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Vaccinia virus immunomodulator A46 : a lipid and protein-binding scaffold for sequestering host TIR-domain proteins
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dc.contributor.author | Fedosyuk, Sofiya | |
dc.contributor.author | Bezerra, Gustavo Arruda | |
dc.contributor.author | Radakovics, Katharina | |
dc.contributor.author | Smith, Terry K. | |
dc.contributor.author | Sammito, Massimo | |
dc.contributor.author | Bobik, Nina | |
dc.contributor.author | Round, Adam | |
dc.contributor.author | Ten Eyck, Lynn F. | |
dc.contributor.author | Djinović-Carugo, Kristina | |
dc.contributor.author | Usón, Isabel | |
dc.contributor.author | Skern, Tim | |
dc.date.accessioned | 2017-01-13T17:30:09Z | |
dc.date.available | 2017-01-13T17:30:09Z | |
dc.date.issued | 2016-12-14 | |
dc.identifier | 248879247 | |
dc.identifier | 2a572925-2525-4739-8a05-4ea79890029b | |
dc.identifier | 85007560046 | |
dc.identifier | 000392202100050 | |
dc.identifier.citation | Fedosyuk , S , Bezerra , G A , Radakovics , K , Smith , T K , Sammito , M , Bobik , N , Round , A , Ten Eyck , L F , Djinović-Carugo , K , Usón , I & Skern , T 2016 , ' Vaccinia virus immunomodulator A46 : a lipid and protein-binding scaffold for sequestering host TIR-domain proteins ' , PLoS Pathogens , vol. 12 , no. 12 , e1006079 . https://doi.org/10.1371/journal.ppat.1006079 | en |
dc.identifier.issn | 1553-7366 | |
dc.identifier.uri | https://hdl.handle.net/10023/10102 | |
dc.description | TS received Austrian Science Fund (FWF) grants P24038, W1221 and W1258. GAB is a member of Max F. Perutz Laboratories and the Vienna International PostDoctoral Program (VIPS). TKS is a holder of Wellcome Trust grant 097831. IU has Spanish Ministry of Economy and Competitiveness grant BIO2013-49604-EXP. | en |
dc.description.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 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. | |
dc.format.extent | 24 | |
dc.format.extent | 2417440 | |
dc.language.iso | eng | |
dc.relation.ispartof | PLoS Pathogens | en |
dc.subject | QH301 Biology | en |
dc.subject | QH426 Genetics | en |
dc.subject | QR180 Immunology | en |
dc.subject | QR355 Virology | en |
dc.subject | Parasitology | en |
dc.subject | Microbiology | en |
dc.subject | Immunology | en |
dc.subject | Molecular Biology | en |
dc.subject | Genetics | en |
dc.subject | Virology | en |
dc.subject | DAS | en |
dc.subject | SDG 3 - Good Health and Well-being | en |
dc.subject.lcc | QH301 | en |
dc.subject.lcc | QH426 | en |
dc.subject.lcc | QR180 | en |
dc.subject.lcc | QR355 | en |
dc.title | Vaccinia virus immunomodulator A46 : a lipid and protein-binding scaffold for sequestering host TIR-domain proteins | en |
dc.type | Journal article | en |
dc.contributor.sponsor | The Wellcome Trust | en |
dc.contributor.institution | University of St Andrews. Biomedical Sciences Research Complex | en |
dc.contributor.institution | University of St Andrews. School of Biology | en |
dc.identifier.doi | 10.1371/journal.ppat.1006079 | |
dc.description.status | Peer reviewed | en |
dc.identifier.grantnumber | 097831/z/11/z | en |
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