(p)ppGpp Regulates a bacterial nucleosidase by an allosteric two-domain switch

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  • Yong Zhang, Københavns Universitet, Danmark
  • René Lysdal Bærentsen
  • Tobias Fuhrer, Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland. aebersold@imsb.biol.ethz.ch
  • ,
  • Uwe Sauer, Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland. aebersold@imsb.biol.ethz.ch
  • ,
  • Kenn Gerdes, Københavns Universitet
  • ,
  • Ditlev Egeskov Brodersen

The stringent response alarmones pppGpp and ppGpp are essential for rapid adaption of bacterial physiology to changes in the environment. In Escherichia coli, the nucleosidase PpnN (YgdH) regulates purine homeostasis by cleaving nucleoside monophosphates and specifically binds (p)ppGpp. Here, we show that (p)ppGpp stimulates the catalytic activity of PpnN both in vitro and in vivo causing accumulation of several types of nucleobases during stress. The structure of PpnN reveals a tetramer with allosteric (p)ppGpp binding sites located between subunits. pppGpp binding triggers a large conformational change that shifts the two terminal domains to expose the active site, providing a structural rationale for the stimulatory effect. We find that PpnN increases fitness and adjusts cellular tolerance to antibiotics and propose a model in which nucleotide levels can rapidly be adjusted during stress by simultaneous inhibition of biosynthesis and stimulation of degradation, thus achieving a balanced physiological response to constantly changing environments.

OriginalsprogEngelsk
TidsskriftMolecular Cell
Vol/bind74
Nummer6
Sider (fra-til)1239-1249.e4
ISSN1097-2765
DOI
StatusUdgivet - apr. 2019

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