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| | ==Structure of the vaccinia virus NF- B antagonist A46== | | ==Structure of the vaccinia virus NF- B antagonist A46== |
| - | <StructureSection load='4lqk' size='340' side='right' caption='[[4lqk]], [[Resolution|resolution]] 1.99Å' scene=''> | + | <StructureSection load='4lqk' size='340' side='right'caption='[[4lqk]], [[Resolution|resolution]] 1.99Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4lqk]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Vaccw Vaccw]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4LQK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4LQK FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4lqk]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Vaccinia_virus_WR Vaccinia virus WR]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4LQK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4LQK FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BR:BROMIDE+ION'>BR</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</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]] 1.99Å</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=BR:BROMIDE+ION'>BR</scene>, <scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">VACWR172, A46R ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10254 VACCW])</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=4lqk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4lqk OCA], [https://pdbe.org/4lqk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4lqk RCSB], [https://www.ebi.ac.uk/pdbsum/4lqk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4lqk 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=4lqk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4lqk OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4lqk RCSB], [http://www.ebi.ac.uk/pdbsum/4lqk PDBsum]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/A46_VACCW A46_VACCW]] Bcl-2-like protein which disrupts the host immune response by inhibiting the TLR4 signaling pathway leading to NF-kappa-B activation. Targets several host TIR adapters including MYD88, TIRAP, TRIF and TICAM2 thereby blocking NF-kappa-B and TRIF-mediated IRF3 activation. | + | [https://www.uniprot.org/uniprot/PG176_VACCW PG176_VACCW] BCL2-like protein which disrupts the host immune response by inhibiting the TLR4 signaling pathway leading to NF-kappa-B activation. Acts close to the plasma membrane and targets several host TIR-domain containing adapter proteins including MYD88, TIRAP, TRIF and TICAM2. In turn, blocks the host NF-kappa-B and TRIF-mediated IRF3 activation.<ref>PMID:20802145</ref> <ref>PMID:27973613</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | </div> | | </div> |
| | + | <div class="pdbe-citations 4lqk" style="background-color:#fffaf0;"></div> |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Vaccw]] | + | [[Category: Large Structures]] |
| - | [[Category: Djinovic-Carugo, K]] | + | [[Category: Vaccinia virus WR]] |
| - | [[Category: Fedosyuk, S]] | + | [[Category: Djinovic-Carugo K]] |
| - | [[Category: Grishkovskaya, I]] | + | [[Category: Fedosyuk S]] |
| - | [[Category: Skern, T]] | + | [[Category: Grishkovskaya I]] |
| - | [[Category: Bcl-2-like fold]]
| + | [[Category: Skern T]] |
| - | [[Category: Viral protein]]
| + | |
| Structural highlights
Function
PG176_VACCW BCL2-like protein which disrupts the host immune response by inhibiting the TLR4 signaling pathway leading to NF-kappa-B activation. Acts close to the plasma membrane and targets several host TIR-domain containing adapter proteins including MYD88, TIRAP, TRIF and TICAM2. In turn, blocks the host NF-kappa-B and TRIF-mediated IRF3 activation.[1] [2]
Publication Abstract from PubMed
Successful vaccinia virus (VACV) replication in the host requires expression of viral proteins that interfere with host immunity, such as antagonists of the activation of the proinflammatory transcription factor NF-kappaB. Two such VACV proteins are A46 and A52. A46 interacts with the Toll-like receptor/interleukin-1R (TIR) domain of Toll-like receptors and intracellular adaptors such as MAL (MyD88 adapter-like), TRAM (TIR domain-containing adapter-inducing interferon-beta (TRIF)-related adaptor molecule), TRIF, and MyD88, whereas A52 binds to the downstream signaling components TRAF6 and IRAK2. Here, we characterize A46 biochemically, determine by microscale thermophoresis binding constants for the interaction of A46 with the TIR domains of MyD88 and MAL, and present the 2.0 A resolution crystal structure of A46 residues 87-229. Full-length A46 behaves as a tetramer; variants lacking the N-terminal 80 residues are dimeric. Nevertheless, both bind to the Toll-like receptor domains of MAL and MyD88 with KD values in the low mum range. Like A52, A46 also shows a Bcl-2-like fold but with biologically relevant differences from that of A52. Thus, A46 uses helices alpha4 and alpha6 to dimerize, compared with the alpha1-alpha6 face used by A52 and other Bcl-2 like VACV proteins. Furthermore, the loop between A46 helices alpha4-alpha5 is flexible and shorter than in A52; there is also evidence for an intramolecular disulfide bridge between consecutive cysteine residues. We used molecular docking to propose how A46 interacts with the BB loop of the TRAM TIR domain. Comparisons of A46 and A52 exemplify how subtle changes in viral proteins with the same fold lead to crucial differences in biological activity.
Characterization and structure of the vaccinia virus NF-kappaB antagonist A46.,Fedosyuk S, Grishkovskaya I, de Almeida Ribeiro E Jr, Skern T J Biol Chem. 2014 Feb 7;289(6):3749-62. doi: 10.1074/jbc.M113.512756. Epub 2013, Dec 19. PMID:24356965[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Lysakova-Devine T, Keogh B, Harrington B, Nagpal K, Halle A, Golenbock DT, Monie T, Bowie AG. Viral inhibitory peptide of TLR4, a peptide derived from vaccinia protein A46, specifically inhibits TLR4 by directly targeting MyD88 adaptor-like and TRIF-related adaptor molecule. J Immunol. 2010 Oct 1;185(7):4261-71. PMID:20802145 doi:10.4049/jimmunol.1002013
- ↑ Fedosyuk S, Bezerra GA, Radakovics K, Smith TK, Sammito M, Bobik N, Round A, Ten Eyck LF, Djinovic-Carugo K, Uson I, Skern T. Vaccinia Virus Immunomodulator A46: A Lipid and Protein-Binding Scaffold for Sequestering Host TIR-Domain Proteins. PLoS Pathog. 2016 Dec 14;12(12):e1006079. doi: 10.1371/journal.ppat.1006079., eCollection 2016 Dec. PMID:27973613 doi:http://dx.doi.org/10.1371/journal.ppat.1006079
- ↑ Fedosyuk S, Grishkovskaya I, de Almeida Ribeiro E Jr, Skern T. Characterization and structure of the vaccinia virus NF-kappaB antagonist A46. J Biol Chem. 2014 Feb 7;289(6):3749-62. doi: 10.1074/jbc.M113.512756. Epub 2013, Dec 19. PMID:24356965 doi:http://dx.doi.org/10.1074/jbc.M113.512756
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