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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
 
 
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