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A nucleotide-switch mechanism mediates opposing catalytic activities of Rel enzymes

Tamman, Hedvig ; Van Nerom, Katleen ; Takada, Hiraku ; Vandenberk, Niels ; Scholl, Daniel ; Polikanov, Yury ; Hofkens, Johan ; Talavera, Ariel ; Hauryliuk, Vasili LU orcid and Hendrix, Jelle , et al. (2020) In Nature Chemical Biology 16. p.834-840
Abstract

Bifunctional Rel stringent factors, the most abundant class of RelA/SpoT homologs, are ribosome-associated enzymes that transfer a pyrophosphate from ATP onto the 3′ of guanosine tri-/diphosphate (GTP/GDP) to synthesize the bacterial alarmone (p)ppGpp, and also catalyze the 3′ pyrophosphate hydrolysis to degrade it. The regulation of the opposing activities of Rel enzymes is a complex allosteric mechanism that remains an active research topic despite decades of research. We show that a guanine-nucleotide-switch mechanism controls catalysis by Thermus thermophilus Rel (RelTt). The binding of GDP/ATP opens the N-terminal catalytic domains (NTD) of RelTt (RelTtNTD) by stretching apart the two... (More)

Bifunctional Rel stringent factors, the most abundant class of RelA/SpoT homologs, are ribosome-associated enzymes that transfer a pyrophosphate from ATP onto the 3′ of guanosine tri-/diphosphate (GTP/GDP) to synthesize the bacterial alarmone (p)ppGpp, and also catalyze the 3′ pyrophosphate hydrolysis to degrade it. The regulation of the opposing activities of Rel enzymes is a complex allosteric mechanism that remains an active research topic despite decades of research. We show that a guanine-nucleotide-switch mechanism controls catalysis by Thermus thermophilus Rel (RelTt). The binding of GDP/ATP opens the N-terminal catalytic domains (NTD) of RelTt (RelTtNTD) by stretching apart the two catalytic domains. This activates the synthetase domain and allosterically blocks hydrolysis. Conversely, binding of ppGpp to the hydrolase domain closes the NTD, burying the synthetase active site and precluding the binding of synthesis precursors. This allosteric mechanism is an activity switch that safeguards against futile cycles of alarmone synthesis and degradation. [Figure not available: see fulltext.].

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type
Contribution to journal
publication status
published
in
Nature Chemical Biology
volume
16
pages
834 - 840
publisher
Nature Publishing Group
external identifiers
  • pmid:32393900
  • scopus:85084513439
ISSN
1552-4450
DOI
10.1038/s41589-020-0520-2
language
English
LU publication?
no
additional info
Funding Information: We acknowledge the use of the synchrotron-radiation facility at the SOLEIL synchrotron Gif-sur-Yvette, France, under proposals 20150717, 20160750 and 20170756. We also thank the staff from Swing, PROXIMA-1 and PROXIMA-2A beamlines at SOLEIL for assistance with data collection. This work was supported by grants from the Fonds National de Recherche Scientifique, nos. FNRS-EQP U.N043.17F, FRFS-WELBIO CR-2017S-03 and FNRS-PDR T.0066.18, and the Joint Programming Initiative on Antimicrobial Resistance (grant no. JPI-EC-AMR-R.8004.18-) to A.G.-P. The Program ‘Actions de Recherche Concerté ’ 2016-2021 and Fonds d’Encouragement à la Recherche from the ULB, Fonds Jean Brachet and the Fondation Van Buren to A.G.-P.; the Molecular Infection Medicine Sweden, Swedish Research council (grant no. 2017-03783), and Ragnar Söderberg foundation fellowship to V.H.; J. Hendrix and J. Hofkens are grateful to the Research Foundation Flanders (FWO Vlaanderen, grant no. G0B4915N) and large infrastructure grant (no. ZW15_09 GOH6316N) and the KU Leuven Research Fund (no. C14/16/053); J.Hofkens thanks financial support of the Flemish government through long-term structural funding Methusalem (CASAS2, Meth/15/04). K.V.N. was supported by a PhD grant from the Fonds National de Recherche Scientifique FNRS-FRIA. N.V. acknowledges the Agency for Innovation by Science and Technology in Flanders for a PhD grant. H. Tamman was supported by a Chargé de Recherches fellowship from the FNRS (no. CR/DM-392). H. Takada was supported by the postdoctoral grant from the Umeå Centre for Microbial Research (UCMR). Publisher Copyright: © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.
id
61eaa402-fd26-4c8a-8a24-32036d61ba21
date added to LUP
2021-09-24 20:35:01
date last changed
2024-04-06 09:24:54
@article{61eaa402-fd26-4c8a-8a24-32036d61ba21,
  abstract     = {{<p>Bifunctional Rel stringent factors, the most abundant class of RelA/SpoT homologs, are ribosome-associated enzymes that transfer a pyrophosphate from ATP onto the 3′ of guanosine tri-/diphosphate (GTP/GDP) to synthesize the bacterial alarmone (p)ppGpp, and also catalyze the 3′ pyrophosphate hydrolysis to degrade it. The regulation of the opposing activities of Rel enzymes is a complex allosteric mechanism that remains an active research topic despite decades of research. We show that a guanine-nucleotide-switch mechanism controls catalysis by Thermus thermophilus Rel (Rel<sub>Tt</sub>). The binding of GDP/ATP opens the N-terminal catalytic domains (NTD) of Rel<sub>Tt</sub> (Rel<sub>Tt</sub><sup>NTD</sup>) by stretching apart the two catalytic domains. This activates the synthetase domain and allosterically blocks hydrolysis. Conversely, binding of ppGpp to the hydrolase domain closes the NTD, burying the synthetase active site and precluding the binding of synthesis precursors. This allosteric mechanism is an activity switch that safeguards against futile cycles of alarmone synthesis and degradation. [Figure not available: see fulltext.].</p>}},
  author       = {{Tamman, Hedvig and Van Nerom, Katleen and Takada, Hiraku and Vandenberk, Niels and Scholl, Daniel and Polikanov, Yury and Hofkens, Johan and Talavera, Ariel and Hauryliuk, Vasili and Hendrix, Jelle and Garcia-Pino, Abel}},
  issn         = {{1552-4450}},
  language     = {{eng}},
  pages        = {{834--840}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Chemical Biology}},
  title        = {{A nucleotide-switch mechanism mediates opposing catalytic activities of Rel enzymes}},
  url          = {{http://dx.doi.org/10.1038/s41589-020-0520-2}},
  doi          = {{10.1038/s41589-020-0520-2}},
  volume       = {{16}},
  year         = {{2020}},
}