A collaborative push to understand bacterial stress
The DiStRes team of Garcia-Pino at the Université libre de Bruxelles (ULB), joined forces with Lund University and the Université de Namur, to tackle the challenge of understanding the various regulatory layers of the different stringent factor. They focused on model organisms such as Thermus thermophilus, Escherichia coli, and Bacillus subtilis, and the important human pathogen Acinetobacter baumannii, a member of so-called ESKAPE group of bacterial pathogens of the greatest concern. The international team solved the three-dimensional structure of various stringent factors in different active catalytic states to cracked the molecular code that determines how fast these enzymes pulse. To slam on breaks on the growth rate, RSH enzymes assume a compact, mushroom-like shape. To let the bacterium grow at the maximum speed, they open up and ‘relaxed’ primed to bind the empty A-sites of ribosomes or engage other bacterial adaptor proteins that become active under particular stress signals.
Notably, one of the outcomes of these research identified a short ‘core’ domain located in between the N-terminal catalytic domains and C-terminal regulatory domains of stringent factors that is the linchpin of the active hydrolase conformation of the enzyme and key for the switch to active synthetase states. Interestingly, the propensity for the different active states correlated with the length and disorder of the core region in of the different families of stringent factors SpoT, Rel and RelA, which could mean that genetic expansion and contraction in the core is a defining evolutionary feature of the specialisation of RSH enzymes into (p)ppGpp synthetases or hydrolases. Since RSH enzymes can sense environmental stresses to modulate stress adaptation through coordinating (p)ppGpp synthesis and hydrolysis, further determining the control of the different states would be an exciting future research direction to enhance understanding of its role in stress signalling through (p)ppGpp hydrolysis.
