Abstract
In Bacillus subtilis, amino acid starvation induces synthesis of the alarmone (p)ppGpp by the bifunctional RelA/SpoT Homolog factor Rel, capable of both synthesising and hydrolysing (p)ppGpp. Rel monitors the aminoacylation status of the ribosomal A-site tRNA by inspecting its CCA end. Here we uncover the molecular mechanism of B. subtilis Rel. Off the ribosome, Rel predominantly assumes a ‘closed’ conformation with dominant (p)ppGpp hydrolysis activity which does not specifically monitor tRNA aminoacylation. Once bound to the ribosome, Rel assumes an ‘open’ conformation, which primes its TGS and Helical domains for recognition and recruitment of cognate deacylated tRNA to the ribosome. Deacylated tRNA locks Rel on the ribosome in a hyperactivated state that processively synthesises (p)ppGpp while hydrolysis is suppressed. The tRNA-dependent locking of Rel on the ribosome and activation of (p)ppGpp synthesis are completely abrogated by tRNA aminoacylation. Binding of pppGpp to an N-terminal allosteric site hyper-enhances its synthetase activity.
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