Molecular basis of specificity and deamidation of eIF4A by Burkholderia lethal factor 1

Abstract

Burkholderia pseudomallei lethal factor 1 (BLF1) exhibits site-specific glutamine deamidase activity against the eukaryotic RNA helicase, eIF4A, thereby blocking mammalian protein synthesis. The structure of a complex between BLF1 C94S and human eIF4A shows that the toxin binds in the cleft between the two RecA-like eIF4A domains forming interactions with residues from both and with the scissile amide of the target glutamine, Gln339, adjacent to the toxin active site. The RecA-like domains adopt a radically twisted orientation compared to other eIF4A structures and the nature and position of conserved residues suggests this may represent a conformation associated with RNA binding. Comparison of the catalytic site of BLF1 with other deamidases and cysteine proteases reveals that they fall into two classes, related by pseudosymmetry, that present either the re or si faces of the target amide/peptide to the nucleophilic sulfur, highlighting constraints in the convergent evolution of their Cys-His active sites.

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Item Type:	Article
Authors/Creators:	Mobbs, G.W. Aziz, A.A. Dix, S.R. Blackburn, G.M. Sedelnikova, S.E. https://orcid.org/0000-0001-5174-6302 Minshull, T.C. Dickman, M.J. Baker, P.J. https://orcid.org/0000-0003-1995-5643 Nathan, S. Raih, M.F. Rice, D.W.
Copyright, Publisher and Additional Information:	© 2022 Crown copyright. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Dates:	Published: 28 March 2022 Published (online): 28 March 2022 Accepted: 17 February 2022
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Science (Sheffield) > School of Biosciences (Sheffield) > Department of Animal and Plant Sciences (Sheffield)
Funding Information:	Funder Grant number Biotechnology and Biological Sciences Research Council BB/M012166/1
Depositing User:	Symplectic Sheffield
Date Deposited:	13 Apr 2022 14:55
Last Modified:	13 Apr 2022 14:55
Status:	Published
Publisher:	Springer Nature
Refereed:	Yes
Identification Number:	10.1038/s42003-022-03186-2
Related URLs:	PubMed URL
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:185671

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Molecular basis of specificity and deamidation of eIF4A by Burkholderia lethal factor 1

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