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Molecular basis of specificity and deamidation of eIF4A by Burkholderia Lethal Factor 1

Mobbs, George W. and Aziz, Adli A. and Dix, Samuel R. and Blackburn, G. M. and Sedelnikova, Sveta E. and Minshull, Thomas C. and Dickman, Mark J. and Baker, Patrick J. and Nathan, Sheila and Firdaus Raih, Mohd and Rice, David W. (2022) Molecular basis of specificity and deamidation of eIF4A by Burkholderia Lethal Factor 1. Communications Biology, 5 . Art. No. 272. ISSN 2399-3642. PMCID PMC8960835. doi:10.1038/s42003-022-03186-2. https://resolver.caltech.edu/CaltechAUTHORS:20220329-4699029

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Abstract

AbstractBurkholderiapseudomallei 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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1038/s42003-022-03186-2DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8960835/PubMed CentralArticle
ORCID:
AuthorORCID
Mobbs, George W.0000-0003-2405-3345
Aziz, Adli A.0000-0002-2665-2467
Dix, Samuel R.0000-0002-6907-1435
Blackburn, G. M.0000-0002-3941-0459
Sedelnikova, Sveta E.0000-0001-5174-6302
Dickman, Mark J.0000-0002-9236-0788
Baker, Patrick J.0000-0003-1995-5643
Nathan, Sheila0000-0002-2132-2346
Firdaus Raih, Mohd0000-0003-4275-4663
Rice, David W.0000-0002-7811-0539
Additional Information:© Crown 2022. 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/. Received 03 November 2021. Accepted 17 February 2022. Published 28 March 2022. A.A.A. acknowledges a Ph.D. scholarship from Majlis Amanah Rakyat (MARA) Malaysia, M.J.D. acknowledges support from the Biotechnology and Biological Sciences Research Council UK (BB/M012166/1), S.R.D., S.N., M.F-R., P.J.B., and D.W.R. acknowledges support from a Royal Society International Collaboration Award (IC170306). We would also like to thank Diamond Light Source (DLS) for the time on beamlines I03 and I04, station staff for assistance with data collection, and STFC for DLS access and funding (MX8987 and MX17773). Contributions. G.W.M., D.W.R., S.N., and P.J.B., designed the research. G.W.M., S.E.S., A.A.A., and S.R.D., performed the experiments and analysed the data. T.C.M. and M.J.D. performed the mass spectrometry. G.W.M., A.A.A., S.R.D., M.F-R., D.W.R., S.N., G.M.B., and P.J.B. wrote the paper. Reporting summary. Further information on research design is available in the Nature Research Reporting Summary linked to this article. Data availability. Images used in data processing are available upon request. The atomic coordinates and structure factors generated in this study are available at the PDB with accession codes, 6RVU, 7PPZ, and 7PQ0. The authors declare no competing interests. Peer review information. Communications Biology thanks Wulf Blankenfeldt and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editors: Joanna Timmins and Christina Karlsson Rosenthal. Peer reviewer reports are available.
Funders:
Funding AgencyGrant Number
Majlis Amanah Rakyat (MARA)UNSPECIFIED
Biotechnology and Biological Sciences Research Council (BBSRC)BB/M012166/1
Royal SocietyIC170306
Diamond Light SourceMX8987
Diamond Light SourceMX17773
PubMed Central ID:PMC8960835
DOI:10.1038/s42003-022-03186-2
Record Number:CaltechAUTHORS:20220329-4699029
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20220329-4699029
Official Citation:Mobbs, G.W., Aziz, A.A., Dix, S.R. et al. Molecular basis of specificity and deamidation of eIF4A by Burkholderia Lethal Factor 1. Commun Biol 5, 272 (2022). https://doi.org/10.1038/s42003-022-03186-2
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:114131
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:29 Mar 2022 12:28
Last Modified:25 Jul 2022 23:14

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  • Mobbs, George W. and Aziz, Adli A. and Dix, Samuel R. and Blackburn, G. M. and Sedelnikova, Sveta E. and Minshull, Thomas C. and Dickman, Mark J. and Baker, Patrick J. and Nathan, Sheila and Firdaus Raih, Mohd and Rice, David W. Molecular basis of specificity and deamidation of eIF4A by Burkholderia Lethal Factor 1. (deposited 29 Mar 2022 12:28) [Currently Displayed]

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