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Protein

Toll-like receptor 9

Gene

TLR9

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Key component of innate and adaptive immunity. TLRs (Toll-like receptors) control host immune response against pathogens through recognition of molecular patterns specific to microorganisms. TLR9 is a nucleotide-sensing TLR which is activated by unmethylated cytidine-phosphate-guanosine (CpG) dinucleotides. Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response (PubMed:11564765, PubMed:17932028). Controls lymphocyte response to Helicobacter infection (By similarity). Upon CpG stimulation, induces B-cell proliferation, activation, survival and antibody production (PubMed:23857366).By similarity3 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei132CpG-DNABy similarity1
Binding sitei208CpG-DNABy similarity1

GO - Molecular functioni

  • 1-phosphatidylinositol-3-kinase activity Source: Reactome
  • interleukin-1 receptor binding Source: UniProtKB
  • protein homodimerization activity Source: UniProtKB
  • siRNA binding Source: UniProtKB
  • transmembrane signaling receptor activity Source: InterPro
  • unmethylated CpG binding Source: UniProtKB

GO - Biological processi

  • axonogenesis Source: GO_Central
  • defense response to bacterium Source: UniProtKB
  • defense response to Gram-negative bacterium Source: UniProtKB
  • I-kappaB phosphorylation Source: BHF-UCL
  • inflammatory response Source: UniProtKB-KW
  • innate immune response Source: BHF-UCL
  • maintenance of gastrointestinal epithelium Source: BHF-UCL
  • MyD88-dependent toll-like receptor signaling pathway Source: InterPro
  • negative regulation of calcium-transporting ATPase activity Source: CACAO
  • negative regulation of interleukin-6 production Source: BHF-UCL
  • negative regulation of interleukin-8 production Source: BHF-UCL
  • negative regulation of NF-kappaB transcription factor activity Source: BHF-UCL
  • negative regulation of toll-like receptor signaling pathway Source: BHF-UCL
  • positive regulation of B cell activation Source: UniProtKB
  • positive regulation of B cell proliferation Source: UniProtKB
  • positive regulation of chemokine production Source: BHF-UCL
  • positive regulation of gene expression Source: CACAO
  • positive regulation of granulocyte macrophage colony-stimulating factor production Source: CACAO
  • positive regulation of I-kappaB kinase/NF-kappaB signaling Source: BHF-UCL
  • positive regulation of immunoglobulin production Source: UniProtKB
  • positive regulation of inflammatory response Source: BHF-UCL
  • positive regulation of interferon-alpha biosynthetic process Source: UniProtKB
  • positive regulation of interferon-beta biosynthetic process Source: UniProtKB
  • positive regulation of interferon-beta production Source: BHF-UCL
  • positive regulation of interferon-gamma biosynthetic process Source: UniProtKB
  • positive regulation of interleukin-10 production Source: BHF-UCL
  • positive regulation of interleukin-12 production Source: BHF-UCL
  • positive regulation of interleukin-18 production Source: BHF-UCL
  • positive regulation of interleukin-6 production Source: BHF-UCL
  • positive regulation of interleukin-8 production Source: BHF-UCL
  • positive regulation of JNK cascade Source: BHF-UCL
  • positive regulation of JUN kinase activity Source: BHF-UCL
  • positive regulation of MAPK cascade Source: UniProtKB
  • positive regulation of NF-kappaB import into nucleus Source: BHF-UCL
  • positive regulation of NF-kappaB transcription factor activity Source: BHF-UCL
  • positive regulation of nitric-oxide synthase biosynthetic process Source: BHF-UCL
  • positive regulation of toll-like receptor signaling pathway Source: BHF-UCL
  • positive regulation of transcription by RNA polymerase II Source: BHF-UCL
  • positive regulation of tumor necrosis factor production Source: BHF-UCL
  • regulation of B cell differentiation Source: UniProtKB
  • regulation of cytokine secretion Source: InterPro
  • regulation of toll-like receptor 9 signaling pathway Source: UniProtKB
  • response to molecule of bacterial origin Source: BHF-UCL
  • toll-like receptor 9 signaling pathway Source: Reactome
  • toll-like receptor signaling pathway Source: Reactome
  • tumor necrosis factor production Source: CACAO

Keywordsi

Molecular functionReceptor
Biological processImmunity, Inflammatory response, Innate immunity

Enzyme and pathway databases

ReactomeiR-HSA-109704 PI3K Cascade
R-HSA-1679131 Trafficking and processing of endosomal TLR
R-HSA-168138 Toll Like Receptor 9 (TLR9) Cascade
R-HSA-975110 TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling
R-HSA-975138 TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation
R-HSA-975155 MyD88 dependent cascade initiated on endosome

Names & Taxonomyi

Protein namesi
Recommended name:
Toll-like receptor 9
Alternative name(s):
CD_antigen: CD289
Gene namesi
Name:TLR9
ORF Names:UNQ5798/PRO19605
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 3

Organism-specific databases

EuPathDBiHostDB:ENSG00000239732.3
HGNCiHGNC:15633 TLR9
MIMi605474 gene
neXtProtiNX_Q9NR96

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini26 – 818ExtracellularSequence analysisAdd BLAST793
Transmembranei819 – 839HelicalSequence analysisAdd BLAST21
Topological domaini840 – 1032CytoplasmicSequence analysisAdd BLAST193

Keywords - Cellular componenti

Cytoplasmic vesicle, Endoplasmic reticulum, Endosome, Lysosome, Membrane

Pathology & Biotechi

Organism-specific databases

DisGeNETi54106
OpenTargetsiENSG00000239732
PharmGKBiPA38010

Chemistry databases

ChEMBLiCHEMBL5804
DrugBankiDB00608 Chloroquine
DB01611 Hydroxychloroquine
DB05463 ISS-1018
DB05475 SCV-07
GuidetoPHARMACOLOGYi1759

Polymorphism and mutation databases

BioMutaiTLR9
DMDMi20140872

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 25Sequence analysisAdd BLAST25
ChainiPRO_000003473726 – 1032Toll-like receptor 9Add BLAST1007

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi35 ↔ 45By similarity
Glycosylationi64N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi98 ↔ 110By similarity
Glycosylationi129N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi178 ↔ 184By similarity
Glycosylationi200N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi210N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi242N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi255 ↔ 268By similarity
Disulfide bondi258 ↔ 265By similarity
Glycosylationi300N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi340N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi469N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi470 ↔ 500By similarity
Glycosylationi474N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi513N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi567N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi694N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi731N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi764 ↔ 790By similarity
Disulfide bondi766 ↔ 809By similarity

Post-translational modificationi

Activated by proteolytic cleavage of the flexible loop between repeats LRR14 and LRR15 within the ectodomain. Cleavage requires UNC93B1. Proteolytically processed by first removing the majority of the ectodomain by either asparagine endopeptidase (AEP) or a cathepsin followed by a trimming event that is solely cathepsin mediated and required for optimal receptor signaling.By similarity

Keywords - PTMi

Disulfide bond, Glycoprotein

Proteomic databases

MaxQBiQ9NR96
PaxDbiQ9NR96
PeptideAtlasiQ9NR96
PRIDEiQ9NR96

PTM databases

iPTMnetiQ9NR96
PhosphoSitePlusiQ9NR96

Expressioni

Tissue specificityi

Highly expressed in spleen, lymph node, tonsil and peripheral blood leukocytes, especially in plasmacytoid pre-dendritic cells. Levels are much lower in monocytes and CD11c+ immature dendritic cells. Also detected in lung and liver.

Gene expression databases

BgeeiENSG00000239732
CleanExiHS_TLR9
GenevisibleiQ9NR96 HS

Interactioni

Subunit structurei

Monomer and homodimer. Exists as a monomer in the absence of unmethylated cytidine-phosphate-guanosine (CpG) ligand. Proteolytic processing of an insertion loop (Z-loop) is required for homodimerization upon binding to the unmethylated CpG ligand leading to its activation (By similarity). Interacts with MYD88 via their respective TIR domains (By similarity). Interacts with BTK (PubMed:17932028). Interacts (via transmembrane domain) with UNC93B1. Interacts with CD300LH; the interaction may promote full activation of TLR9-triggered innate responses (By similarity). Interacts with CNPY3 and HSP90B1; this interaction is required for proper folding in the endoplasmic reticulum (PubMed:20865800). Interacts with SMPDL3B (By similarity).By similarity2 Publications

GO - Molecular functioni

  • interleukin-1 receptor binding Source: UniProtKB
  • protein homodimerization activity Source: UniProtKB

Protein-protein interaction databases

BioGridi11990220 interactors.
DIPiDIP-52371N
IntActiQ9NR96 8 interactors.
STRINGi9606.ENSP00000417517

Chemistry databases

BindingDBiQ9NR96

Structurei

3D structure databases

ProteinModelPortaliQ9NR96
SMRiQ9NR96
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Repeati62 – 85LRR 1Add BLAST24
Repeati87 – 110LRR 2Add BLAST24
Repeati122 – 147LRR 3Add BLAST26
Repeati150 – 166LRR 4Add BLAST17
Repeati167 – 190LRR 5Add BLAST24
Repeati198 – 221LRR 6Add BLAST24
Repeati223 – 242LRR 7Add BLAST20
Repeati243 – 268LRR 8Add BLAST26
Repeati283 – 306LRR 9Add BLAST24
Repeati308 – 332LRR 10Add BLAST25
Repeati333 – 356LRR 11Add BLAST24
Repeati363 – 386LRR 12Add BLAST24
Repeati390 – 413LRR 13Add BLAST24
Repeati415 – 440LRR 14Add BLAST26
Repeati470 – 494LRR 15Add BLAST25
Repeati496 – 519LRR 16Add BLAST24
Repeati520 – 543LRR 17Add BLAST24
Repeati545 – 572LRR 18Add BLAST28
Repeati574 – 598LRR 19Add BLAST25
Repeati600 – 622LRR 20Add BLAST23
Repeati627 – 650LRR 21Add BLAST24
Repeati652 – 675LRR 22Add BLAST24
Repeati676 – 699LRR 23Add BLAST24
Repeati701 – 723LRR 24Add BLAST23
Repeati724 – 747LRR 25Add BLAST24
Repeati749 – 772LRR 26Add BLAST24
Domaini868 – 1016TIRPROSITE-ProRule annotationAdd BLAST149

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni47 – 51Interaction with CpG-DNABy similarity5
Regioni72 – 77Interaction with CpG-DNABy similarity6
Regioni95 – 109Interaction with CpG-DNABy similarityAdd BLAST15
Regioni179 – 181Interaction with CpG-DNABy similarity3

Sequence similaritiesi

Belongs to the Toll-like receptor family.Curated

Keywords - Domaini

Leucine-rich repeat, Repeat, Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG1747 Eukaryota
KOG4641 Eukaryota
COG4886 LUCA
GeneTreeiENSGT00760000119006
HOVERGENiHBG018601
InParanoidiQ9NR96
KOiK10161
OrthoDBiEOG091G0BWK
PhylomeDBiQ9NR96
TreeFamiTF325595

Family and domain databases

Gene3Di3.40.50.101401 hit
InterProiView protein in InterPro
IPR001611 Leu-rich_rpt
IPR003591 Leu-rich_rpt_typical-subtyp
IPR000157 TIR_dom
IPR027181 TLR9
IPR035897 Toll_tir_struct_dom_sf
PANTHERiPTHR24373:SF37 PTHR24373:SF37, 1 hit
PfamiView protein in Pfam
PF13516 LRR_6, 2 hits
PF13855 LRR_8, 7 hits
PF01582 TIR, 1 hit
SMARTiView protein in SMART
SM00369 LRR_TYP, 18 hits
SM00255 TIR, 1 hit
SUPFAMiSSF52200 SSF52200, 1 hit
PROSITEiView protein in PROSITE
PS51450 LRR, 17 hits
PS50104 TIR, 1 hit

Sequences (5)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 5 isoformsi produced by alternative splicing. AlignAdd to basket

Note: Additional isoforms seem to exist.
Isoform 1 (identifier: Q9NR96-1) [UniParc]FASTAAdd to basket
Also known as: A

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MGFCRSALHP LSLLVQAIML AMTLALGTLP AFLPCELQPH GLVNCNWLFL
60 70 80 90 100
KSVPHFSMAA PRGNVTSLSL SSNRIHHLHD SDFAHLPSLR HLNLKWNCPP
110 120 130 140 150
VGLSPMHFPC HMTIEPSTFL AVPTLEELNL SYNNIMTVPA LPKSLISLSL
160 170 180 190 200
SHTNILMLDS ASLAGLHALR FLFMDGNCYY KNPCRQALEV APGALLGLGN
210 220 230 240 250
LTHLSLKYNN LTVVPRNLPS SLEYLLLSYN RIVKLAPEDL ANLTALRVLD
260 270 280 290 300
VGGNCRRCDH APNPCMECPR HFPQLHPDTF SHLSRLEGLV LKDSSLSWLN
310 320 330 340 350
ASWFRGLGNL RVLDLSENFL YKCITKTKAF QGLTQLRKLN LSFNYQKRVS
360 370 380 390 400
FAHLSLAPSF GSLVALKELD MHGIFFRSLD ETTLRPLARL PMLQTLRLQM
410 420 430 440 450
NFINQAQLGI FRAFPGLRYV DLSDNRISGA SELTATMGEA DGGEKVWLQP
460 470 480 490 500
GDLAPAPVDT PSSEDFRPNC STLNFTLDLS RNNLVTVQPE MFAQLSHLQC
510 520 530 540 550
LRLSHNCISQ AVNGSQFLPL TGLQVLDLSH NKLDLYHEHS FTELPRLEAL
560 570 580 590 600
DLSYNSQPFG MQGVGHNFSF VAHLRTLRHL SLAHNNIHSQ VSQQLCSTSL
610 620 630 640 650
RALDFSGNAL GHMWAEGDLY LHFFQGLSGL IWLDLSQNRL HTLLPQTLRN
660 670 680 690 700
LPKSLQVLRL RDNYLAFFKW WSLHFLPKLE VLDLAGNQLK ALTNGSLPAG
710 720 730 740 750
TRLRRLDVSC NSISFVAPGF FSKAKELREL NLSANALKTV DHSWFGPLAS
760 770 780 790 800
ALQILDVSAN PLHCACGAAF MDFLLEVQAA VPGLPSRVKC GSPGQLQGLS
810 820 830 840 850
IFAQDLRLCL DEALSWDCFA LSLLAVALGL GVPMLHHLCG WDLWYCFHLC
860 870 880 890 900
LAWLPWRGRQ SGRDEDALPY DAFVVFDKTQ SAVADWVYNE LRGQLEECRG
910 920 930 940 950
RWALRLCLEE RDWLPGKTLF ENLWASVYGS RKTLFVLAHT DRVSGLLRAS
960 970 980 990 1000
FLLAQQRLLE DRKDVVVLVI LSPDGRRSRY VRLRQRLCRQ SVLLWPHQPS
1010 1020 1030
GQRSFWAQLG MALTRDNHHF YNRNFCQGPT AE
Length:1,032
Mass (Da):115,860
Last modified:January 31, 2002 - v2
Checksum:i71280AA9680EDCE2
GO
Isoform 2 (identifier: Q9NR96-2) [UniParc]FASTAAdd to basket
Also known as: B

The sequence of this isoform differs from the canonical sequence as follows:
     1-57: Missing.

Show »
Length:975
Mass (Da):109,628
Checksum:i61D105163587A75F
GO
Isoform 3 (identifier: Q9NR96-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-1: M → MPMKWSGWRWSWGPATHTALPPPQ

Show »
Length:1,055
Mass (Da):118,517
Checksum:i4072A104D14022F6
GO
Isoform 4 (identifier: Q9NR96-4) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-1: M → MLYSSCKSRLLDSVEQDFHLEIAKK

Show »
Length:1,056
Mass (Da):118,652
Checksum:i9159C051473E88FC
GO
Isoform 5 (identifier: Q9NR96-5) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-16: MGFCRSALHPLSLLVQ → M

Show »
Length:1,017
Mass (Da):114,237
Checksum:i7EF80765E4675C9C
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti200N → S in AAQ89443 (PubMed:12975309).Curated1
Sequence conflicti330F → L in AAQ89443 (PubMed:12975309).Curated1
Sequence conflicti530H → R in AAF78037 (PubMed:11022120).Curated1
Sequence conflicti688Q → R in AAF78037 (PubMed:11022120).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_0246685R → C. Corresponds to variant dbSNP:rs5743842Ensembl.1
Natural variantiVAR_05236479H → Q. Corresponds to variant dbSNP:rs5743843Ensembl.1
Natural variantiVAR_034555863R → Q. Corresponds to variant dbSNP:rs5743845Ensembl.1
Natural variantiVAR_052365882A → T. Corresponds to variant dbSNP:rs5743846Ensembl.1
Natural variantiVAR_036077901R → H in a colorectal cancer sample; somatic mutation. 1 PublicationCorresponds to variant dbSNP:rs755472700Ensembl.1
Natural variantiVAR_036078933T → M in a colorectal cancer sample; somatic mutation. 1 PublicationCorresponds to variant dbSNP:rs746622200Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0065201 – 57Missing in isoform 2. 1 PublicationAdd BLAST57
Alternative sequenceiVSP_0065231 – 16MGFCR…SLLVQ → M in isoform 5. 1 PublicationAdd BLAST16
Alternative sequenceiVSP_0065211M → MPMKWSGWRWSWGPATHTAL PPPQ in isoform 3. 1 Publication1
Alternative sequenceiVSP_0065221M → MLYSSCKSRLLDSVEQDFHL EIAKK in isoform 4. 1 Publication1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF259262 mRNA Translation: AAF72189.1
AF259263 mRNA Translation: AAF72190.1
AF245704 mRNA Translation: AAF78037.1
AF246972 mRNA Translation: AAG01734.1
AF246973 mRNA Translation: AAG01735.1
AF246974 mRNA Translation: AAG01736.1
AB045180 mRNA Translation: BAB19259.1
EU170540 Genomic DNA Translation: ABW37075.1
EU170541 Genomic DNA Translation: ABW37076.1
EU170542 Genomic DNA Translation: ABW37077.1
EU170543 Genomic DNA Translation: ABW37078.1
AB445673 mRNA Translation: BAG55070.1
DQ019992 Genomic DNA Translation: AAZ95513.1
DQ019993 Genomic DNA Translation: AAZ95514.1
DQ019994 Genomic DNA Translation: AAZ95515.1
DQ019995 Genomic DNA Translation: AAZ95516.1
DQ019996 Genomic DNA Translation: AAZ95517.1
DQ019999 Genomic DNA Translation: AAZ95520.1
AY359085 mRNA Translation: AAQ89443.1
CH471055 Genomic DNA Translation: EAW65191.1
BC032713 mRNA Translation: AAH32713.1
CCDSiCCDS2848.1 [Q9NR96-1]
RefSeqiNP_059138.1, NM_017442.3 [Q9NR96-1]
UniGeneiHs.87968

Genome annotation databases

EnsembliENST00000360658; ENSP00000353874; ENSG00000239732 [Q9NR96-1]
GeneIDi54106
KEGGihsa:54106
UCSCiuc003dda.2 human [Q9NR96-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiTLR9_HUMAN
AccessioniPrimary (citable) accession number: Q9NR96
Secondary accession number(s): B3Y661
, D1CS56, Q6UVZ2, Q9HD68, Q9HD69, Q9HD70, Q9NYC2, Q9NYC3
Entry historyiIntegrated into UniProtKB/Swiss-Prot: January 31, 2002
Last sequence update: January 31, 2002
Last modified: March 28, 2018
This is version 165 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome