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| <StructureSection load='5ezu' size='340' side='right'caption='[[5ezu]], [[Resolution|resolution]] 1.55Å' scene=''> | | <StructureSection load='5ezu' size='340' side='right'caption='[[5ezu]], [[Resolution|resolution]] 1.55Å' scene=''> |
| == Structural highlights == | | == Structural highlights == |
- | <table><tr><td colspan='2'>[[5ezu]] is a 2 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=5EZU OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5EZU FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5ezu]] is a 2 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=5EZU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5EZU FirstGlance]. <br> |
- | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MYR:MYRISTIC+ACID'>MYR</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]] 1.55Å</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MYR:MYRISTIC+ACID'>MYR</scene></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=5ezu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ezu OCA], [http://pdbe.org/5ezu PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ezu RCSB], [http://www.ebi.ac.uk/pdbsum/5ezu PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ezu 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=5ezu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ezu OCA], [https://pdbe.org/5ezu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ezu RCSB], [https://www.ebi.ac.uk/pdbsum/5ezu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ezu ProSAT]</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/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. |
| <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| </StructureSection> | | </StructureSection> |
| [[Category: Large Structures]] | | [[Category: Large Structures]] |
- | [[Category: Vaccw]] | + | [[Category: Vaccinia virus WR]] |
- | [[Category: Bezerra, G A]] | + | [[Category: Bezerra GA]] |
- | [[Category: Fedosyuk, S]] | + | [[Category: Fedosyuk S]] |
- | [[Category: Sammito, M]] | + | [[Category: Sammito M]] |
- | [[Category: Skern, T]] | + | [[Category: Skern T]] |
- | [[Category: Uson, I]] | + | [[Category: Uson I]] |
- | [[Category: A46]]
| + | |
- | [[Category: Ab initio phasing]]
| + | |
- | [[Category: Beta sheet]]
| + | |
- | [[Category: Fatty acid]]
| + | |
- | [[Category: Immunomodulator]]
| + | |
- | [[Category: Myristic acid]]
| + | |
- | [[Category: Vaccinia virus]]
| + | |
- | [[Category: Viral protein]]
| + | |
| Structural highlights
Function
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.
Publication Abstract from PubMed
Vaccinia virus interferes with early events of the activation pathway of the transcriptional factor NF-kB by binding to numerous host TIR-domain containing adaptor proteins. We have previously determined the X-ray structure of the A46 C-terminal domain; however, the structure and function of the A46 N-terminal domain and its relationship to the C-terminal domain have remained unclear. Here, we biophysically characterize residues 1-83 of the N-terminal domain of A46 and present the X-ray structure at 1.55 A. Crystallographic phases were obtained by a recently developed ab initio method entitled ARCIMBOLDO_BORGES that employs tertiary structure libraries extracted from the Protein Data Bank; data analysis revealed an all beta-sheet structure. This is the first such structure solved by this method which should be applicable to any protein composed entirely of beta-sheets. The A46(1-83) structure itself is a beta-sandwich containing a co-purified molecule of myristic acid inside a hydrophobic pocket and represents a previously unknown lipid-binding fold. Mass spectrometry analysis confirmed the presence of long-chain fatty acids in both N-terminal and full-length A46; mutation of the hydrophobic pocket reduced the lipid content. Using a combination of high resolution X-ray structures of the N- and C-terminal domains and SAXS analysis of full-length protein A46(1-240), we present here a structural model of A46 in a tetrameric assembly. Integrating affinity measurements and structural data, we propose how A46 simultaneously interferes with several TIR-domain containing proteins to inhibit NF-kappaB activation and postulate that A46 employs a bipartite binding arrangement to sequester the host immune adaptors TRAM and MyD88.
Vaccinia Virus Immunomodulator A46: A Lipid and Protein-Binding Scaffold for Sequestering Host TIR-Domain Proteins.,Fedosyuk S, Bezerra GA, Radakovics K, Smith TK, Sammito M, Bobik N, Round A, Ten Eyck LF, Djinovic-Carugo K, Uson I, Skern T PLoS Pathog. 2016 Dec 14;12(12):e1006079. doi: 10.1371/journal.ppat.1006079., eCollection 2016 Dec. PMID:27973613[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ 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
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