A magic alarmone to rescue hungry bacteria

Amino acid starvation is sensed in Escherichia coli and Bacillus subtilis by long stringent factors (Rel and RelA) of the RSH superfamily through monitoring the aminoacylation status of ribosomal A-site tRNAs. Their activation results in the synthesis of the ‘magic spots’ alarmones (p)ppGpp: major phenotypic modulators of bacteria. Besides starvation, (p)ppGpp is involved as a messenger in a myriad of cellular processes from cell division to virulence, and its cellular levels are controlled by RSH enzymes.

These are unusual proteins in that they are positively regulated by their product (p)ppGpp, which facilitates an acute response to stress. We previously localized the allosteric pppGpp binding site to the catalytic region of E. coli RelA and B. subtilis Rel, but the exact location of the site and the molecular details of this allosteric regulatory mechanism have remained elusive. In a collaborative effort, the group of Abel Garcia-Pino (Welbio Investigator at the ULB) together with the group of Vasili Hauryliuk (University of Lund) discovered the elusive molecular bases of the allosteric regulation of stringent factors by ‘magic spots’.

Interestingly, this effect of (p)ppGpp is only part of a complex regulatory story and not sufficient for full activation of RelA/Rel. For this the enzyme must be recruited to the starved ribosome, a particularly crucial step in the response to starvation. There the ribosome also supresses (p)ppGpp hydrolysis, further mitigating the intra-domain allosteric cross talk of the enzyme. These layers of regulation constitute molecular checkpoints that ensure both fidelity (through two layers of auto-inhibition) and responsiveness (through a positive feed-forward activation loop) of long stringent factors-mediated response to starvation.

Reference : Roghanian et al. (2021) Mol Cell 81 : 3310 – 3322

Source : Abel Garcia-Pino

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