Skip to content

Research at St Andrews

Vaccinia virus immunomodulator A46: a lipid and protein-binding scaffold for sequestering host TIR-domain proteins

Research output: Contribution to journalArticle

DOI

Open Access permissions

Open

Author(s)

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

School/Research organisations

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.

Close

Details

Original languageEnglish
Article numbere1006079
Number of pages24
JournalPLoS Pathogens
Volume12
Issue number12
DOIs
StatePublished - 14 Dec 2016

Discover related content
Find related publications, people, projects and more using interactive charts.

View graph of relations

Related by author

  1. Simplifying nature: towards the design of broad spectrum kinetoplastid inhibitors, inspired by acetogenins

    Gould, E. R., King, E. F. B., Menzies, S. K., Fraser, A. L., Tulloch, L. B., Zacharova, M. K., Smith, T. K. & Florence, G. J. 15 Nov 2017 In : Bioorganic & Medicinal Chemistry. 25, 22, p. 6126-6136

    Research output: Contribution to journalArticle

  2. CHARACTERIZATION OF THE TRYPANOSOMATID SECONDARY ALTERNATIVE OXIDASE - A NOVEL POTENTIAL DRUG TARGET

    Menzies, S. K., Tulloch, L. B., Fraser, A. L., Gould, E. R., King, E. F., Zacharova, M. K., Florence, G. J. & Smith, T. K. Nov 2017 In : American Journal of Tropical Medicine and Hygiene. 95, 5, p. 410-410 1 p.

    Research output: Contribution to journalAbstract

  3. ADIPOSE TISSUE IS A MAJOR RESERVOIR OF FUNCTIONALLY DISTINCT TRYPANOSOMA BRUCEI PARASITES

    Trindade, S., Rijo-Ferreira, F., Carvalho, T., Pinto-Neves, D., Guegan, F., Aresta-Branco, F., Bento, F., Young, S. A., Pinto, A., Van den Abbeele, J., Ribeiro, R. M., Dias, S., Smith, T. K. & Figueiredo, L. M. Nov 2017 In : American Journal of Tropical Medicine and Hygiene. 95, 5, p. 606-606 1 p.

    Research output: Contribution to journalAbstract

  4. ANALOGS OF THE NATURAL PRODUCT CHAMUVARININ TARGET THE TRYPANOSOMATID FOF1-ATP SYNTHASE MITOCHONDRIAL COMPLEX V

    Menzies, S. K., Tulloch, L. B., Fraser, A. L., Gould, E. R., King, E. F., Zacharova, M. K., Florence, G. J. & Smith, T. K. Nov 2017 In : American Journal of Tropical Medicine and Hygiene. 95, 5, p. 164-164 1 p.

    Research output: Contribution to journalAbstract

Related by journal

  1. Human cytomegalovirus IE1 downregulates Hes1 in neural progenitor cells as a potential E3 ubiquitin ligase

    Liu, X-J., Yang, B., Huang, S-N., Wu, C-C., Li, X-J., Cheng, S., Jiang, X., Hu, F., Ming, Y-Z., Nevels, M. M., Britt, W. J., Rayner, S., Tang, Q., Zeng, W-B., Zhao, F. & Luo, M-H. 27 Jul 2017 In : PLoS Pathogens. 13, 7, 28 p., e1006542

    Research output: Contribution to journalArticle

  2. Human cytomegalovirus immediate-early 1 protein rewires upstream STAT3 to downstream STAT1 signaling switching an IL6-type to an IFNγ-like response

    Harwardt, T., Lukas, S., Zenger, M., Reitberger, T., Danzer, D., Übner, T., Munday, D. C., Nevels, M. & Paulus, C. 7 Jul 2016 In : PLoS Pathogens. 12, 7, 39 p., e1005748

    Research output: Contribution to journalArticle

  3. NEDDylation is essential for Kaposi’s Sarcoma-associated herpesvirus latency and lytic reactivation and represents a novel anti-KSHV target

    Hughes, D. J., Wood, J. J., Jackson, B. R., Baquero-Pérez, B. & Whitehouse, A. 20 Mar 2015 In : PLoS Pathogens. 11, 3, 26 p., e1004771

    Research output: Contribution to journalArticle

  4. Plasma membrane-located purine nucleotide transport proteins are key components for host exploitation by microsporidian intracellular parasites

    Heinz, E., Hacker, C., Dean, P., Mifsud, J., Goldberg, A. V., Williams, T. A., Nakjang, S., Gregory, A., Hirt, R. P., Lucocq, J. M., Kunji, E. R. S. & Embley, T. M. 4 Dec 2014 In : PLoS Pathogens. 10, 12, e1004547

    Research output: Contribution to journalArticle

Related by journal

  1. PLoS Pathogens (Journal)

    Smith, T. K. (Member of editorial board)
    2015 → …

    Activity: Publication peer-review and editorial workEditor of research journal

ID: 248879247