Structural Mechanism for the Fine-tuning of CcpA Function by The Small Molecule Effectors Glucose 6-Phosphate and Fructose 1,6-Bisphosphate

Schumacher, Maria A.; Seidel, Gerald; Hillen, Wolfgang; Brennan, Richard G.

doi:10.1016/j.jmb.2007.02.054

Cited by 66 publications

(69 citation statements)

References 46 publications

(66 reference statements)

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“…Similarly, the phosphorylation of Crh is also enhanced by glycolytic intermediates in an HPr kinase-dependent fashion (70). In addition to enhancing the phosphorylation of the corepressors HPr and Crh, glucose-6-phosphate and fructose-1,6-bisphosphate are bound by CcpA when it is complexed with the phosphorylated corepressors (199). When CcpA is in its DNA binding-competent form, it regulates transcription through interactions with catabolite-responsive elements (cre) located in or near carbon catabolite-repressed promoters (164).…”

Section: Catabolite-responsive Regulatorsmentioning

confidence: 99%

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

Somerville

Proctor

2009

Microbiol Mol Biol Rev

327

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: 99%

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

Somerville

Proctor

2009

Microbiol Mol Biol Rev

327

348

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“…Only HPr(Ser-P), but none of the other HPr forms, is able to productively interact with CcpA and to exert CCR (38,44). In vitro experiments suggested that in addition to its role in the activation of HPrK kinase, FBP enhances DNA binding of the CcpA/ HPr(Ser-P) complex by directly binding to CcpA (46,47). The role of Crh in CCR is still unclear.…”

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confidence: 99%

Carbon Catabolite Repression in Bacillus subtilis : Quantitative Analysis of Repression Exerted by Different Carbon Sources

et al. 2008

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In many bacteria glucose is the preferred carbon source and represses the utilization of secondary substrates. In Bacillus subtilis, this carbon catabolite repression (CCR) is achieved by the global transcription regulator CcpA, whose activity is triggered by the availability of its phosphorylated cofactors, HPr(Ser46-P) and Crh(Ser46-P). Phosphorylation of these proteins is catalyzed by the metabolite-controlled kinase HPrK/P. Recent studies have focused on glucose as a repressing substrate. Here, we show that many carbohydrates cause CCR. The substrates form a hierarchy in their ability to exert repression via the CcpA-mediated CCR pathway. Of the two cofactors, HPr is sufficient for complete CCR. In contrast, Crh cannot substitute for HPr on substrates that cause a strong repression. Determination of the phosphorylation state of HPr in vivo revealed a correlation between the strength of repression and the degree of phosphorylation of HPr at Ser46. Sugars transported by the phosphotransferase system (PTS) cause the strongest repression. However, the phosphorylation state of HPr at its His15 residue and PTS transport activity have no impact on the global CCR mechanism, which is a major difference compared to the mechanism operative in Escherichia coli. Our data suggest that the hierarchy in CCR exerted by the different substrates is exclusively determined by the activity of HPrK/P.

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“…In C. perfringens, and many low-GϩC-content, gram-positive bacteria, carbon catabolite control is under the regulation of CcpA (catabolite control protein A), a pleiotropic transcriptional regulator belonging to the LacI/GalR family of transcription factors (27,39,43). CcpA functions as a DNA binding protein, either activating or repressing genes generally in the presence of a preferred carbon source (35,43). More precisely, surface-associated motility is an interesting example of social bacterial behavior that could be regulated by nutrient (i.e., carbon) availability in nature.…”

mentioning

confidence: 99%

Carbon Catabolite Repression of Type IV Pilus-Dependent Gliding Motility in the Anaerobic Pathogen Clostridium perfringens

et al. 2008

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Clostridium perfringens is an anaerobic, gram-positive, spore-forming bacterium responsible for the production of severe histotoxic and gastrointestinal diseases in humans and animals. In silico analysis of the three available genome-sequenced C. perfringens strains (13, SM101, and ATCC13124) revealed that genes that encode flagellar proteins and genes involved in chemotaxis are absent. However, those strains exhibit type IV pilus (TFP)-dependent gliding motility. Since carbon catabolite regulation has been implicated in the control of different bacterial behaviors, we investigated the effects of glucose and other readily metabolized carbohydrates on C. perfringens gliding motility. Our results demonstrate that carbon catabolite regulation constitutes an important physiological regulatory mechanism that reduces the proficiencies of the gliding motilities of a large number of unrelated human-and animal-derived pathogenic C. perfringens strains. Glucose produces a strong dose-dependent inhibition of gliding development without affecting vegetative growth. Maximum gliding inhibition was observed at a glucose concentration (1%) previously reported to also inhibit other important behaviors in C. perfringens, such as spore development. The inhibition of gliding development in the presence of glucose was due, at least in part, to the repression of the genes pilT and pilD, whose products are essential for TFP-dependent gliding proficiency. The inhibitory effects of glucose on pilT and pilD expression were under the control of the key regulatory protein CcpA (catabolite control protein A). The deficiency in CcpA activity of a ccpA knockout C. perfringens mutant strain restored the expressions of pilT and pilD and gliding proficiency in the presence of 1% glucose. The carbon catabolite repression of the gliding motility of the ccpA mutant strain was restored after the introduction of a complementing plasmid harboring a wild-type copy of ccpA. These results point to a central role for CcpA in orchestrating the negative effect of carbon catabolite regulation on C. perfringens gliding motility. Furthermore, we discovered a novel positive role for CcpA in pilT and pilD expression and gliding proficiency in the absence of catabolite regulation. Carbon catabolite repression of gliding motility and the dual role of CcpA, either as repressor or as activator of gliding, are analyzed in the context of the different social behaviors and diseases produced by C. perfringens.

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Structural Mechanism for the Fine-tuning of CcpA Function by The Small Molecule Effectors Glucose 6-Phosphate and Fructose 1,6-Bisphosphate

Cited by 66 publications

References 46 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

Carbon Catabolite Repression in Bacillus subtilis : Quantitative Analysis of Repression Exerted by Different Carbon Sources

Carbon Catabolite Repression of Type IV Pilus-Dependent Gliding Motility in the Anaerobic Pathogen Clostridium perfringens

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