Abstract
The stringent response enables bacteria to respond to nutrient limitation and other stress conditions through production of the nucleotide-based second messengers ppGpp and pppGpp, collectively known as (p)ppGpp. Here, we report that (p)ppGpp inhibits the signal recognition particle (SRP)-dependent protein targeting pathway, which is essential for membrane protein biogenesis and protein secretion. More specifically, (p)ppGpp binds to the SRP GTPases Ffh and FtsY, and inhibits the formation of the SRP receptor-targeting complex, which is central for the coordinated binding of the translating ribosome to the SecYEG translocon. Cryo-EM analysis of SRP bound to translating ribosomes suggests that (p)ppGpp may induce a distinct conformational stabilization of the NG domain of Ffh and FtsY in Bacillus subtilis but not in E. coli.
Highlights
2, Wieland Steinchen[1], The stringent response enables bacteria to respond to nutrient limitation and other stress conditions through production of the nucleotide-based second messengers ppGpp and pppGpp, collectively known as (p)ppGpp
A major advantage of using YohP is that signal recognition particle (SRP) acts post-translationally during YohP insertion and the (p)ppGpp effect on SRP/FtsY-dependent insertion can be analyzed without impairing the GTP-dependent steps of translation, which are known targets of (p)ppGpp
In vitro synthesized YohP was incubated with E. coli inverted inner membrane vesicles (INV) and membrane insertion was determined by proteinase K
Summary
2, Wieland Steinchen[1], The stringent response enables bacteria to respond to nutrient limitation and other stress conditions through production of the nucleotide-based second messengers ppGpp and pppGpp, collectively known as (p)ppGpp. The bacterial signal recognition particle (SRP) GTPases Ffh and FtsY were identified in this screen, suggesting that (p)ppGpp may potentially regulate the essential SRPdependent pathway of membrane protein insertion. This appears plausible, since in bacteria the biogenesis of a large portion of transmembrane and some secreted proteins relies on the SRP machinery We show that the alarmones (p)ppGpp bind to the GTPase domains of SRP and its receptor FtsY resulting in an inhibition of targeting complex formation This in turn restricts the SRP-dependent pathway of membrane protein insertion and secretion during stressful times
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