Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/32771
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dc.contributor.authorAbdel-Fattah, W.-
dc.contributor.authorScheidt, V.-
dc.contributor.authorUthman, Shanow-
dc.contributor.authorStark, M. J.-
dc.contributor.authorSchaffrath, Raffael-
dc.date.accessioned2015-07-21T09:13:59Z-
dc.date.available2015-07-21T09:13:59Z-
dc.date.issued2013-05-03-
dc.identifier.citationToxins (Basel), 2013, 5 (5) (Special Issue Diphtheria Toxin), pp. 958-968en
dc.identifier.urihttp://www.mdpi.com/2072-6651/5/5/958en
dc.identifier.urihttp://hdl.handle.net/2381/32771-
dc.description.abstractDiphtheria toxin (DT) inhibits eukaryotic translation elongation factor 2 (eEF2) by ADP-ribosylation in a fashion that requires diphthamide, a modified histidine residue on eEF2. In budding yeast, diphthamide formation involves seven genes, DPH1-DPH7. In an effort to further study diphthamide synthesis and interrelation among the Dph proteins, we found, by expression in E. coli and co-immune precipitation in yeast, that Dph1 and Dph2 interact and that they form a complex with Dph3. Protein-protein interaction mapping shows that Dph1-Dph3 complex formation can be dissected by progressive DPH1 gene truncations. This identifies N- and C-terminal domains on Dph1 that are crucial for diphthamide synthesis, DT action and cytotoxicity of sordarin, another microbial eEF2 inhibitor. Intriguingly, dph1 truncation mutants are sensitive to overexpression of DPH5, the gene necessary to synthesize diphthine from the first diphthamide pathway intermediate produced by Dph1-Dph3. This is in stark contrast to dph6 mutants, which also lack the ability to form diphthamide but are resistant to growth inhibition by excess Dph5 levels. As judged from site-specific mutagenesis, the amidation reaction itself relies on a conserved ATP binding domain in Dph6 that, when altered, blocks diphthamide formation and confers resistance to eEF2 inhibition by sordarin.en
dc.language.isoenen
dc.publisherMDPI, Basel, Switzerlanden
dc.relation.urihttp://www.ncbi.nlm.nih.gov/pubmed/23645155-
dc.rightsCopyright © the authors, 2013. This is an open-access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/3.0/ ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en
dc.subjectDiphtheria Toxinen
dc.subjectEscherichia colien
dc.subjectHistidineen
dc.subjectIndenesen
dc.subjectMutationen
dc.subjectProtein Interaction Mappingen
dc.subjectSaccharomyces cerevisiaeen
dc.subjectSaccharomyces cerevisiae Proteinsen
dc.titleInsights into diphthamide, key diphtheria toxin effectoren
dc.typeJournal Articleen
dc.identifier.doi10.3390/toxins5050958-
dc.identifier.eissn2072-6651-
dc.identifier.piitoxins5050958-
dc.description.statusPeer-revieweden
dc.description.versionPublisher Versionen
dc.type.subtypeJournal Article;Research Support, Non-U.S. Gov't-
pubs.organisational-group/Organisationen
pubs.organisational-group/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGYen
pubs.organisational-group/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Biological Sciencesen
pubs.organisational-group/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Biological Sciences/Department of Geneticsen
dc.dateaccepted2013-04-26-
Appears in Collections:Published Articles, Dept. of Genetics

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