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| | ==TIRAP phosphoinositide-binding motif== | | ==TIRAP phosphoinositide-binding motif== |
| - | <StructureSection load='5t7q' size='340' side='right'caption='[[5t7q]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''> | + | <StructureSection load='5t7q' size='340' side='right'caption='[[5t7q]]' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5t7q]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5T7Q OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5T7Q FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5t7q]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5T7Q OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5T7Q 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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5t7q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5t7q OCA], [https://pdbe.org/5t7q PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5t7q RCSB], [https://www.ebi.ac.uk/pdbsum/5t7q PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5t7q ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5t7q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5t7q OCA], [http://pdbe.org/5t7q PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5t7q RCSB], [http://www.ebi.ac.uk/pdbsum/5t7q PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5t7q 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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| | </div> | | </div> |
| | <div class="pdbe-citations 5t7q" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5t7q" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[TIR domain-containing adapter protein|TIR domain-containing adapter protein]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Armstrong, G]] | + | [[Category: Armstrong G]] |
| - | [[Category: Capelluto, D G.S]] | + | [[Category: Capelluto DGS]] |
| - | [[Category: Ellena, J F]] | + | [[Category: Ellena JF]] |
| - | [[Category: Xiao, S]] | + | [[Category: Xiao S]] |
| - | [[Category: Zhao, X]] | + | [[Category: Zhao X]] |
| - | [[Category: Phosphoinositide]]
| + | |
| - | [[Category: Phosphoinositide-binding motif]]
| + | |
| - | [[Category: Phosphorylation]]
| + | |
| - | [[Category: Signaling protein]]
| + | |
| - | [[Category: Structure]]
| + | |
| - | [[Category: Tirap]]
| + | |
| 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
Pathogen-activated Toll-like receptors (TLRs), such as TLR2 and TLR4, dimerize and move laterally across the plasma membrane to phosphatidylinositol (4,5)-bisphosphate-enriched domains. At these sites, TLRs interact with the TIR domain-containing adaptor protein (TIRAP), triggering a signaling cascade that leads to innate immune responses. Membrane recruitment of TIRAP is mediated by its phosphoinositide (PI)-binding motif (PBM). We show that TIRAP PBM transitions from a disordered to a helical conformation in the presence of either zwitterionic micelles or monodispersed PIs. TIRAP PBM bound PIs through basic and nonpolar residues with high affinity, favoring a more ordered structure. TIRAP is phosphorylated at Thr28 within its PBM, which leads to its ubiquitination and degradation. We demonstrate that phosphorylation distorts the helical structure of TIRAP PBM, reducing PI interactions and cell membrane targeting. Our study provides the basis for TIRAP membrane insertion and the mechanism by which it is removed from membranes to avoid sustained innate immune responses.
Membrane targeting of TIRAP is negatively regulated by phosphorylation in its phosphoinositide-binding motif.,Zhao X, Xiong W, Xiao S, Tang TX, Ellena JF, Armstrong GS, Finkielstein CV, Capelluto DG Sci Rep. 2017 Feb 22;7:43043. doi: 10.1038/srep43043. PMID:28225045[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
- ↑ Zhao X, Xiong W, Xiao S, Tang TX, Ellena JF, Armstrong GS, Finkielstein CV, Capelluto DG. Membrane targeting of TIRAP is negatively regulated by phosphorylation in its phosphoinositide-binding motif. Sci Rep. 2017 Feb 22;7:43043. doi: 10.1038/srep43043. PMID:28225045 doi:http://dx.doi.org/10.1038/srep43043
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