(pp)pGpp - signalling nucleotides required for bacterial stress adaptation

Nucleotide signalling molecules contribute to the regulation of cellular pathways in all forms of life. (pp)pGpp is the effector molecule for the stringent response, a signalling pathway employed by all bacteria to cope with cell stresses, for example when faced with a lack of nutrients. Once synthesised, (pp)pGpp is responsible for controlling a cellular switch resulting in the downregulation of pathways involved in active growth, i.e. transcription and translation, and the upregulation of genes involved in stress adaptation. Our work focuses on identifying and characterising target proteins for this signalling nucleotide to establish precisely how this molecule controls cellular pathways and growth. We have used the development of a genome-wide screen to identify receptor proteins for (pp)pGpp and pulled out four ribosome-associated GTPases (RA-GTPases), RsgA, RbgA, Era and HflX. Each enzyme is a cofactor in ribosome assembly, where they cycle between the ON (GTP-bound) and OFF (GDP-bound) states. Entry into the OFF-state occurs upon hydrolysis of GTP, with GTPase activity increasing substantially upon ribosome association. When bound to (p)ppGpp, GTPase activity is inhibited, reducing 70S ribosome assembly. Our current work focuses on elucidating the mechanism behind this, as well as the identification of additional pathways that are controlled by (pp)pGpp. 

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