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(p)ppGpp controls stringent factors by exploiting antagonistic allosteric coupling between catalytic domains

Roghanian, Mohammad ; Van Nerom, Katleen ; Takada, Hiraku ; Caballero-Montes, Julien ; Tamman, Hedvig ; Kudrin, Pavel ; Talavera, Ariel ; Dzhygyr, Ievgen ; Ekström, Simon LU and Atkinson, Gemma C LU orcid , et al. (2021) In Molecular Cell 81(16). p.6-3322
Abstract

Amino acid starvation is sensed by Escherichia coli RelA and Bacillus subtilis Rel through monitoring the aminoacylation status of ribosomal A-site tRNA. These enzymes are positively regulated by their product-the alarmone nucleotide (p)ppGpp-through an unknown mechanism. The (p)ppGpp-synthetic activity of Rel/RelA is controlled via auto-inhibition by the hydrolase/pseudo-hydrolase (HD/pseudo-HD) domain within the enzymatic N-terminal domain region (NTD). We localize the allosteric pppGpp site to the interface between the SYNTH and pseudo-HD/HD domains, with the alarmone stimulating Rel/RelA by exploiting intra-NTD autoinhibition dynamics. We show that without stimulation by pppGpp, starved ribosomes cannot efficiently activate... (More)

Amino acid starvation is sensed by Escherichia coli RelA and Bacillus subtilis Rel through monitoring the aminoacylation status of ribosomal A-site tRNA. These enzymes are positively regulated by their product-the alarmone nucleotide (p)ppGpp-through an unknown mechanism. The (p)ppGpp-synthetic activity of Rel/RelA is controlled via auto-inhibition by the hydrolase/pseudo-hydrolase (HD/pseudo-HD) domain within the enzymatic N-terminal domain region (NTD). We localize the allosteric pppGpp site to the interface between the SYNTH and pseudo-HD/HD domains, with the alarmone stimulating Rel/RelA by exploiting intra-NTD autoinhibition dynamics. We show that without stimulation by pppGpp, starved ribosomes cannot efficiently activate Rel/RelA. Compromised activation by pppGpp ablates Rel/RelA function in vivo, suggesting that regulation by the second messenger (p)ppGpp is necessary for mounting an acute starvation response via coordinated enzymatic activity of individual Rel/RelA molecules. Control by (p)ppGpp is lacking in the E. coli (p)ppGpp synthetase SpoT, thus explaining its weak synthetase activity.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Molecular Cell
volume
81
issue
16
pages
6 - 3322
publisher
Cell Press
external identifiers
  • scopus:85112792870
  • pmid:34416138
ISSN
1097-4164
DOI
10.1016/j.molcel.2021.07.026
language
English
LU publication?
yes
id
d8c96a37-8ca7-4fc6-9fcb-507cf792384d
date added to LUP
2021-08-21 18:49:16
date last changed
2025-04-20 20:08:15
@article{d8c96a37-8ca7-4fc6-9fcb-507cf792384d,
  abstract     = {{<p>Amino acid starvation is sensed by Escherichia coli RelA and Bacillus subtilis Rel through monitoring the aminoacylation status of ribosomal A-site tRNA. These enzymes are positively regulated by their product-the alarmone nucleotide (p)ppGpp-through an unknown mechanism. The (p)ppGpp-synthetic activity of Rel/RelA is controlled via auto-inhibition by the hydrolase/pseudo-hydrolase (HD/pseudo-HD) domain within the enzymatic N-terminal domain region (NTD). We localize the allosteric pppGpp site to the interface between the SYNTH and pseudo-HD/HD domains, with the alarmone stimulating Rel/RelA by exploiting intra-NTD autoinhibition dynamics. We show that without stimulation by pppGpp, starved ribosomes cannot efficiently activate Rel/RelA. Compromised activation by pppGpp ablates Rel/RelA function in vivo, suggesting that regulation by the second messenger (p)ppGpp is necessary for mounting an acute starvation response via coordinated enzymatic activity of individual Rel/RelA molecules. Control by (p)ppGpp is lacking in the E. coli (p)ppGpp synthetase SpoT, thus explaining its weak synthetase activity.</p>}},
  author       = {{Roghanian, Mohammad and Van Nerom, Katleen and Takada, Hiraku and Caballero-Montes, Julien and Tamman, Hedvig and Kudrin, Pavel and Talavera, Ariel and Dzhygyr, Ievgen and Ekström, Simon and Atkinson, Gemma C and Garcia-Pino, Abel and Hauryliuk, Vasili}},
  issn         = {{1097-4164}},
  language     = {{eng}},
  number       = {{16}},
  pages        = {{6--3322}},
  publisher    = {{Cell Press}},
  series       = {{Molecular Cell}},
  title        = {{(p)ppGpp controls stringent factors by exploiting antagonistic allosteric coupling between catalytic domains}},
  url          = {{http://dx.doi.org/10.1016/j.molcel.2021.07.026}},
  doi          = {{10.1016/j.molcel.2021.07.026}},
  volume       = {{81}},
  year         = {{2021}},
}