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TLR4_PIG
ID   TLR4_PIG                Reviewed;         841 AA.
AC   Q68Y56;
DT   25-OCT-2004, integrated into UniProtKB/Swiss-Prot.
DT   11-OCT-2004, sequence version 1.
DT   25-MAY-2022, entry version 105.
DE   RecName: Full=Toll-like receptor 4;
DE   AltName: CD_antigen=CD284;
DE   Flags: Precursor;
GN   Name=TLR4;
OS   Sus scrofa (Pig).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Laurasiatheria; Artiodactyla; Suina; Suidae; Sus.
OX   NCBI_TaxID=9823;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   TISSUE=Alveolus;
RA   Shinkai H., Uenishi H.;
RT   "The function of porcine TLR4 gene.";
RL   Submitted (AUG-2004) 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 NOX4. Interacts with CNPY3 and
CC       HSP90B1; this interaction is required for proper folding in the
CC       endoplasmic reticulum. Interacts with MAP3K21; this interaction leads
CC       to negative regulation of TLR4 signaling. Interacts with CD36,
CC       following CD36 stimulation by oxLDL or amyloid-beta 42, and forms a
CC       heterodimer with TLR6. The trimeric complex is internalized and
CC       triggers inflammatory response. LYN kinase activity facilitates TLR4-
CC       TLR6 heterodimerization and signal initiation. Interacts with TICAM1 in
CC       response to LPS in a WDFY1-dependent manner. Interacts with WDFY1 in
CC       response to LPS. Interacts with SMPDL3B. Interacts with CEACAM1; upon
CC       lipopolysaccharide stimulation, forms a complex including TLR4 and the
CC       phosphorylated form of SYK and CEACAM1, which in turn, recruits PTPN6
CC       that dephosphorylates SYK, reducing the production of reactive oxygen
CC       species (ROS) and lysosome disruption, which in turn, reduces the
CC       activity of the inflammasome. Interacts with RFTN1; the interaction
CC       occurs in response to lipopolysaccharide stimulation. Interacts with
CC       SCIMP; the interaction occurs in response to lipopolysaccharide
CC       stimulation and is enhanced by phosphorylation of SCIMP by LYN (By
CC       similarity). This interaction facilitates the phosphorylation of TLR4
CC       by LYN which elicits a selective cytokine response in macrophages (By
CC       similarity). Interacts with TRAF3IP3 (By similarity). Interacts with
CC       TREM1; this interaction enhances TLR4-mediated inflammatory response
CC       (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. {ECO:0000250}.
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; AB188301; BAD36843.1; -; mRNA.
DR   AlphaFoldDB; Q68Y56; -.
DR   SMR; Q68Y56; -.
DR   STRING; 9823.ENSSSCP00000005897; -.
DR   PaxDb; Q68Y56; -.
DR   eggNOG; KOG4641; Eukaryota.
DR   InParanoid; Q68Y56; -.
DR   Proteomes; UP000008227; Unplaced.
DR   Proteomes; UP000314985; 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: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; 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; 11.
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..841
FT                   /note="Toll-like receptor 4"
FT                   /id="PRO_0000034726"
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          374..395
FT                   /note="LRR 8"
FT   REPEAT          400..422
FT                   /note="LRR 9"
FT   REPEAT          423..444
FT                   /note="LRR 10"
FT   REPEAT          448..469
FT                   /note="LRR 11"
FT   REPEAT          472..495
FT                   /note="LRR 12"
FT   REPEAT          497..518
FT                   /note="LRR 13"
FT   REPEAT          521..542
FT                   /note="LRR 14"
FT   REPEAT          545..568
FT                   /note="LRR 15"
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        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        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"
FT   DISULFID        281..306
FT                   /evidence="ECO:0000250"
FT   DISULFID        390..391
FT                   /evidence="ECO:0000250"
FT   DISULFID        583..609
FT                   /evidence="ECO:0000250"
FT   DISULFID        585..628
FT                   /evidence="ECO:0000250"
SQ   SEQUENCE   841 AA;  96309 MW;  C52B2622D1C0E253 CRC64;
     MIPRIRLAVA TIPAMAFLSC LRSESWDPCV QVVPNISYQC MELNFYKIPD NIPTSVKILD
     LSFNYLSHLD SNSFSSFPEL QVLDLSRCEI QTIDDDAYQG LNYLSTLILT GNPIQSLALG
     AFSGLPSLQK LVAVETNLAS LEDFPIGHLK TLNELNVAHN HIHSFKLPEY FSNLPNLEHL
     DLSKNKIENI YHEHLQVLHQ VPLHNLSLDL SLNPLNFIEP GAFNKIRLNG LTLRSNFNSS
     DVMKTCIQGL AGSKVNQLVL GEFKNERNLE SFDKSVLEEL CNLTLEQFRI AHFGEFPDDV
     SDLFNCLANA SVISLLSLNL HGLEALPNDF RWQHLEVVNC KLQQFPALKF NSLKKFVFKD
     NKHMHTFTEI NLPNLQFLDL SGNHLSFKGC CSHNEFGTTK LKHLDLSFNE IITMKSNFMG
     LEQLEYLDFQ HSSLKQANDF SIFLSLRNLH YLDISYTNIH VVFRGIFAGL VSLQTLKMAG
     NSFQNNLLPD VFTDLTNLIL LDLSKCQLEQ VSQRAFHSLP RLQVLNMSHN RLLFLDTLPY
     KPLHSLRILD CSYNLIVASK EQELQHLPRS LAFLNLTKND FSCACEHQTF LQWVKDQKQL
     LVGAEQMVCT QPLEMQDLPV LSFRNATCQI SEAVISASVL TFLLVSVAGI LVYKFYFHLL
     LFVGCKKYGR GESTYDAFVI YSSQDEDWVR NELVKNLEEG VPPFHLCLHY RDFIPGVAIA
     ANIIQEGFHK SRKVIVVVSQ HFIQSRWCIF EYEIAQTWQF LRSHAGIIFI VLQKLEKSLL
     RQQVELYRLL SRNTYLEWED SVLGRHIFWR RLKKALLDGK PWSPEGTEDS ESNQHDTTAF
     T
 
 
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