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

par Roghanian, Mohammad;Van Nerom, Katleen ;Takada, Hiraku;Caballero Montes, Julien ;Tamman, Hedvig ;Kudrin, Pavel;Talavera Perez, Ariel ;Dzhygyr, Ievgen;Ekström, Simon;Atkinson, Gemma Catherine;Garcia-Pino, Abel ;Hauryliuk, Vasili
Référence Molecular cell, 81, 16, page (3310-3322.e6)
Publication Publié, 2021-08-01

Article révisé par les pairs

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Résumé :

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.