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| | <SX load='5uzb' size='340' side='right' viewer='molstar' caption='[[5uzb]], [[Resolution|resolution]] 7.00Å' scene=''> | | <SX load='5uzb' size='340' side='right' viewer='molstar' caption='[[5uzb]], [[Resolution|resolution]] 7.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5uzb]] is a 14 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5UZB OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5UZB FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5uzb]] is a 14 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5UZB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5UZB FirstGlance]. <br> |
| - | </td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TIRAP, MAL ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 7Å</td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5uzb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5uzb OCA], [http://pdbe.org/5uzb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5uzb RCSB], [http://www.ebi.ac.uk/pdbsum/5uzb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5uzb ProSAT]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5uzb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5uzb OCA], [https://pdbe.org/5uzb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5uzb RCSB], [https://www.ebi.ac.uk/pdbsum/5uzb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5uzb ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/TIRAP_HUMAN TIRAP_HUMAN]] Adapter involved in TLR2 and TLR4 signaling pathways in the innate immune response. Acts via IRAK2 and TRAF-6, leading to the activation of NF-kappa-B, MAPK1, MAPK3 and JNK, and resulting in cytokine secretion and the inflammatory response. Positively regulates the production of TNF-alpha and interleukin-6.<ref>PMID:18292575</ref> <ref>PMID:19509286</ref> | + | [https://www.uniprot.org/uniprot/TIRAP_HUMAN TIRAP_HUMAN] Adapter involved in TLR2 and TLR4 signaling pathways in the innate immune response. Acts via IRAK2 and TRAF-6, leading to the activation of NF-kappa-B, MAPK1, MAPK3 and JNK, and resulting in cytokine secretion and the inflammatory response. Positively regulates the production of TNF-alpha and interleukin-6.<ref>PMID:18292575</ref> <ref>PMID:19509286</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[TIR domain-containing adaptor protein|TIR domain-containing adaptor protein]] | + | *[[TIR domain-containing adapter protein|TIR domain-containing adapter protein]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </SX> | | </SX> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Carrol, A O]]
| + | [[Category: Chauvin B]] |
| - | [[Category: Chauvin, B]] | + | [[Category: Croll T]] |
| - | [[Category: Croll, T]] | + | [[Category: DiMaio F]] |
| - | [[Category: DiMaio, F]] | + | [[Category: Egelman EH]] |
| - | [[Category: Egelman, E H]] | + | [[Category: Gambin Y]] |
| - | [[Category: Gambin, Y]] | + | [[Category: Hassan Z]] |
| - | [[Category: Hassan, Z]] | + | [[Category: Hedger A]] |
| - | [[Category: Hedger, A]] | + | [[Category: Horsefield S]] |
| - | [[Category: Horsefield, S]] | + | [[Category: Kobe B]] |
| - | [[Category: Kobe, B]] | + | [[Category: Landsberg MJ]] |
| - | [[Category: Landsberg, M J]] | + | [[Category: Lavrencic P]] |
| - | [[Category: Lavrencic, P]] | + | [[Category: Mansell A]] |
| - | [[Category: Mansell, A]] | + | [[Category: Mobli M]] |
| - | [[Category: Mobli, M]] | + | [[Category: Morgan GP]] |
| - | [[Category: Morgan, G P]] | + | [[Category: O'Carrol A]] |
| - | [[Category: Sierecki, E]] | + | [[Category: Sierecki E]] |
| - | [[Category: Stacey, K J]] | + | [[Category: Stacey KJ]] |
| - | [[Category: Vajjhala, P R]] | + | [[Category: Vajjhala PR]] |
| - | [[Category: Ve, T]] | + | [[Category: Ve T]] |
| - | [[Category: Yu, X]] | + | [[Category: Yu X]] |
| - | [[Category: Adaptor protein]]
| + | |
| - | [[Category: Homotypic protein interaction]]
| + | |
| - | [[Category: Immune system]]
| + | |
| - | [[Category: Tir domain]]
| + | |
| - | [[Category: Tlr signaling]]
| + | |
| Structural highlights
Function
TIRAP_HUMAN Adapter involved in TLR2 and TLR4 signaling pathways in the innate immune response. Acts via IRAK2 and TRAF-6, leading to the activation of NF-kappa-B, MAPK1, MAPK3 and JNK, and resulting in cytokine secretion and the inflammatory response. Positively regulates the production of TNF-alpha and interleukin-6.[1] [2]
Publication Abstract from PubMed
Toll-like receptor (TLR) signaling is a key innate immunity response to pathogens. Recruitment of signaling adapters such as MAL (TIRAP) and MyD88 to the TLRs requires Toll/interleukin-1 receptor (TIR)-domain interactions, which remain structurally elusive. Here we show that MAL TIR domains spontaneously and reversibly form filaments in vitro. They also form cofilaments with TLR4 TIR domains and induce formation of MyD88 assemblies. A 7-A-resolution cryo-EM structure reveals a stable MAL protofilament consisting of two parallel strands of TIR-domain subunits in a BB-loop-mediated head-to-tail arrangement. Interface residues that are important for the interaction are conserved among different TIR domains. Although large filaments of TLR4, MAL or MyD88 are unlikely to form during cellular signaling, structure-guided mutagenesis, combined with in vivo interaction assays, demonstrated that the MAL interactions defined within the filament represent a template for a conserved mode of TIR-domain interaction involved in both TLR and interleukin-1 receptor signaling.
Structural basis of TIR-domain-assembly formation in MAL- and MyD88-dependent TLR4 signaling.,Ve T, Vajjhala PR, Hedger A, Croll T, DiMaio F, Horsefield S, Yu X, Lavrencic P, Hassan Z, Morgan GP, Mansell A, Mobli M, O'Carroll A, Chauvin B, Gambin Y, Sierecki E, Landsberg MJ, Stacey KJ, Egelman EH, Kobe B Nat Struct Mol Biol. 2017 Jul 31. doi: 10.1038/nsmb.3444. PMID:28759049[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Semaan N, Alsaleh G, Gottenberg JE, Wachsmann D, Sibilia J. Etk/BMX, a Btk family tyrosine kinase, and Mal contribute to the cross-talk between MyD88 and FAK pathways. J Immunol. 2008 Mar 1;180(5):3485-91. PMID:18292575
- ↑ Nagpal K, Plantinga TS, Wong J, Monks BG, Gay NJ, Netea MG, Fitzgerald KA, Golenbock DT. A TIR domain variant of MyD88 adapter-like (Mal)/TIRAP results in loss of MyD88 binding and reduced TLR2/TLR4 signaling. J Biol Chem. 2009 Sep 18;284(38):25742-8. doi: 10.1074/jbc.M109.014886. Epub 2009, Jun 9. PMID:19509286 doi:http://dx.doi.org/10.1074/jbc.M109.014886
- ↑ Ve T, Vajjhala PR, Hedger A, Croll T, DiMaio F, Horsefield S, Yu X, Lavrencic P, Hassan Z, Morgan GP, Mansell A, Mobli M, O'Carroll A, Chauvin B, Gambin Y, Sierecki E, Landsberg MJ, Stacey KJ, Egelman EH, Kobe B. Structural basis of TIR-domain-assembly formation in MAL- and MyD88-dependent TLR4 signaling. Nat Struct Mol Biol. 2017 Jul 31. doi: 10.1038/nsmb.3444. PMID:28759049 doi:http://dx.doi.org/10.1038/nsmb.3444
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