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| | ==Crystal structure of Pellino2 FHA Domain at 1.8 Angstroms resolution== | | ==Crystal structure of Pellino2 FHA Domain at 1.8 Angstroms resolution== |
| - | <StructureSection load='3ega' size='340' side='right' caption='[[3ega]], [[Resolution|resolution]] 1.80Å' scene=''> | + | <StructureSection load='3ega' size='340' side='right'caption='[[3ega]], [[Resolution|resolution]] 1.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3ega]] is a 1 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=3EGA OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3EGA FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3ega]] is a 1 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=3EGA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3EGA FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.8Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3egb|3egb]]</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=3ega FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ega OCA], [https://pdbe.org/3ega PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3ega RCSB], [https://www.ebi.ac.uk/pdbsum/3ega PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3ega ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PELI2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=3ega FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ega OCA], [http://pdbe.org/3ega PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3ega RCSB], [http://www.ebi.ac.uk/pdbsum/3ega PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3ega ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/PELI2_HUMAN PELI2_HUMAN]] E3 ubiquitin ligase catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins. Involved in the TLR and IL-1 signaling pathways via interaction with the complex containing IRAK kinases and TRAF6. Mediates IL1B-induced IRAK1 'Lys-63'-linked polyubiquitination and possibly 'Lys-48'-linked ubiquitination. May be important for LPS- and IL1B-induced MAP3K7-dependent, but not MAP3K3-dependent, NF-kappa-B activation. Can activate the MAP (mitogen activated protein) kinase pathway leading to activation of ELK1.<ref>PMID:12804775</ref> <ref>PMID:12860405</ref> <ref>PMID:17675297</ref> <ref>PMID:17997719</ref> <ref>PMID:22669975</ref> | + | [https://www.uniprot.org/uniprot/PELI2_HUMAN PELI2_HUMAN] E3 ubiquitin ligase catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins. Involved in the TLR and IL-1 signaling pathways via interaction with the complex containing IRAK kinases and TRAF6. Mediates IL1B-induced IRAK1 'Lys-63'-linked polyubiquitination and possibly 'Lys-48'-linked ubiquitination. May be important for LPS- and IL1B-induced MAP3K7-dependent, but not MAP3K3-dependent, NF-kappa-B activation. Can activate the MAP (mitogen activated protein) kinase pathway leading to activation of ELK1.<ref>PMID:12804775</ref> <ref>PMID:12860405</ref> <ref>PMID:17675297</ref> <ref>PMID:17997719</ref> <ref>PMID:22669975</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Ferguson, K M]] | + | [[Category: Large Structures]] |
| - | [[Category: Lin, C]] | + | [[Category: Ferguson KM]] |
| - | [[Category: Schmitz, K R]] | + | [[Category: Lin C]] |
| - | [[Category: E3 ubiquitin ligase]] | + | [[Category: Schmitz KR]] |
| - | [[Category: Fha domain]]
| + | |
| - | [[Category: Pellino]]
| + | |
| - | [[Category: Phosphoprotein]]
| + | |
| - | [[Category: Protein binding]]
| + | |
| - | [[Category: Substrate binding domain]]
| + | |
| Structural highlights
Function
PELI2_HUMAN E3 ubiquitin ligase catalyzing the covalent attachment of ubiquitin moieties onto substrate proteins. Involved in the TLR and IL-1 signaling pathways via interaction with the complex containing IRAK kinases and TRAF6. Mediates IL1B-induced IRAK1 'Lys-63'-linked polyubiquitination and possibly 'Lys-48'-linked ubiquitination. May be important for LPS- and IL1B-induced MAP3K7-dependent, but not MAP3K3-dependent, NF-kappa-B activation. Can activate the MAP (mitogen activated protein) kinase pathway leading to activation of ELK1.[1] [2] [3] [4] [5]
Publication Abstract from PubMed
Pellino proteins are RING E3 ubiquitin ligases involved in signaling events downstream of the Toll and interleukin-1 (IL-1) receptors, key initiators of innate immune and inflammatory responses. Pellino proteins associate with and ubiquitinate proteins in these pathways, including the interleukin-1 receptor associated kinase-1 (IRAK1). We determined the X-ray crystal structure of a Pellino2 fragment lacking only the RING domain. This structure reveals that the IRAK1-binding region of Pellino proteins consists largely of a previously unidentified forkhead-associated (FHA) domain. FHA domains are well-characterized phosphothreonine-binding modules, and this cryptic example in Pellino2 can drive interaction of this protein with phosphorylated IRAK1. The Pellino FHA domain is decorated with an unusual appendage or "wing" composed of two long inserts that lie within the FHA homology region. Delineating how this E3 ligase associates with substrates, and how these interactions are regulated by phosphorylation, is crucial for a complete understanding of Toll/IL-1 receptor signaling.
Pellino proteins contain a cryptic FHA domain that mediates interaction with phosphorylated IRAK1.,Lin CC, Huoh YS, Schmitz KR, Jensen LE, Ferguson KM Structure. 2008 Dec 10;16(12):1806-16. PMID:19081057[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Jensen LE, Whitehead AS. Pellino2 activates the mitogen activated protein kinase pathway. FEBS Lett. 2003 Jun 19;545(2-3):199-202. PMID:12804775
- ↑ Strelow A, Kollewe C, Wesche H. Characterization of Pellino2, a substrate of IRAK1 and IRAK4. FEBS Lett. 2003 Jul 17;547(1-3):157-61. PMID:12860405
- ↑ Butler MP, Hanly JA, Moynagh PN. Kinase-active interleukin-1 receptor-associated kinases promote polyubiquitination and degradation of the Pellino family: direct evidence for PELLINO proteins being ubiquitin-protein isopeptide ligases. J Biol Chem. 2007 Oct 12;282(41):29729-37. Epub 2007 Aug 3. PMID:17675297 doi:http://dx.doi.org/10.1074/jbc.M704558200
- ↑ Ordureau A, Smith H, Windheim M, Peggie M, Carrick E, Morrice N, Cohen P. The IRAK-catalysed activation of the E3 ligase function of Pellino isoforms induces the Lys63-linked polyubiquitination of IRAK1. Biochem J. 2008 Jan 1;409(1):43-52. PMID:17997719 doi:10.1042/BJ20071365
- ↑ Kim TW, Yu M, Zhou H, Cui W, Wang J, DiCorleto P, Fox P, Xiao H, Li X. Pellino 2 is critical for Toll-like receptor/interleukin-1 receptor (TLR/IL-1R)-mediated post-transcriptional control. J Biol Chem. 2012 Jul 20;287(30):25686-95. doi: 10.1074/jbc.M112.352625. Epub, 2012 Jun 5. PMID:22669975 doi:http://dx.doi.org/10.1074/jbc.M112.352625
- ↑ Lin CC, Huoh YS, Schmitz KR, Jensen LE, Ferguson KM. Pellino proteins contain a cryptic FHA domain that mediates interaction with phosphorylated IRAK1. Structure. 2008 Dec 10;16(12):1806-16. PMID:19081057 doi:10.1016/j.str.2008.09.011
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