Descriptions
TLR9 (Toll-like receptor 9) plays a key role in the innate immune system in response to unmethylated CpG DNA. After stimulation of cells with CpG DNA, TLR9 redistributes from the endoplasmic reticulum to lysosomes, where a signaling cascade is triggered by recruitment of the MyD88 adaptor molecule. TLR9 is a type I transmembrane protein characterized by an extracellular leucine-rich repeat (LRR) domain, a transmembrane helix, and an intracellular Toll/interleukin-1 receptor (TIR) homology domain. TLR9 undergoes proteolytic cleavage, executed by cysteine proteases, in the endolysosomal compartment, and molecular modeling shows that the cleavage sites are situated between LRR14 and LRR15, as being part of a flexible loop that could render TLR9 susceptible to proteolysis. On a molar basis, the C-terminal cleavage fragment of TLR9 binds CpG DNA more strongly than does full-length TLR9, although full-length TLR9 binds CpG DNA. The broadly specific inhibitor z-FA-fmk is most effective at blocking the cleavage and, accordingly, abrogated TNF production in cells exposed to the TLR9 agonist CpG DNA.
Autoinhibitory domains (AIDs)
Target domain |
23-805 (LRR domains) |
Relief mechanism |
Cleavage |
Assay |
|
Accessory elements
No accessory elements
References
- Tanji H et al. (2016) "Autoinhibition and relief mechanism by the proteolytic processing of Toll-like receptor 8", Proceedings of the National Academy of Sciences of the United States of America, 113, 3012-7
- Park B et al. (2008) "Proteolytic cleavage in an endolysosomal compartment is required for activation of Toll-like receptor 9", Nature immunology, 9, 1407-14
Autoinhibited structure
Activated structure
1 structures for Q5I2M3
| Entry ID | Method | Resolution | Chain | Position | Source |
|---|---|---|---|---|---|
| AF-Q5I2M3-F1 | Predicted | AlphaFoldDB |
7 variants for Q5I2M3
| Variant ID(s) | Position | Change | Description | Diseaes Association | Provenance |
|---|---|---|---|---|---|
| rs325798380 | 21 | A>V | No | EVA | |
| rs690248232 | 170 | Y>* | No | EVA | |
| rs792040168 | 284 | R>H | No | EVA | |
| rs694935539 | 396 | R>H | No | EVA | |
| rs708529321 | 441 | G>V | No | EVA | |
| rs704811138 | 655 | K>R | No | EVA | |
| rs329632652 | 911 | L>V | No | EVA |
No associated diseases with Q5I2M3
25 regional properties for Q5I2M3
| Type | Name | Position | InterPro Accession |
|---|---|---|---|
| domain | Toll/interleukin-1 receptor homology (TIR) domain | 865 - 1013 | IPR000157 |
| repeat | Leucine-rich repeat | 123 - 144 | IPR001611-1 |
| repeat | Leucine-rich repeat | 199 - 253 | IPR001611-2 |
| repeat | Leucine-rich repeat | 284 - 343 | IPR001611-3 |
| repeat | Leucine-rich repeat | 475 - 532 | IPR001611-4 |
| repeat | Leucine-rich repeat | 628 - 650 | IPR001611-5 |
| repeat | Leucine-rich repeat | 677 - 698 | IPR001611-6 |
| repeat | Leucine-rich repeat | 701 - 761 | IPR001611-7 |
| repeat | Leucine-rich repeat, typical subtype | 121 - 143 | IPR003591-1 |
| repeat | Leucine-rich repeat, typical subtype | 197 - 218 | IPR003591-2 |
| repeat | Leucine-rich repeat, typical subtype | 219 - 241 | IPR003591-3 |
| repeat | Leucine-rich repeat, typical subtype | 282 - 305 | IPR003591-4 |
| repeat | Leucine-rich repeat, typical subtype | 306 - 331 | IPR003591-5 |
| repeat | Leucine-rich repeat, typical subtype | 362 - 385 | IPR003591-6 |
| repeat | Leucine-rich repeat, typical subtype | 389 - 412 | IPR003591-7 |
| repeat | Leucine-rich repeat, typical subtype | 475 - 493 | IPR003591-8 |
| repeat | Leucine-rich repeat, typical subtype | 494 - 516 | IPR003591-9 |
| repeat | Leucine-rich repeat, typical subtype | 519 - 542 | IPR003591-10 |
| repeat | Leucine-rich repeat, typical subtype | 573 - 597 | IPR003591-11 |
| repeat | Leucine-rich repeat, typical subtype | 626 - 649 | IPR003591-12 |
| repeat | Leucine-rich repeat, typical subtype | 675 - 698 | IPR003591-13 |
| repeat | Leucine-rich repeat, typical subtype | 700 - 722 | IPR003591-14 |
| repeat | Leucine-rich repeat, typical subtype | 724 - 746 | IPR003591-15 |
| repeat | Leucine-rich repeat, typical subtype | 748 - 771 | IPR003591-16 |
| repeat | Leucine-rich repeat unit | 392 - 421 | IPR041283 |
Functions
7 GO annotations of cellular component
| Name | Definition |
|---|---|
| early phagosome | A membrane-bounded intracellular vesicle as initially formed upon the ingestion of particulate material by phagocytosis. |
| endolysosome | An transient hybrid organelle formed by fusion of a late endosome with a lysosome, and in which active degradation takes place. |
| endoplasmic reticulum | The irregular network of unit membranes, visible only by electron microscopy, that occurs in the cytoplasm of many eukaryotic cells. The membranes form a complex meshwork of tubular channels, which are often expanded into slitlike cavities called cisternae. The ER takes two forms, rough (or granular), with ribosomes adhering to the outer surface, and smooth (with no ribosomes attached). |
| endoplasmic reticulum membrane | The lipid bilayer surrounding the endoplasmic reticulum. |
| endosome | A vacuole to which materials ingested by endocytosis are delivered. |
| lysosome | A small lytic vacuole that has cell cycle-independent morphology found in most animal cells and that contains a variety of hydrolases, most of which have their maximal activities in the pH range 5-6. The contained enzymes display latency if properly isolated. About 40 different lysosomal hydrolases are known and lysosomes have a great variety of morphologies and functions. |
| plasma membrane | The membrane surrounding a cell that separates the cell from its external environment. It consists of a phospholipid bilayer and associated proteins. |
4 GO annotations of molecular function
| Name | Definition |
|---|---|
| pattern recognition receptor activity | Combining with a pathogen-associated molecular pattern (PAMP), a structure conserved among microbial species to initiate an innate immune response. |
| protein homodimerization activity | Binding to an identical protein to form a homodimer. |
| siRNA binding | Binding to a small interfering RNA, a 21-23 nucleotide RNA that is processed from double stranded RNA (dsRNA) by an RNAse enzyme. |
| unmethylated CpG binding | Binding to uan nmethylated CpG motif. Unmethylated CpG dinucleotides are often associated with gene promoters. |
18 GO annotations of biological process
| Name | Definition |
|---|---|
| canonical NF-kappaB signal transduction | The process in which a signal is passed on to downstream components within the cell through the I-kappaB-kinase (IKK)-dependent activation of NF-kappaB. The cascade begins with activation of a trimeric IKK complex (consisting of catalytic kinase subunits IKKalpha and/or IKKbeta, and the regulatory scaffold protein NEMO) and ends with the regulation of transcription of target genes by NF-kappaB. In a resting state, NF-kappaB dimers are bound to I-kappaB proteins, sequestering NF-kappaB in the cytoplasm. Phosphorylation of I-kappaB targets I-kappaB for ubiquitination and proteasomal degradation, thus releasing the NF-kappaB dimers, which can translocate to the nucleus to bind DNA and regulate transcription. |
| defense response to virus | Reactions triggered in response to the presence of a virus that act to protect the cell or organism. |
| inflammatory response | The immediate defensive reaction (by vertebrate tissue) to infection or injury caused by chemical or physical agents. The process is characterized by local vasodilation, extravasation of plasma into intercellular spaces and accumulation of white blood cells and macrophages. |
| innate immune response | Innate immune responses are defense responses mediated by germline encoded components that directly recognize components of potential pathogens. |
| positive regulation of B cell activation | Any process that activates or increases the frequency, rate or extent of B cell activation. |
| positive regulation of B cell proliferation | Any process that activates or increases the rate or extent of B cell proliferation. |
| positive regulation of immunoglobulin production | Any process that activates or increases the frequency, rate, or extent of immunoglobulin production. |
| positive regulation of interferon-alpha production | Any process that activates or increases the frequency, rate, or extent of interferon-alpha production. |
| positive regulation of interferon-beta production | Any process that activates or increases the frequency, rate, or extent of interferon-beta production. |
| positive regulation of interleukin-6 production | Any process that activates or increases the frequency, rate, or extent of interleukin-6 production. |
| positive regulation of MAPK cascade | Any process that activates or increases the frequency, rate or extent of signal transduction mediated by the MAPK cascade. |
| positive regulation of toll-like receptor 9 signaling pathway | Any process that activates or increases the frequency, rate, or extent of toll-like receptor 9 signaling pathway. |
| positive regulation of type II interferon production | Any process that activates or increases the frequency, rate, or extent of interferon-gamma production. Interferon-gamma is also known as type II interferon. |
| regulation of B cell differentiation | Any process that modulates the frequency, rate or extent of B cell differentiation. |
| regulation of nitrogen compound metabolic process | Any process that modulates the frequency, rate or extent of the chemical reactions and pathways involving nitrogen or nitrogenous compounds. |
| regulation of primary metabolic process | Any process that modulates the frequency, rate or extent of the chemical reactions and pathways within a cell or an organism involving those compounds formed as a part of the normal anabolic and catabolic processes. These processes take place in most, if not all, cells of the organism. |
| regulation of toll-like receptor 9 signaling pathway | Any process that modulates the frequency, rate, or extent of toll-like receptor 9 signaling pathway. |
| toll-like receptor signaling pathway | The series of molecular signals initiated by a ligand binding to a toll-like receptor of a target cell. Toll-like receptors directly bind pattern motifs from a variety of microbial sources to initiate an innate immune response. |
10 homologous proteins in AiPD
| UniProt AC | Gene Name | Protein Name | Species | Evidence Code |
|---|---|---|---|---|
| Q5I2M5 | TLR9 | Toll-like receptor 9 | Bos taurus (Bovine) | SS |
| Q5I2M7 | TLR9 | Toll-like receptor 9 | Felis catus (Cat) (Felis silvestris catus) | SS |
| Q5I2M8 | TLR9 | Toll-like receptor 9 | Canis lupus familiaris (Dog) (Canis familiaris) | SS |
| P08953 | Tl | Protein toll | Drosophila melanogaster (Fruit fly) | PR |
| Q2EEY0 | TLR9 | Toll-like receptor 9 | Equus caballus (Horse) | SS |
| Q9NYK1 | TLR7 | Toll-like receptor 7 | Homo sapiens (Human) | EV |
| Q9NR96 | TLR9 | Toll-like receptor 9 | Homo sapiens (Human) | EV |
| P58681 | Tlr7 | Toll-like receptor 7 | Mus musculus (Mouse) | SS |
| Q9EQU3 | Tlr9 | Toll-like receptor 9 | Mus musculus (Mouse) | SS |
| A5H2Z9 | Tlr7 | Toll-like receptor 7 | Rattus norvegicus (Rat) | SS |
| 10 | 20 | 30 | 40 | 50 | 60 |
| MGPRCTLHPL | SLLVQVTALA | AALAQGRLPA | FLPCELQPHG | LVNCNWLFLK | SVPHFSAAAP |
| 70 | 80 | 90 | 100 | 110 | 120 |
| RANVTSLSLL | SNRIHHLHDS | DFVHLSSLRT | LNLKWNCPPA | GLSPMHFPCH | MTIEPNTFLA |
| 130 | 140 | 150 | 160 | 170 | 180 |
| VPTLEELNLS | YNSITTVPAL | PDSLVSLSLS | RTNILVLDPT | HLTGLHALRY | LYMDGNCYYK |
| 190 | 200 | 210 | 220 | 230 | 240 |
| NPCQGALEVV | PGALLGLGNL | THLSLKYNNL | TEVPRSLPPS | LETLLLSYNH | IVTLTPEDLA |
| 250 | 260 | 270 | 280 | 290 | 300 |
| NLTALRVLDV | GGNCRRCDHA | RNPCRECPKD | HPKLHSDTFS | HLSRLEGLVL | KDSSLYNLDT |
| 310 | 320 | 330 | 340 | 350 | 360 |
| RWFRGLDRLQ | VLDLSENFLY | DCITKTTAFQ | GLARLRSLNL | SFNYHKKVSF | AHLHLAPSFG |
| 370 | 380 | 390 | 400 | 410 | 420 |
| HLRSLKELDM | HGIFFRSLSE | TTLQPLVQLP | MLQTLRLQMN | FINQAQLSIF | GAFPGLLYVD |
| 430 | 440 | 450 | 460 | 470 | 480 |
| LSDNRISGAA | RPVAITREVD | GRERVWLPSR | NLAPRPLDTL | RSEDFMPNCK | AFSFTLDLSR |
| 490 | 500 | 510 | 520 | 530 | 540 |
| NNLVTIQSEM | FARLSRLECL | RLSHNSISQA | VNGSQFVPLT | SLRVLDLSHN | KLDLYHGRSF |
| 550 | 560 | 570 | 580 | 590 | 600 |
| TELPRLEALD | LSYNSQPFTM | QGVGHNLSFV | AQLPALRYLS | LAHNDIHSRV | SQQLCSASLC |
| 610 | 620 | 630 | 640 | 650 | 660 |
| ALDFSGNDLS | RMWAEGDLYL | RFFQGLRSLV | WLDLSQNHLH | TLLPRALDNL | PKSLKHLHLR |
| 670 | 680 | 690 | 700 | 710 | 720 |
| DNNLAFFNWS | SLTLLPKLET | LDLAGNQLKA | LSNGSLPSGT | QLRRLDLSGN | SIGFVNPGFF |
| 730 | 740 | 750 | 760 | 770 | 780 |
| ALAKQLEELN | LSANALKTVE | PSWFGSMVGN | LKVLDVSANP | LHCACGATFV | GFLLEVQAAV |
| 790 | 800 | 810 | 820 | 830 | 840 |
| PGLPSRVKCG | SPGQLQGHSI | FAQDLRLCLD | ETLSWNCFGI | SLLAMALGLV | VPMLHHLCGW |
| 850 | 860 | 870 | 880 | 890 | 900 |
| DLWYCFHLCL | AWLPHRGQRR | GADALFYDAF | VVFDKAQSAV | ADWVYNELRV | QLEERRGRRA |
| 910 | 920 | 930 | 940 | 950 | 960 |
| LRLCLEERDW | LPGKTLFENL | WASVYSSRKT | LFVLAHTDRV | SGLLRASFLL | AQQRLLEDRK |
| 970 | 980 | 990 | 1000 | 1010 | 1020 |
| DVVVLVILRP | DAYRSRYVRL | RQRLCRQSVL | LWPHQPRGQG | SFWAQLGTAL | TRDNHHFYNR |
| NFCRGPTTAE |