CD284;
DE Flags: Precursor;
GN Name=TLR4;
OS Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea;
OC Cricetidae; Cricetinae; Cricetulus.
OX NCBI_TaxID=10029;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY.
RC TISSUE=Macrophage;
RX PubMed=10683379; DOI=10.1172/jci8541;
RA Lien E., Means T.K., Heine H., Yoshimura A., Kusumoto S., Fukase K.,
RA Fenton M.J., Oikawa M., Qureshi N., Monks B., Finberg R.W., Ingalls R.R.,
RA Golenbock D.T.;
RT "Toll-like receptor 4 imparts ligand-specific recognition of bacterial
RT lipopolysaccharide.";
RL J. Clin. Invest. 105:497-504(2000).
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 -!- TISSUE SPECIFICITY: Expressed in macrophages.
CC {ECO:0000269|PubMed:10683379}.
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; AF153676; AAD41891.1; -; mRNA.
DR RefSeq; NP_001233691.1; NM_001246762.1.
DR AlphaFoldDB; Q9WV82; -.
DR SMR; Q9WV82; -.
DR STRING; 10029.NP_001233691.1; -.
DR Ensembl; ENSCGRT00001018473; ENSCGRP00001014236; ENSCGRG00001015165.
DR GeneID; 100689329; -.
DR KEGG; cge:100689329; -.
DR CTD; 7099; -.
DR eggNOG; KOG4641; Eukaryota.
DR GeneTree; ENSGT00940000160778; -.
DR OMA; CKHSAER; -.
DR OrthoDB; 282372at2759; -.
DR GO; GO:0005769; C:early endosome; IEA:UniProtKB-SubCell.
DR GO; GO:0009897; C:external side of plasma membrane; IEA:Ensembl.
DR GO; GO:0005794; C:Golgi apparatus; IEA:Ensembl.
DR GO; GO:0005887; C:integral component of plasma membrane; IEA:Ensembl.
DR GO; GO:0046696; C:lipopolysaccharide receptor complex; ISS:UniProtKB.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:Ensembl.
DR GO; GO:0001891; C:phagocytic cup; IEA:Ensembl.
DR GO; GO:0001726; C:ruffle; IEA:UniProtKB-SubCell.
DR GO; GO:0042802; F:identical protein binding; IEA:Ensembl.
DR GO; GO:0001530; F:lipopolysaccharide binding; IEA:Ensembl.
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:0046982; F:protein heterodimerization activity; IEA:Ensembl.
DR GO; GO:0005102; F:signaling receptor binding; IEA:Ensembl.
DR GO; GO:0004888; F:transmembrane signaling receptor activity; IEA:InterPro.
DR GO; GO:0002218; P:activation of innate immune response; IEA:Ensembl.
DR GO; GO:0014002; P:astrocyte development; IEA:Ensembl.
DR GO; GO:0002322; P:B cell proliferation involved in immune response; IEA:Ensembl.
DR GO; GO:1904646; P:cellular response to amyloid-beta; IEA:Ensembl.
DR GO; GO:0071346; P:cellular response to interferon-gamma; IEA:Ensembl.
DR GO; GO:0071223; P:cellular response to lipoteichoic acid; IEA:Ensembl.
DR GO; GO:0071260; P:cellular response to mechanical stimulus; IEA:Ensembl.
DR GO; GO:0140052; P:cellular response to oxidised low-density lipoprotein particle stimulus; IEA:Ensembl.
DR GO; GO:0036120; P:cellular response to platelet-derived growth factor stimulus; IEA:Ensembl.
DR GO; GO:0050829; P:defense response to Gram-negative bacterium; IEA:Ensembl.
DR GO; GO:0032497; P:detection of lipopolysaccharide; ISS:UniProtKB.
DR GO; GO:0070371; P:ERK1 and ERK2 cascade; IEA:Ensembl.
DR GO; GO:0007252; P:I-kappaB phosphorylation; IEA:Ensembl.
DR GO; GO:0060729; P:intestinal epithelial structure maintenance; IEA:Ensembl.
DR GO; GO:0007254; P:JNK cascade; IEA:Ensembl.
DR GO; GO:0042116; P:macrophage activation; IEA:Ensembl.
DR GO; GO:0045342; P:MHC class II biosynthetic process; IEA:Ensembl.
DR GO; GO:0002755; P:MyD88-dependent toll-like receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0120163; P:negative regulation of cold-induced thermogenesis; IEA:Ensembl.
DR GO; GO:0070373; P:negative regulation of ERK1 and ERK2 cascade; IEA:Ensembl.
DR GO; GO:0032689; P:negative regulation of interferon-gamma production; IEA:Ensembl.
DR GO; GO:0032700; P:negative regulation of interleukin-17 production; IEA:Ensembl.
DR GO; GO:0032707; P:negative regulation of interleukin-23 production; IEA:Ensembl.
DR GO; GO:0032715; P:negative regulation of interleukin-6 production; IEA:Ensembl.
DR GO; GO:0032720; P:negative regulation of tumor necrosis factor production; IEA:Ensembl.
DR GO; GO:0006809; P:nitric oxide biosynthetic process; IEA:Ensembl.
DR GO; GO:0002537; P:nitric oxide production involved in inflammatory response; IEA:Ensembl.
DR GO; GO:0070427; P:nucleotide-binding oligomerization domain containing 1 signaling pathway; IEA:Ensembl.
DR GO; GO:0070431; P:nucleotide-binding oligomerization domain containing 2 signaling pathway; IEA:Ensembl.
DR GO; GO:0006909; P:phagocytosis; IEA:Ensembl.
DR GO; GO:0030890; P:positive regulation of B cell proliferation; IEA:Ensembl.
DR GO; GO:1903974; P:positive regulation of cellular response to macrophage colony-stimulating factor stimulus; IEA:Ensembl.
DR GO; GO:2000343; P:positive regulation of chemokine (C-X-C motif) ligand 2 production; IEA:Ensembl.
DR GO; GO:1900017; P:positive regulation of cytokine production involved in inflammatory response; IEA:Ensembl.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IEA:Ensembl.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB signaling; IEA:Ensembl.
DR GO; GO:0050729; P:positive regulation of inflammatory response; IEA:Ensembl.
DR GO; GO:0032727; P:positive regulation of interferon-alpha production; IEA:Ensembl.
DR GO; GO:0032728; P:positive regulation of interferon-beta production; IEA:Ensembl.
DR GO; GO:0032729; P:positive regulation of interferon-gamma production; IEA:Ensembl.
DR GO; GO:0032731; P:positive regulation of interleukin-1 beta production; ISS:UniProtKB.
DR GO; GO:0032733; P:positive regulation of interleukin-10 production; IEA:Ensembl.
DR GO; GO:0032735; P:positive regulation of interleukin-12 production; IEA:Ensembl.
DR GO; GO:0032755; P:positive regulation of interleukin-6 production; IEA:Ensembl.
DR GO; GO:0032757; P:positive regulation of interleukin-8 production; IEA:Ensembl.
DR GO; GO:0046330; P:positive regulation of JNK cascade; IEA:Ensembl.
DR GO; GO:0043032; P:positive regulation of macrophage activation; IEA:Ensembl.
DR GO; GO:0060907; P:positive regulation of macrophage cytokine production; IEA:Ensembl.
DR GO; GO:0043406; P:positive regulation of MAP kinase activity; IEA:Ensembl.
DR GO; GO:1904466; P:positive regulation of matrix metallopeptidase secretion; IEA:Ensembl.
DR GO; GO:0045348; P:positive regulation of MHC class II biosynthetic process; IEA:Ensembl.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IEA:Ensembl.
DR GO; GO:1901224; P:positive regulation of NIK/NF-kappaB signaling; IEA:Ensembl.
DR GO; GO:0045429; P:positive regulation of nitric oxide biosynthetic process; IEA:Ensembl.
DR GO; GO:0051770; P:positive regulation of nitric-oxide synthase biosynthetic process; IEA:Ensembl.
DR GO; GO:1900227; P:positive regulation of NLRP3 inflammasome complex assembly; ISS:UniProtKB.
DR GO; GO:0070430; P:positive regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway; IEA:Ensembl.
DR GO; GO:0070434; P:positive regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway; IEA:Ensembl.
DR GO; GO:1903223; P:positive regulation of oxidative stress-induced neuron death; IEA:Ensembl.
DR GO; GO:0010572; P:positive regulation of platelet activation; IEA:Ensembl.
DR GO; GO:1903428; P:positive regulation of reactive oxygen species biosynthetic process; IEA:Ensembl.
DR GO; GO:0014911; P:positive regulation of smooth muscle cell migration; IEA:Ensembl.
DR GO; GO:0048661; P:positive regulation of smooth muscle cell proliferation; IEA:Ensembl.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IEA:Ensembl.
DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; IEA:Ensembl.
DR GO; GO:0002730; P:regulation of dendritic cell cytokine production; IEA:Ensembl.
DR GO; GO:0034142; P:toll-like receptor 4 signaling pathway; IEA:Ensembl.
DR GO; GO:0035666; P:TRIF-dependent toll-like receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0002246; P:wound healing involved in inflammatory response; IEA:Ensembl.
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; PF13855; LRR_8; 2.
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; 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; Repeat; Signal; Transmembrane;
KW Transmembrane helix.
FT SIGNAL 1..25
FT /evidence="ECO:0000255"
FT CHAIN 26..838
FT /note="Toll-like receptor 4"
FT /id="PRO_0000034718"
FT TOPO_DOM 26..629
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 630..650
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 651..838
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 26..53
FT /note="LRRNT"
FT REPEAT 54..75
FT /note="LRR 1"
FT REPEAT 78..99
FT /note="LRR 2"
FT REPEAT 102..123
FT /note="LRR 3"
FT REPEAT 126..147
FT /note="LRR 4"
FT REPEAT 150..171
FT /note="LRR 5"
FT REPEAT 175..198
FT /note="LRR 6"
FT REPEAT 204..224
FT /note="LRR 7"
FT REPEAT 226..235
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..468
FT /note="LRR 12"
FT REPEAT 470..493
FT /note="LRR 13"
FT REPEAT 495..516
FT /note="LRR 14"
FT REPEAT 519..539
FT /note="LRR 15"
FT REPEAT 543..564
FT /note="LRR 16"
FT DOMAIN 576..627
FT /note="LRRCT"
FT DOMAIN 670..813
FT /note="TIR"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00204"
FT CARBOHYD 34
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 115
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 172
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 204
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 237
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 492
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 572
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 622
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 28..39
FT /evidence="ECO:0000250|UniProtKB:O00206"
FT DISULFID 280..304
FT /evidence="ECO:0000250|UniProtKB:O00206"
FT DISULFID 388..389
FT /evidence="ECO:0000250|UniProtKB:O00206"
FT DISULFID 580..606
FT /evidence="ECO:0000250|UniProtKB:O00206"
FT DISULFID 582..625
FT /evidence="ECO:0000250|UniProtKB:O00206"
SQ SEQUENCE 838 AA; 96278 MW; 129B33596E908B48 CRC64;
MMPSFCLAGT LMMALFLSSL RPESLDPCVE VDSNTSYQCM DRNLNKIPDN IPSSVKHLDL
SFNPLKTLGS HSFFNFPELK LLDLSRCEIE TIEDKAYQGL HQLTTLILTG NPIQNLSKGT
FSGLANLQNL VAVEIKLASL DSLPIGHLVT LKKLNVAHNL IHSFKLPEYF SNLTNLEHLD
LSNNYIQTIY YTDLQTLREN PQLNLSLELS LNPIDFIQPG AFQGIRLHEL TLRSNFNSTN
VMKTCIHNLD GLQVHRLILG EFKNERNVER FDRYVIEGLC KVTIEEFRFT YANEFSEDIT
DFDCLANVSA MSLANVYLKR LEDIPKYFKW QTLAVIRCEL KQFPPLELPF LKRLIFITNK
GATSFPEVNL PSLTFLDLSG NGMSFRGCCS YTDLGARSLK HLDLSFNGVI SMSENFMGLE
QLEYLDFQHS TLKKATEFSM FLPLEKLLYL DISYTNTKID FNGIFFGLTS LNTLKMAGNS
FKDNILSNVF TNTTNLTFLD ISKCQLQQVS WGVFDTLHRL ELLNMSHNNL LLLDLFHYKQ
LHSLKTLDCS FNHIETSKGI MQHFPKSLAF LNLTNNPFAC ICEHQNFLQW VKDQRLFLVK
TEQMTCATPV EMKDSLVLDF RNATCYVQKT IISVSVISVL VVSTIAFLVY KFYFHLILIA
GCKKYSRGES IYDAFVIYSS QDEDWVRNEL VKNLEEGVPP FQLCLHYRDF IPGVAIAANI
IQEGFHKSRK VIVVVSRHFI QSRWCIFEYE IAQTWQFLSS HSGIIFIVLE KVEKSLLKQQ
VELYRLLSRN TYLEWEDNAL GRHIFWRRLK KALLDGRAWN PEGATEAENN QQETTTSI
