Regulation of stringent factor by branched-chain amino acids

Abstract

Significance Stringent response is an important physiological process in microorganisms mediated by the alarmone molecules (p)ppGpp. RelA/SpoT homolog (RSH) proteins regulate the cellular alarmone concentration by their dual function as both synthetase and hydrolase. It has been known for decades that RSH proteins have an amino acid-binding ACT domain, with its role unknown. Here, we show that the ACT domain of Rel from Rhodobacter capsulatus indeed binds branched-chain amino acids (BCAAs) and that this binding increases its hydrolase activity. Thus, even though the stringent response is well known to be initiated by activation of alarmone synthetase activity via an interaction of Rel proteins with stalled ribosomes, there also exists another trigger involving the inhibition of (p)ppGpp hydrolysis via BCAA depletion.