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| Title | Vaccinia Virus Immunomodulator A46: A Lipid and Protein-Binding Scaffold for Sequestering Host TIR-Domain Proteins. |
|---|---|
| Journal, issue, pages | PLoS Pathog, Vol. 12, Issue 12, Page e1006079, Year 2016 |
| Publish date | Dec 14, 2016 |
 Authors | Sofiya Fedosyuk / Gustavo Arruda Bezerra / Katharina Radakovics / Terry K Smith / Massimo Sammito / Nina Bobik / Adam Round / Lynn F Ten Eyck / Kristina Djinović-Carugo / Isabel Usón / Tim Skern /        |
| PubMed Abstract | 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 ...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 Å. 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 β-sheet structure. This is the first such structure solved by this method which should be applicable to any protein composed entirely of β-sheets. The A46(1-83) structure itself is a β-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-κB activation and postulate that A46 employs a bipartite binding arrangement to sequester the host immune adaptors TRAM and MyD88. |
 External links | PLoS Pathog / PubMed:27973613 / PubMed Central |
| Methods | SAS (X-ray synchrotron) / X-ray diffraction |
| Resolution | 1.55 Å |
| Structure data |  SASDBK7:  SASDBL7:  PDB-5ezu: |
| Chemicals |  ChemComp-MYR:  ChemComp-HOH: |
| Source |
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 Keywords |  VIRAL PROTEIN / immunomodulator / beta sheet / ab initio phasing / vaccinia virus / A46 / fatty acids / myristic acid |
