| Toll-like receptor 2 |
PDB rendering based on 1fyw. |
| Available structures |
| PDB |
Ortholog search: PDBe, RCSB |
| List of PDB id codes |
|
1FYW, 1FYX, 1O77, 2Z7X, 2Z80
|
|
|
| Identifiers |
| Symbols |
TLR2; CD282; TIL4 |
| External IDs |
OMIM: 603028 MGI: 1346060 HomoloGene: 20695 ChEMBL: 4163 GeneCards: TLR2 Gene |
| Gene Ontology |
| Molecular function |
• lipopolysaccharide receptor activity
• receptor activity
• transmembrane signaling receptor activity
• protein binding
• pattern recognition receptor activity
• triacyl lipopeptide binding
• diacyl lipopeptide binding
• peptidoglycan binding
• protein heterodimerization activity
• Gram-positive bacterial cell surface binding
• lipoteichoic acid binding
|
| Cellular component |
• cytoplasm
• plasma membrane
• integral to plasma membrane
• external side of plasma membrane
• cell surface
• Toll-like receptor 1-Toll-like receptor 2 protein complex
• Toll-like receptor 2-Toll-like receptor 6 protein complex
|
| Biological process |
• toll-like receptor signaling pathway
• response to molecule of fungal origin
• positive regulation of leukocyte migration
• cell surface pattern recognition receptor signaling pathway
• MyD88-dependent toll-like receptor signaling pathway
• induction of apoptosis
• inflammatory response
• immune response
• signal transduction
• I-kappaB phosphorylation
• Toll signaling pathway
• positive regulation of Wnt receptor signaling pathway
• lipopolysaccharide-mediated signaling pathway
• negative regulation of interleukin-12 production
• negative regulation of interleukin-17 production
• positive regulation of chemokine production
• positive regulation of interferon-beta production
• positive regulation of interleukin-12 production
• positive regulation of interleukin-18 production
• positive regulation of interleukin-6 production
• positive regulation of interleukin-8 production
• positive regulation of tumor necrosis factor production
• positive regulation of toll-like receptor signaling pathway
• toll-like receptor 1 signaling pathway
• toll-like receptor 2 signaling pathway
• toll-like receptor 4 signaling pathway
• positive regulation of NF-kappaB import into nucleus
• detection of triacyl bacterial lipopeptide
• detection of diacyl bacterial lipopeptide
• positive regulation of tumor necrosis factor biosynthetic process
• chloramphenicol transport
• negative regulation of growth of symbiont in host
• innate immune response
• positive regulation of nitric oxide biosynthetic process
• positive regulation of transcription from RNA polymerase II promoter
• positive regulation of cytokine secretion
• positive regulation of inflammatory response
• defense response to Gram-positive bacterium
• positive regulation of NF-kappaB transcription factor activity
• positive regulation of nitric-oxide synthase biosynthetic process
• induction by symbiont of defense-related host nitric oxide production
• positive regulation of macrophage cytokine production
• cellular response to bacterial lipopeptide
• cellular response to lipoteichoic acid
• cellular response to peptidoglycan
• cellular response to diacyl bacterial lipopeptide
• cellular response to triacyl bacterial lipopeptide
|
| Sources: Amigo / QuickGO |
|
| RNA expression pattern |
|
| More reference expression data |
| Orthologs |
| Species |
Human |
Mouse |
|
| Entrez |
7097 |
24088 |
|
| Ensembl |
ENSG00000137462 |
ENSMUSG00000027995 |
|
| UniProt |
O60603 |
Q9QUN7 |
|
| RefSeq (mRNA) |
NM_003264.3 |
NM_011905.3 |
|
| RefSeq (protein) |
NP_003255.2 |
NP_036035.3 |
|
| Location (UCSC) |
Chr 4:
154.62 – 154.63 Mb |
Chr 3:
83.84 – 83.84 Mb |
|
| PubMed search |
[1] |
[2] |
|
|
|
Toll-like receptor 2 also known as TLR-2 is a protein that in humans is encoded by the TLR2 gene.[1] TLR2 has also been designated as CD282 (cluster of differentiation 282). TLR-2 plays a role in the immune system. TLR-2 is a membrane protein, a receptor, which is expressed on the surface of certain cells and recognizes foreign substances and passes on appropriate signals to the cells of the immune system.
|
Contents
- 1 Function
- 2 Background
- 3 Mechanism
- 4 Expression
- 5 Agonists
- 6 Interactions
- 7 References
- 8 Further reading
|
Function
The protein encoded by this gene is a member of the Toll-like receptor (TLR) family, which plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. This gene is expressed most abundantly in peripheral blood leukocytes, and mediates host response to Gram-positive bacteria and yeast via stimulation of NF-κB.[2] Recent research indicates that in the intestine, TLR2 functionality is essential for regulating the expression of CYP1A1,[3] which is a key enzyme in detoxication of carcinogenic polycyclic aromatic hydrocarbons such as benzo(a)pyrene.[4]
Background
The immune system recognizes foreign pathogens and eliminates them. This occurs in several phases. In the early inflammation phase, the pathogens are recognized by antibodies that are already present (innate or acquired through prior infection; see also cross-reactivity). Immune-system components (e.g. complement) that are bound to the antibodies and kept around in reserve then disable them, and they are phagocytized by scavenger cells (e.g. macrophages). Dendritic cells are likewise capable of phagocytizing but do not do it for the purpose of direct pathogen elimination. Rather, they infiltrate the spleen and lymph nodes, and each presents components of an antigen there, as the result of which specific antibodies are formed that recognize precisely that antigen.
These newly formed antibodies would arrive too late in an acute infection, however, so what we think of as "immunology" constitutes only the second half of the process. Because this phase would always start too late to play an essential role in the defense process, a faster-acting principle is applied ahead of it, one that occurs only in forms of life that are phylogenetically more highly developed.
What are called pattern-recognition receptors come into play here. This refers to receptors that recognize the gross, primarily structural features of molecules not innate to the host organism. These include, for example, lipids with a totally different basic chemical structure. Such receptors are bound directly to cells of the immune system and cause immediate activation of their respective nonspecific immune cells.
A prime example of such a foreign ligand is bacterial endotoxin, whose effects have been known for generations. When it enters the bloodstream it causes systematic activation of the early-phase response, with all the side effects of septic shock. This is known in the laboratory as the Shwartzman phenomenon. The intended effect is to mobilize the organism for combat, so to speak, and eliminate most of the pathogens.
Mechanism
As a membrane surface receptor, TLR-2 recognizes many bacterial, fungal, viral, and certain endogenous substances. In general, this results in the uptake (internalization, phagocytosis) of bound molecules by endosomes/phagosomes and in cellular activation; thus such elements of innate immunity as macrophages, PMNs and dendritic cells assume functions of nonspecific immune defense, B1a and MZ B cells form the first antibodies, and specific antibody formation gets started in the process. Cytokines participating in this include tumor necrosis factor-alpha (TNF-α) and various interleukins (IL-1α, IL-1β, IL-6, IL-8, IL-12). Before the TLRs were known, several of the substances mentioned were classified as modulins. Due to the cytokine pattern, which corresponds more closely to Th1, an immune deviation is seen in this direction in most experimental models, away from Th2 characteristics. Conjugates are being developed as vaccines or are already being used without a priori knowledge.
A peculiarity first recognized in 2006 is the expression of TLR-2 on Tregs (a type of T cell), which experience both TCR-controlled proliferation and functional inactivation. This leads to disinhibition of the early inflammation phase and of specific antibody formation. Following a reduction in pathogen count, many pathogen-specific Tregs are present that, now without a TLR-2 signal, become active and inhibit the specific and inflammatory immune reactions (see also TNF-β, IL-10). Older literature that ascribes a direct immunity-stimulating effect via TLR-2 to a given molecule must be interpreted in light of the fact that the TLR-2 knockouts employed typically have very few Tregs.
Functionally relevant polymorphisms are reported that cause functional impairment and thus, in general, reduced survival rates, in particular in infections/sepsis with Gram-positive bacteria.
Signal transduction is depicted under Toll-like receptor.
Expression
TLR-2 is expressed on microglia, Schwann cells, monocytes, macrophages, dendritic cells, polymorphonuclear leukocytes (PMNs or PMLs), B cells (B1a, MZ B, B2), and T cells, including Tregs (CD4+CD25+ regulatory T cells). In some cases, it occurs in a heterodimer (combination molecule), e.g., paired with TLR-1 or TLR-6. TLR-2 is also found in the epithelia of air passages, pulmonary alveoli, renal tubules, and the Bowman's capsules in renal corpuscles. In the skin, it is found on keratinocytes and sebaceous glands; spc1 is induced here, allowing a bactericidal sebum to be formed.
Agonists
| Agonist |
Organism |
| Lipoteichoic acid |
Gram-positive bacteria |
| atypical LPS |
Leptospirosis and Porphyromonas gingivalis |
| MALP-2 and MALP-404 (lipoproteins) |
Mycoplasma |
| - |
Chlamydophila pneumoniae |
| OspA |
Borrelia burgdorferi (Lyme disease) |
| Porin |
Neisseria meningitidis Haemophilus influenzae |
| Antigen mixtures |
Propionibacterium acnes |
| LcrV |
Yersinia |
| Lipomannan |
Mycobacterium: Mycobacterium tuberculosis |
| GPI anchor |
Trypanosoma cruzi |
| Lysophosphatidylserine |
Schistosoma mansoni |
| Lipophosphoglycan (LPG) |
Leishmania major |
| Glycophosphatidylinositol (GPI) |
Plasmodium falciparum |
| Zymosan (a beta-glucan) |
Saccharomyces cerevisiae |
| - |
Malassezia (commensal yeast) |
| Antigen mixtures |
Aspergillus fumigatus, Candida albicans |
| hsp60, as peptide transporter and adjuvant for antigen presentation |
- |
| - |
Herpes simplex virus |
| - |
Varicella zoster virus |
| - |
Cytomegalovirus (CMV) |
| Hemagglutinin |
Measles |
Interactions
TLR 2 has been shown to interact with TLR 1[5] and TOLLIP.[6]
References
- ^ Rock FL, Hardiman G, Timans JC, Kastelein RA, Bazan JF (January 1998). "A family of human receptors structurally related to Drosophila Toll". Proc. Natl. Acad. Sci. U.S.A. 95 (2): 588–93. doi:10.1073/pnas.95.2.588. PMC 18464. PMID 9435236. http://www.pnas.org/content/95/2/588.
- ^ "Entrez Gene: TLR2". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7097.
- ^ Do, KN; Fink, LN; Jensen, TE; Gautier, L; Parlesak, A (2012). "TLR2 controls intestinal carcinogen detoxication by CYP1A1.". PLoS ONE 7 (3): e32309. doi:10.1371/journal.pone.0032309. http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0032309.
- ^ Uno, S.; Dalton, TP; Dragin, N; Curran, CP et al. (2006). "Oral Benzo[a]pyrene in Cyp1 knockout mouse lines: CYP1A1 important in detoxication, CYP1B1 metabolism required for immune damage independent of total-body burden and clearance rate.". Mol Pharmacol. 69 (4): 1103–1112. doi:10.1124/mol.105.021501. PMID 16377763.
- ^ Takeuchi, Osamu; Sato Shintaro, Horiuchi Takao, Hoshino Katsuaki, Takeda Kiyoshi, Dong Zhongyun, Modlin Robert L, Akira Shizuo (Jul. 2002). "Cutting edge: role of Toll-like receptor 1 in mediating immune response to microbial lipoproteins". J. Immunol. (United States) 169 (1): 10–4. ISSN 0022-1767. PMID 12077222.
- ^ Zhang, Guolong; Ghosh Sankar (Mar. 2002). "Negative regulation of toll-like receptor-mediated signaling by Tollip". J. Biol. Chem. (United States) 277 (9): 7059–65. doi:10.1074/jbc.M109537200. ISSN 0021-9258. PMID 11751856.
Further reading
- Aderem A, Ulevitch RJ (2000). "Toll-like receptors in the induction of the innate immune response". Nature 406 (6797): 782–7. doi:10.1038/35021228. PMID 10963608.
- Muzio M, Polentarutti N, Bosisio D, et al. (2001). "Toll-like receptor family and signalling pathway". Biochem. Soc. Trans. 28 (5): 563–6. PMID 11044375.
- Hallman M, Rämet M, Ezekowitz RA; r??Met (2002). "Toll-like receptors as sensors of pathogens". Pediatr. Res. 50 (3): 315–21. doi:10.1203/00006450-200109000-00004. PMID 11518816.
- Dziarski R, Gupta D (2001). "Role of MD-2 in TLR2- and TLR4-mediated recognition of Gram-negative and Gram-positive bacteria and activation of chemokine genes". J. Endotoxin Res. 6 (5): 401–5. PMID 11521063.
- Lien E, Ingalls RR (2002). "Toll-like receptors". Crit. Care Med. 30 (1 Suppl): S1–11. doi:10.1097/00003246-200201001-00001. PMID 11782555.
- Xu D, Komai-Koma M, Liew FY (2005). "Expression and function of Toll-like receptor on T cells". Cell. Immunol. 233 (2): 85–9. doi:10.1016/j.cellimm.2005.04.019. PMID 15950961.
- Lorenz E (2007). "TLR2 and TLR4 expression during bacterial infections". Curr. Pharm. Des. 12 (32): 4185–93. doi:10.2174/138161206778743547. PMID 17100621.
|
PDB gallery
|
|
|
|
|
1fyw: CRYSTAL STRUCTURE OF THE TIR DOMAIN OF HUMAN TLR2
|
|
|
|
1fyx: CRYSTAL STRUCTURE OF P681H MUTANT OF TIR DOMAIN OF HUMAN TLR2
|
|
|
|
1o77: CRYSTAL STRUCTURE OF THE C713S MUTANT OF THE TIR DOMAIN OF HUMAN TLR2
|
|
|
|
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
|
Signaling pathway: TLR signaling pathway
|
|
| Receptor |
TLR 4
TLR 1 · TLR 2 · TLR 6
TLR 5 · TLR 10
|
|
| Other external |
CD14 · MD2 · LBP
|
|
| Internal |
adaptor: Myd88 · TRIF · TIRAP · TRAF6 · TOLLIP
IRAK1 · IRAK4
IRF3
TLR 3 · TLR 7 · TLR 8 · TLR 9
|
|
|
B trdu: iter (nrpl/grfl/cytl/horl), csrc (lgic, enzr, gprc, igsr, intg, nrpr/grfr/cytr), itra (adap, gbpr, mapk), calc, lipd; path (hedp, wntp, tgfp+mapp, notp, jakp, fsap, hipp, tlrp)
|
|
