Co‐ordinated regulation of the extracytoplasmic stress factor, sigmaE, with other <scp><i>E</i></scp><i>scherichia coli</i> sigma factors by <scp>(p)ppGpp</scp> and <scp>DksA</scp> may be achieved by specific regulation of individual holoenzymes

Gopalkrishnan, Saumya; Nicoloff, Hervé; Ades, Sarah E.

doi:10.1111/mmi.12674

Cited by 27 publications

(38 citation statements)

References 77 publications

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“…The structures described in this work provide straightforward models of how DksA alone and together with ppGpp block transcription initiation. However, DksA/ppGpp and TraR are also able to activate transcription at promoters such as those encoding genes for amino acid biosynthesis (Gopalkrishnan et al, 2017;Paul et al, 2005) and promoters regulated by the alternative σ E factor (Gopalkrishnan et al, 2014). Mechanisms of transcription activation via secondary channel binding proteins cannot be elucidated directly from the crystal structures determined in this study.…”

Section: Activation Of Transcription By Ppgpp and Dksamentioning

confidence: 82%

Allosteric effector ppGpp potentiates the inhibition of transcript initiation by DksA

Molodtsov

Sineva

Zhang

et al. 2017

Preprint

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SUMMARYDksA and ppGpp are the central players in the Escherichia coli stringent response and mediate a complete reprogramming of the transcriptome from one optimized for rapid growth to one adapted for survival during nutrient limitation. A major component of the response is a reduction in ribosome synthesis, which is accomplished by the synergistic action of DksA and ppGpp bound to RNA polymerase (RNAP) inhibiting transcription of rRNAs. Here, we report the X-ray crystal structures of E. coli RNAP holoenzyme in complex with DksA alone and with ppGpp. The structures show that DksA accesses the template strand at the active site and the downstream DNA binding site of RNAP simultaneously and reveal that binding of the allosteric effector ppGpp reshapes the RNAP–DksA complex. The structural data support a model for transcriptional inhibition in which ppGpp potentiates the destabilization of open complexes on rRNA promoters by DksA. We also determined the structure of RNAP–TraR complex, which reveals the mechanism of ppGpp-independent transcription inhibition by TraR. This work establishes new ground for understanding the pleiotropic effects of DksA and ppGpp on transcriptional regulation in proteobacteria.HighlightsDksA has two modes of binding to RNA polymeraseDksA is capable of inhibiting the catalysis and influences the DNA binding of RNAPppGpp acts as an allosteric effector of DksA functionppGpp stabilizes DksA in a more functionally important binding mode

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Section: Activation Of Transcription By Ppgpp and Dksamentioning

confidence: 82%

Allosteric effector ppGpp potentiates the inhibition of transcript initiation by DksA

Molodtsov

Sineva

Zhang

et al. 2017

Preprint

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“…Full appreciation of the role of Csr in extracytoplasmic stress will require further investigation of CsrA inhibitory effects on RseA (35). Interestingly, ppGpp activates rpoE expression in the stationary phase of growth, independently of envelope stress (109), which should create additional positive feedback between the Csr and ECF systems (Fig. 5B).…”

Section: Interaction Of Csr With Other Global Regulatory Systemsmentioning

confidence: 99%

Global Regulation by CsrA and Its RNA Antagonists

Romeo

Babitzke²

2018

Microbiol Spectr

147

145

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The sequence-specific RNA binding protein CsrA is employed by diverse bacteria in the posttranscriptional regulation of gene expression. Its binding interactions with RNA have been documented at atomic resolution and shown to alter RNA secondary structure, RNA stability, translation and/or Rho-mediated transcription termination through a growing number of molecular mechanisms. In Gammaproteobacteria, small regulatory RNAs that contain multiple CsrA binding sites compete with mRNA for binding to CsrA, thereby sequestering and antagonizing this protein. Both the synthesis and turnover of these sRNAs are regulated, allowing CsrA activity to be rapidly and efficiently adjusted in response to nutritional conditions and stresses. Feedback loops between the Csr regulatory components improve the dynamics of signal response by the Csr system. The Csr system of E. coli is intimately interconnected with other global regulatory systems, permitting it to contribute to regulation by those systems. In some species, a protein antagonist of CsrA functions as part of a checkpoint for flagellum biosynthesis. In other species, a protein antagonist participates in a mechanism in which a type III secretion system is used for sensing interactions with host cells. Recent transcriptomics studies reveal vast effects of CsrA on gene expression through direct binding to hundreds of mRNAs, and indirectly through its effects on the expression of dozens of transcription factors. CsrA binding to basepairing sRNAs and novel mRNA segments, such as the 3′ UTR and deep within coding regions, predict its participation in yet to be discovered regulatory mechanisms.

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“…Nevertheless, recent reports indicated that DksA and ppGpp can have independent or opposing effects (16–20) or their effects may very specifically depend on the individual promoters, holoenzymes involved or stress conditions (21). One of the examples is the bacteriophage lambda pR promoter, which was shown to be inhibited by ppGpp and stimulated by DksA (18,22).…”

Section: Introductionmentioning

confidence: 99%

The dual role of DksA protein in the regulation ofEscherichia colipArgX promoter

et al. 2016

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Gene expression regulation by the stringent response effector, ppGpp, is facilitated by DksA protein; however DksA and ppGpp can play independent roles in transcription. In Escherichia coli, the pArgX promoter which initiates the transcription of four tRNA genes was shown to be inhibited by ppGpp. Our studies on the role of DksA in pArgX regulation revealed that it can stimulate transcription by increasing the binding of RNA polymerase to the promoter and the productive transcription complex formation. However, when DksA is present together with ppGpp a severe down-regulation of promoter activity is observed. Our results indicate that DksA facilitates the effects of ppGpp to drive formation of inactive dead-end complexes formed by RNA polymerase at the ArgX promoter. In vivo, ppGpp-mediated regulation of pArgX transcription is dependent on DksA activity. The potential mechanisms of opposing pArgX regulation by ppGpp and DksA are discussed. pArgX is the first reported example of the promoter stimulated by DksA and inhibited by ppGpp in vitro when an overall inhibition occurs in the presence of both regulators. A dual role is thus proposed for DksA in the regulation of the pArgX promoter activity.

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Co‐ordinated regulation of the extracytoplasmic stress factor, sigmaE, with other Escherichia coli sigma factors by (p)ppGpp and DksA may be achieved by specific regulation of individual holoenzymes

Cited by 27 publications

References 77 publications

Allosteric effector ppGpp potentiates the inhibition of transcript initiation by DksA

Allosteric effector ppGpp potentiates the inhibition of transcript initiation by DksA

Global Regulation by CsrA and Its RNA Antagonists

The dual role of DksA protein in the regulation ofEscherichia colipArgX promoter

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