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

Burkholderiapseudomallei 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 t...

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Published in:Communications Biology
Main Author: Mobbs G.W.; Aziz A.A.; Dix S.R.; Blackburn G.M.; Sedelnikova S.E.; Minshull T.C.; Dickman M.J.; Baker P.J.; Nathan S.; Raih M.F.; Rice D.W.
Format: Article
Language:English
Published: Nature Research 2022
Online Access:https://www.scopus.com/inward/record.uri?eid=2-s2.0-85127296518&doi=10.1038%2fs42003-022-03186-2&partnerID=40&md5=42193cdc9b8ebc9e5ae18aa38e51237d
id 2-s2.0-85127296518
spelling 2-s2.0-85127296518
Mobbs G.W.; Aziz A.A.; Dix S.R.; Blackburn G.M.; Sedelnikova S.E.; Minshull T.C.; Dickman M.J.; Baker P.J.; Nathan S.; Raih M.F.; Rice D.W.
Molecular basis of specificity and deamidation of eIF4A by Burkholderia Lethal Factor 1
2022
Communications Biology
5
1
10.1038/s42003-022-03186-2
https://www.scopus.com/inward/record.uri?eid=2-s2.0-85127296518&doi=10.1038%2fs42003-022-03186-2&partnerID=40&md5=42193cdc9b8ebc9e5ae18aa38e51237d
Burkholderiapseudomallei 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. © 2022, Crown.
Nature Research
23993642
English
Article
All Open Access; Gold Open Access
author Mobbs G.W.; Aziz A.A.; Dix S.R.; Blackburn G.M.; Sedelnikova S.E.; Minshull T.C.; Dickman M.J.; Baker P.J.; Nathan S.; Raih M.F.; Rice D.W.
spellingShingle Mobbs G.W.; Aziz A.A.; Dix S.R.; Blackburn G.M.; Sedelnikova S.E.; Minshull T.C.; Dickman M.J.; Baker P.J.; Nathan S.; Raih M.F.; Rice D.W.
Molecular basis of specificity and deamidation of eIF4A by Burkholderia Lethal Factor 1
author_facet Mobbs G.W.; Aziz A.A.; Dix S.R.; Blackburn G.M.; Sedelnikova S.E.; Minshull T.C.; Dickman M.J.; Baker P.J.; Nathan S.; Raih M.F.; Rice D.W.
author_sort Mobbs G.W.; Aziz A.A.; Dix S.R.; Blackburn G.M.; Sedelnikova S.E.; Minshull T.C.; Dickman M.J.; Baker P.J.; Nathan S.; Raih M.F.; Rice D.W.
title Molecular basis of specificity and deamidation of eIF4A by Burkholderia Lethal Factor 1
title_short Molecular basis of specificity and deamidation of eIF4A by Burkholderia Lethal Factor 1
title_full Molecular basis of specificity and deamidation of eIF4A by Burkholderia Lethal Factor 1
title_fullStr Molecular basis of specificity and deamidation of eIF4A by Burkholderia Lethal Factor 1
title_full_unstemmed Molecular basis of specificity and deamidation of eIF4A by Burkholderia Lethal Factor 1
title_sort Molecular basis of specificity and deamidation of eIF4A by Burkholderia Lethal Factor 1
publishDate 2022
container_title Communications Biology
container_volume 5
container_issue 1
doi_str_mv 10.1038/s42003-022-03186-2
url https://www.scopus.com/inward/record.uri?eid=2-s2.0-85127296518&doi=10.1038%2fs42003-022-03186-2&partnerID=40&md5=42193cdc9b8ebc9e5ae18aa38e51237d
description Burkholderiapseudomallei 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. © 2022, Crown.
publisher Nature Research
issn 23993642
language English
format Article
accesstype All Open Access; Gold Open Access
record_format scopus
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