Interaction of<i>Bacillus subtilis</i>CodY with GTP

Handke, Luke D.; Shivers, Robert P.; Sonenshein, Abraham L.

doi:10.1128/jb.01115-07

Cited by 96 publications

(113 citation statements)

References 44 publications

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“…The interaction of CodY with BCAA is mediated through a cyclic GMP, adenylyl cyclase, FhlA (GAF) domain; however, the mechanism of interaction with GTP remains speculative (134). CodY's affinity for its DNA binding site is increased by binding, but not hydrolyzing, GTP, and this affinity is increased further by a BCAA interacting with the GAF domain (82). These observations highlight the central role of CodY in gram-positive metabolic regulation.…”

Section: Catabolite-responsive Regulatorsmentioning

confidence: 63%

At the Crossroads of Bacterial Metabolism and Virulence Factor Synthesis in Staphylococci

Somerville

Proctor

2009

Microbiol Mol Biol Rev

329

348

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SUMMARY Bacteria live in environments that are subject to rapid changes in the availability of the nutrients that are necessary to provide energy and biosynthetic intermediates for the synthesis of macromolecules. Consequently, bacterial survival depends on the ability of bacteria to regulate the expression of genes coding for enzymes required for growth in the altered environment. In pathogenic bacteria, adaptation to an altered environment often includes activating the transcription of virulence genes; hence, many virulence genes are regulated by environmental and nutritional signals. Consistent with this observation, the regulation of most, if not all, virulence determinants in staphylococci is mediated by environmental and nutritional signals. Some of these external signals can be directly transduced into a regulatory response by two-component regulators such as SrrAB; however, other external signals require transduction into intracellular signals. Many of the external environmental and nutritional signals that regulate virulence determinant expression can also alter bacterial metabolic status (e.g., iron limitation). Altering the metabolic status results in the transduction of external signals into intracellular metabolic signals that can be “sensed” by regulatory proteins (e.g., CodY, Rex, and GlnR). This review uses information derived primarily using Bacillus subtilis and Escherichia coli to articulate how gram-positive pathogens, with emphasis on Staphylococcus aureus and Staphylococcus epidermidis, regulate virulence determinant expression in response to a changing environment.

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Section: Catabolite-responsive Regulatorsmentioning

confidence: 63%

At the Crossroads of Bacterial Metabolism and Virulence Factor Synthesis in Staphylococci

Somerville

Proctor

2009

Microbiol Mol Biol Rev

329

348

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“…In a GTP-bound state, CodY binds to DNA and represses the transcription of a number of genes involved in the adaptation to nutrient limitation. However, upon entry of cells in stationary phase, GTP levels decrease, leading to the release of CodY from DNA, de-repression, and transcription of target genes (31). Intracellular GTP levels do therefore play a significant role in modulating the stringent response.…”

Section: Significancementioning

confidence: 99%

ppGpp negatively impacts ribosome assembly affecting growth and antimicrobial tolerance in Gram-positive bacteria

Corrigan

Bellows

Wood

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

188

227

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The stringent response is a survival mechanism used by bacteria to deal with stress. It is coordinated by the nucleotides guanosine tetraphosphate and pentaphosphate [(p)ppGpp], which interact with target proteins to promote bacterial survival. Although this response has been well characterized in proteobacteria, very little is known about the effectors of this signaling system in Grampositive species. Here, we report on the identification of seven target proteins for the stringent response nucleotides in the Grampositive bacterium Staphylococcus aureus. We demonstrate that the GTP synthesis enzymes HprT and Gmk bind with a high affinity, leading to an inhibition of GTP production. In addition, we identified five putative GTPases-RsgA, RbgA, Era, HflX, and ObgE-as (p)ppGpp target proteins. We show that RsgA, RbgA, Era, and HflX are functional GTPases and that their activity is promoted in the presence of ribosomes but strongly inhibited by the stringent response nucleotides. By characterizing the function of RsgA in vivo, we ascertain that this protein is involved in ribosome assembly, with an rsgA deletion strain, or a strain inactivated for GTPase activity, displaying decreased growth, a decrease in the amount of mature 70S ribosomes, and an increased level of tolerance to antimicrobials. We additionally demonstrate that the interaction of ppGpp with cellular GTPases is not unique to the staphylococci, as homologs from Bacillus subtilis and Enterococcus faecalis retain this ability. Taken together, this study reveals ribosome inactivation as a previously unidentified mechanism through which the stringent response functions in Gram-positive bacteria.ribosome | stringent response | tolerance | ppGpp | Staphylococcus aureus

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“…The activity of B. subtilis CodY as a DNA-binding protein (20,23,35) is increased by interaction with two types of effectors, branched-chain amino acids (isoleucine, leucine, and valine [ILV]) (10,15,22,23,30,36) and GTP (17,29,31,36), allowing the bacteria to change the pattern of CodY-dependent gene expression in response to the availability of nutrients in the growth medium.…”

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confidence: 99%

CodY-Mediated Regulation of Guanosine Uptake in Bacillus subtilis

Belitsky

Sonenshein

2011

J Bacteriol

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CodY is a global transcriptional regulator known to control expression of more than 100 genes and operons in Bacillus subtilis. Some of the most strongly repressed targets of CodY, the nupNOPQ (formerly, yufNOPQ) genes, were found to encode a guanosine transporter. Using DNase I footprinting experiments, we identified two high-affinity CodY-binding sites in the regulatory region of the nupN gene. The two sites are located 50 bp upstream and 163 bp downstream of the transcription start site. The downstream site was responsible for 6-to 8-fold nupN repression in the absence of the upstream site. When the upstream site was intact, however, only a minor contribution of the downstream site to nupN regulation could be detected under the conditions tested. Both sites contained 15-bp CodY-binding motifs with two mismatches each with respect to the consensus sequence, AATTTTCWGTTTTAA. However, the experimentally determined binding sites included additional sequences flanking the 15-bp CodY-binding motifs. An additional version of the 15-bp CodY-binding motif, with 5 mismatches with respect to the consensus but essential for efficient regulation by CodY, was found within the upstream site. The presence of multiple 15-bp motifs may be a common feature of CodY-binding sites.Bacillus subtilis cells are able to take up purine and pyrimidine nucleosides, allowing these compounds to serve as substrates for nucleotide biosynthesis via salvage pathways and as sources of carbon and nitrogen (40). Although two major transporters for pyrimidine and purine nucleosides, NupC and NupG, respectively, have been described in B. subtilis, mutants lacking NupC or NupG retain considerable ability to take up pyrimidine or purine nucleosides (19, 33). Thus, additional transporters for both pyrimidine and purine nucleosides remain to be identified (2,19,33).The B. subtilis nupNOPQ (formerly, yufNOPQ) genes appear to encode the components of an ABC transport system of unknown specificity. The first gene of this apparent operon, nupN, codes for an apparent lipoprotein that could serve as the substrate-binding, specificity-determining subunit of the transporter. The putative product of nupN is homologous (43 to 50% identity) to several proteins that are involved in purine and pyrimidine nucleoside transport in Treponema pallidum, Streptococcus mutans, and Lactococcus lactis (9,26,41). The nupO and nupPQ genes appear to encode the ATP-binding protein and integral membrane proteins typical of ABC transporters, respectively.The nupNOPQ genes were previously shown to be among the genes that are most highly repressed by CodY as detected by DNA microarray analysis and lacZ fusions (29). CodY is a global transcriptional regulator that controls expression of more than 100 genes and operons in B. subtilis.Many of the CodY-regulated genes are involved in nitrogen or carbon metabolism (14,29,(37)(38)(39). The main role of CodY in B. subtilis appears to be establishing the temporal hierarchy of utilization of various nitrogen (and carbon) compounds under cond...

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Interaction ofBacillus subtilisCodY with GTP

Cited by 96 publications

References 44 publications

At the Crossroads of Bacterial Metabolism and Virulence Factor Synthesis in Staphylococci

At the Crossroads of Bacterial Metabolism and Virulence Factor Synthesis in Staphylococci

ppGpp negatively impacts ribosome assembly affecting growth and antimicrobial tolerance in Gram-positive bacteria

CodY-Mediated Regulation of Guanosine Uptake in Bacillus subtilis

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