Versatile modes of cellular regulation via cyclic dinucleotides

Krasteva, Petya V.; Sondermann, Holger

doi:10.1038/nchembio.2337

Cited by 109 publications

(119 citation statements)

References 100 publications

(187 reference statements)

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“…In bacterial pathogens, c‐di‐GMP is often involved in regulating the expression of virulence factors (Cotter and Stibitz, ; Hengge, ; Römling et al ., ; Jenal et al ., ). Effects of c‐di‐GMP are mediated by its binding to a variety of receptors that include PilZ and MshEN domains, several types of transcriptional regulators, diguanylate cyclases themselves and other binding proteins (Chou and Galperin, ; Krasteva and Sondermann, ). c‐di‐GMP‐specific phosphodiesterases (PDEs, containing either EAL or HD‐GYP domains) hydrolyse c‐di‐GMP to linear pGpG to reverse the effects of the DGCs and affect a variety of c‐di‐GMP‐regulated systems. Many PDEs have extracytoplasmic or intracellular sensor domains, which allow them to regulate c‐di‐GMP levels independently of the respective DGCs.…”

Section: Distribution Of Environmental Sensors In Selected Bacteriamentioning

confidence: 99%

What bacteria want

Galperin

2018

Environmental Microbiology

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Bacterial signal transduction systems are responsible for sensing environmental cues and adjusting the cellular behaviour and/or metabolism in response to these cues. They also monitor the intracellular conditions and the status of the cell envelope and the cytoplasmic membrane and trigger various stress responses to counteract adverse changes. This surveillance involves several classes of sensor proteins: histidine kinases; chemoreceptors; membrane components of the sugar phosphotransferase system; adenylate, diadenylate and diguanylate cyclases and certain cAMP, c-di-AMP and c-di-GMP phosphodiesterases; extracytoplasmic function sigma factors and Ser/Thr/Tyr protein kinases and phosphoprotein phosphatases. We have compiled a detailed listing of sensor proteins that are encoded in the genomes of Escherichia coli, Bacillus subtilis and 10 widespread pathogens: Chlamydia trachomatis, Haemophilus influenzae, Helicobacter pylori, Mycobacterium tuberculosis, Mycoplasma pneumoniae, Neisseria gonorrhoeae, Porphyromonas gingivalis, Rickettsia typhi, Streptococcus pyogenes and Treponema pallidum, and checked what, if anything, is known about their functions. This listing shows significant gaps in the understanding of which environmental and intracellular cues are perceived by these bacteria and which cellular responses are triggered by the changes in the respective parameters. A better understanding of bacterial preferences may suggest new ways to modulate the expression of virulence factors and therefore decrease the reliance on antibiotics to fight infection.

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Section: Distribution Of Environmental Sensors In Selected Bacteriamentioning

confidence: 99%

What bacteria want

Galperin

2018

Environmental Microbiology

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“…Second, Orn is a key enzyme in bacterial cyclic-di-GMP (c-di-GMP) signaling. The nucleotide second messenger c-di-GMP is produced in bacteria in response to environmental cues and controls a wide range of cellular pathways, including cell adhesion, biofilm formation, and virulence 11–14 . Since the discovery of c-di-GMP over 30 years ago, it has been known that the signal is degraded by a two-step process with a linear pGpG diribonucleotide intermediate 15 .…”

Section: Introductionmentioning

confidence: 99%

Oligoribonuclease functions as a diribonucleotidase to bypass a key bottleneck in RNA degradation

et al. 2019

Preprint

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23Degradation of RNA polymers is a multistep process catalyzed by specific subsets of RNases. In 24 all cases, degradation is completed by exoribonucleases that recycle RNA fragments into 25 nucleotide monophosphate. In γ-proteobacteria, a group of up to eight 3'-5' exoribonucleases 26 have been implicated in RNA degradation. Oligoribonuclease (Orn) is unique among them as its 27 activity is required for clearing short RNA fragments, a function important for cellular fitness. 28 However, the mechanistic basis for this substrate selectivity remained unclear. Here we show 29 that Orn's activity as a general exoribonuclease has been vastly overestimated by demonstrating 30 that the enzyme exhibits a much narrower substrate preference for diribonucleotides. Co-crystal 31 structures of Orn with substrates reveal an active site optimized for diribonucleotides that does 32 not accommodate longer substrates. While other cellular RNases process oligoribonucleotides 33 down to diribonucleotide entities, our functional studies demonstrate that Orn is the one and 34 only diribonucleotidase that completes the final stage of the RNA degradation pathway. 35Together, these results indicate that Orn is a dedicated diribonucleotidase that clears the 36 diribonucleotide pool that otherwise affects cellular physiology and viability. 37 38 14 . Since the discovery of c-di-GMP over 30 years ago, it has been known that the signal is degraded 56 by a two-step process with a linear pGpG diribonucleotide intermediate 15 . While the enzyme for 57 linearizing c-di-GMP to pGpG was discovered early on 16,17 , the identity of the enzyme that degrades 58 pGpG remained elusive. Two recent studies showed that Orn is the primary enzyme that degrades 59 pGpG in Pseudomonas aeruginosa 18,19 . In an orn deletion strain, the accrual of linear pGpG has a 60 profound effect on cells. Specifically, the increase in pGpG inhibits upstream phosphodiesterases that 61 degrade c-di-GMP, thereby triggering phenotypes associated with high cellular c-di-GMP levels. 62 However, the molecular basis of Orn's unique cellular functions in γ-proteobacteria that distinguishes 63 it from all other exoribonucleases remains unexplained. 64Since its discovery over 50 years ago 20 , Orn has been presumed to degrade 65 oligoribonucleotides 21-23 . This notion largely derived from assays utilizing two types of substrates. In 66 one series of experiments, 3 H polyuridine (poly(U)) was incubated with Orn, other enzymes, or lysates 67 and analyzed by paper chromatography, which offers limited resolution overall [21][22][23] . In a second set of 68 experiments, Orn was incubated with oligoribonucleotides that had been tagged at their 5' terminus by 69

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“…The intracellular levels of c-di-GMP are controlled by the opposite activities of diguanylate cyclases (DGCs), containing GGDEF domains, and phosphodiesterases (PDEs), containing either EAL or HD-GYP domains [1]. The activity of DGCs and PDEs is often allosterically regulated in a remarkably complex way by environmental/metabolic signals acting on the large variety of sensory domains neighbouring the catalytic ones [1,2]. Representative of this complexity are the so-called hybrid proteins, where the GGDEF and EAL domains are fused into the same polypeptide chain.…”

Section: Introductionmentioning

confidence: 99%

Insights into the GTP‐dependent allosteric control of c‐di‐GMP hydrolysis from the crystal structure of PA0575 protein from Pseudomonas aeruginosa

et al. 2018

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Bis-(3'-5')-cyclic diguanylic acid (c-di-GMP) belongs to the class of cyclic dinucleotides, key carriers of cellular information in prokaryotic and eukaryotic signal transduction pathways. In bacteria, the intracellular levels of c-di-GMP and their complex physiological outputs are dynamically regulated by environmental and internal stimuli, which control the antagonistic activities of diguanylate cyclases (DGCs) and c-di-GMP specific phosphodiesterases (PDEs). Allostery is one of the major modulators of the c-di-GMP-dependent response. Both the c-di-GMP molecule and the proteins interacting with this second messenger are characterized by an extraordinary structural plasticity, which has to be taken into account when defining and possibly predicting c-di-GMP-related processes. Here, we report a structure-function relationship study on the catalytic portion of the PA0575 protein from Pseudomonas aeruginosa, bearing both putative DGC and PDE domains. The kinetic and structural studies indicate that the GGDEF-EAL portion is a GTP-dependent PDE. Moreover, the crystal structure confirms the high degree of conformational flexibility of this module. We combined structural analysis and protein engineering studies to propose the possible molecular mechanism guiding the nucleotide-dependent allosteric control of catalysis; we propose that the role exerted by GTP via the GGDEF domain is to allow the two EAL domains to form a dimer, the species competent to enter PDE catalysis.

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Versatile modes of cellular regulation via cyclic dinucleotides

Cited by 109 publications

References 100 publications

What bacteria want

What bacteria want

Oligoribonuclease functions as a diribonucleotidase to bypass a key bottleneck in RNA degradation

Insights into the GTP‐dependent allosteric control of c‐di‐GMP hydrolysis from the crystal structure of PA0575 protein from Pseudomonas aeruginosa

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