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At least 19 recordsLinked to original sources
PubMed1992

The cAMP-CRP/CytR nucleoprotein complex in Escherichia coli: two pairs of closely linked binding sites for the cAMP-CRP activator complex are involved in combinatorial regulation of the cdd promoter.

Transcription initiation at CytR regulated promoters in Escherichia coli is controlled by a combinatorial regulatory system in which the cAMP receptor protein (CRP) functions as both an activator and a co-repressor. By combining genetic studies and footprinting analyses, we demonstrate that regulated expression of the CytR controlled cdd promoter requires three CRP-binding sites: a high affinity site (CRP-1) and two overlapping low affinity sites (CRP-2 and CRP-3) centred at positions -41, -91 and -93, respectively. In the absence of CytR, cAMP-CRP interacts at one set of sites (CRP-1 and CRP-2) and both of these binding sites are required for full promoter activation. In the presence of CytR, however, the two regulators bind cooperatively to cddP forming a nucleoprotein complex in which cAMP-CRP binds to CRP-1 and CRP-3 and CytR occupies the sequence between these sites. Thus, association of the two regulators involves a repositioning of the cAMP-CRP complex. Moreover, mutant cdd promoters in which CRP-2 and CRP-3 have been deleted are partially regulated by CytR, and cAMP-CRP and CytR still bind cooperatively to these promoters. These findings provide clues to an understanding of how cAMP-CRP and CytR interact at a structurally diverse set of promoters.

Bacterial Proteins↗
PubMed1991

Comparison of cAMP receptor protein (CRP) and a cAMP-independent form of CRP by Raman spectroscopy and DNA binding.

The secondary structures of the cAMP receptor protein (CRP), a complex of CRP and cAMP, and a cAMP-independent receptor protein mutant (CRP*141 gln) were examined by using Raman spectroscopy. Spectra were obtained from CRP and CRP*141 gln dissolved in 0.3 M NaCl and 30 mM sodium phosphate at protein concentrations of 30-40 mg/mL. CRP and CRP.cAMP1 were compared at lower protein concentrations (10-12 mg/mL) in a solvent of 0.35 M NaCl and 20 mM sodium phosphate. Raman analysis indicates that CRP structural changes induced by one bound cAMP or by the Gly to Gln mutation at residue 141 are small. Spectra of the three CRP samples are essentially identical from 400 to 1900 cm-1. This result differs from the Raman spectroscopy study of CRP and CRP.cAMP2 cocrystals [DeGrazia et al. (1990) Biochemistry 29, 3557]. The latter work showed spectral differences between CRP and CRP.cAMP2 consistent with alterations in the protein conformation. These studies indicate that CRP and CRP.cAMP1 in solution are similar in structure and differ from CRP.cAMP2 cocrystals. Protease digestion and a DNA binding assay were also employed to characterize the wild-type and mutant proteins. CRP*141 gln exhibited the same conformational characteristics of previously reported cAMP-independent mutant proteins. It was sensitive to proteolytic attack in the absence of cAMP, or upon addition of cGMP. In the absence of cAMP, both wild-type and mutant CRPs bound noncooperatively to a 62 bp lac promoter DNA. The equilibrium constants were approximately 10(6) M-1 in 0.1 M Na+. CRP*141 gln had a 2-4-fold higher affinity for the 62 bp DNA than CRP.(ABSTRACT TRUNCATED AT 250 WORDS)

Cyclic AMP↗
PubMed1992

cAMP-CRP activator complex and the CytR repressor protein bind co-operatively to the cytRP promoter in Escherichia coli and CytR antagonizes the cAMP-CRP-induced DNA bend.

Initiation of transcription from the cytRP promoter in Escherichia coli is activated by the cAMP-CRP complex and negatively regulated by the CytR repressor protein. By combining gel retardation and footprinting assays, we show that cAMP-CRP binds to a single site centered at position -64 and induces a considerable bend in the DNA. CytR binds to a region immediately downstream from, and partially overlapping, the CRP site, and induces a modest bend into the DNA. In combination, cAMP-CRP and CytR bind co-operatively to cytRP forming a nucleoprotein complex in which the proteins directly interact with each other and bind to the same face of the DNA helix. CytR binding concomitantly antagonizes the cAMP-CRP-induced bend. This study indicates that the minimal DNA region required to obtain CytR regulation consists of a single binding site for each of cAMP-CRP and CytR. The case described here, in which a protein-induced DNA bend is modulated by a second protein, may illustrate a mechanism that applies to other regulatory systems.

Bacterial Proteins↗
PubMed1992

Transcription activation by cAMP receptor protein (CRP) at the Escherichia coli gal P1 promoter. Crucial role for the spacing between the CRP binding site and the -10 region.

The cAMP-CRP complex activates the initiation of transcription at the Escherichia coli gal P1 promoter, and the activation efficiency is highly sensitive to the location of the complex on this promoter region. Moving the CRP binding site by one base pair toward the start of transcription significantly decreases the extent of activation in vivo and actually turns the cAMP-CRP complex into an inhibitor in in vitro experiments. A structural analysis of open complexes formed on the two promoter fragments at 37 degrees C has revealed three elements crucial for an optimal activation process: a strong upstream anchorage of RNA polymerase, a cooperative binding of CRP and RNA polymerase, and an accurate orientation of the two promoter regions located upstream and downstream of the CRP binding site. Furthermore, structural analysis of polymerase promoter complexes at lower temperatures suggests that RNA polymerase initially recognizes the upstream region of the gal P1 promoter and subsequently interacts with sequences from the -10 to +20 region to yield the final open complex structure. The involvement of CRP in these sequential events has been examined.

Base Sequence↗
PubMed1991

A novel function of the cAMP-CRP complex in Escherichia coli: cAMP-CRP functions as an adaptor for the CytR repressor in the deo operon.

Unlike classical bacterial repressors, the CytR repressor of Escherichia coli cannot independently regulate gene expression. Here we show that CytR binding to the deoP2 promoter relies on interaction with the master gene regulatory protein, CRP, and, furthermore, that cAMP-CRP and CytR bind co-operatively to deoP2. Using mutant promoters we show that tandem, properly spaced DNA-bound cAMP-CRP complexes are required for this co-operative binding. These data suggest that CytR forms a bridge between tandem cAMP-CRP complexes, and that cAMP-CRP functions as an adaptor for CytR. The implications of this new version of negative control in E. coli on bacterial gene expression and on combinatorial gene regulation in higher organisms are discussed.

Bacterial Proteins↗
PubMed1978

Determination of the rates of synthesis and degradation of adenosine 3',5'-cyclic monophosphate in Escherichia coli CRP- and CRP+ strains.

We have developed a method for estimating the rates of synthesis and degradation of adenosine 3',5'-cyclic monophosphate (cAMP) in Escherichia coli during balanced growth. Applying this method, we have found that an E. coli CRP- mutant 5333 (deficient for cAMP receptor protein) synthesizes cAMP about 25 times faster than does its CRP+ parent 1100. This accounts for the abnormally high intracellular and extracellular cAMP accumulation in 5333.

Cyclic AMP↗
PubMed2026

Actuation of CRP activating region 3 by acetylation modulates V. cholerae sugar utilization and virulence.

UNLABELLED: The cyclic AMP receptor protein or CRP is a global regulator of bacterial metabolism that activates transcription of genes required for utilization of alternative carbon sources in response to the second messenger cAMP, which is synthesized in the setting of glucose scarcity. CRP activates transcription through contact with RNA polymerase at three sites termed activating regions (ARs) 1-3. AR3 was previously reported to be functional only when CRP K52 was mutated to a neutral residue and to be essential for transcription only in the absence of AR1 and AR2. Multiple proteomic studies have reported acetylation of CRP K52. This post-translational modification is predicted to activate AR3. To probe the role of K52 acetylation (K52QAc) and AR3 at the genome level, we used ChIP-seq and RNA-seq analysis to compare WT CRP with a CRP K52Q mutant that mimics CRP K52Ac. We report that CRP K52Q binds to hundreds of new sites on the chromosome, resulting in increased abundance of known as well as previously unknown transcripts. These transcripts increase uptake and metabolism of dietary sugars such as maltose and galactose, repress acetate consumption, and augment virulence gene expression. We attribute the repression of acetate consumption to a novel small RNA, CrbZ, which is positively regulated by CRP K52Q in LB broth and by WT CRP specifically in minimal medium containing maltose. This study highlights the role of post-translational modifications in molding the CRP regulon to optimize pathogen metabolism and virulence gene expression in the human intestine in response to nutritional cues. SIGNIFICANCE STATEMENT: As a model in the field of bacterial transcription, the structure and function of the cAMP receptor protein (CRP), a global transcription regulator, has been exhaustively investigated. These studies have established three activating regions (ARs) where CRP contacts RNA polymerase, of which only two were thought to participate in transcription activation by native CRP. Here we provide evidence that post-translational acetylation of V. cholerae CRP lysine 52 actuates AR3, enabling occupancy of hundreds of novel CRP binding sites and the transcription of genes encoding novel small RNAs. These changes alter virulence gene expression, promote utilization of dietary carbon sources, and delay acetate uptake. We propose that acetylation of CRP K52 engages AR3, thus optimizing V. cholerae fitness in the human intestine.

Journal Article↗
PubMed1992

A new aspect of transcriptional control of the Escherichia coli crp gene: positive autoregulation.

Transcription of the Escherichia coli crp gene is negatively regulated by CRP-cAMP that binds to a specific site located downstream of the crp promoter. A second binding site for CRP-cAMP (CRP site II) exists upstream of the crp promoter. Using an in vitro transcription assay, we have demonstrated that CRP-cAMP activates transcription of crp in certain conditions. A promoter which carries an altered CRP-binding site II is no longer activated by CRP-cAMP, indicating that CRP site II mediates the activation of crp transcription. The concentrations of cAMP that are required for positive autoregulation are higher than those for negative autoregulation. Evidence for positive and negative autoregulation in vivo is presented by a quantitative S1 nuclease analysis.

Base Sequence↗
PubMed1979

C-reactive protein (CRP) in early diagnosis of neonatal septicemia.

The usefulness of CRP in early detection of neonatal septicemia/meningitis and urinary tract infection was studied in a neonatal unit using a semiquantitative latex-agglutination as a rapid screening method, and electroimmuno assay as reference method for CRP determination. In 94% of non-infected infants CRP was less than or equal to 15 mg/l and 82% had CRP less than 10 mg/l up to 3 days of age. After 3 days of age 96% had CRP less than 10 mg/l. The initial CRP level was increased in 16 out of 18 patients (89%) with bacterial septicemia. Low CRP was seen in one patient with total agranulocytosis and septicemia from Streptococcus type B and in one patient with Staphylococcus albus sepsis. A rise in CRP was also seen in very pre-term infants with septicemia. Increased initial CRP was uncommon in neonatal urinary tract infection (2 of 9), but a rise was seen in 3 additional patients. A comparison between CRP, total neutrophil blood cell count and band neutrophil count as diagnostic parameters was in favour of CRP at this early stage of infection. CRP is of definite value as an aid in early diagnosis of neonatal septicemia and bacterial meningitis.

C-Reactive Protein↗
PubMed2025

GWAS of CRP response to statins further supports the role of APOE in statin response: A GIST consortium study.

Statins are first-line treatments in the primary and secondary prevention of cardiovascular disease. Clinical studies show statins act independently of lipid-lowering mechanisms to decrease C-reactive protein (CRP), an inflammation marker. We aim to elucidate genetic loci associated with CRP statin response. CRP statin response is the change in log-CRP between off-treatment and on-treatment measurements. Cohort-level Genome-Wide Association Studies (GWAS) of CRP response were performed using 1000 Genomes imputed data, testing &#x223c;10 million common genetic variants. GWAS meta-analysis combined results from seven cohorts and clinical trials totalling 14,070 statin-treated individuals of European ancestry within the GIST consortium. Secondary analyses included statin-by-placebo interaction analyses, and lookups in African ancestry cohorts. Our GWAS identified two genome-wide significant (P&#x202f;<&#x202f;5e-8) loci: APOE and HNF1A for CRP statin response corrected for baseline CRP. The missense lead variant rs429358 at APOE, contributing to the APOE-E4 haplotype, is a risk locus for dyslipidaemia, Alzheimer's and coronary artery disease (CAD). The HNF1A locus is associated with diabetes, cholesterol levels, and CAD. Both loci are also associated with baseline CRP levels, and neither locus achieved a significant (P&#x202f;<&#x202f;0.05) result from the statin v. placebo interaction meta-analysis using randomized clinical trial data. However, the interaction result (P-int=0.09) for APOE was suggestive and possibly underpowered. The APOE-E4 signal may therefore be associated with both CRP and LDL-cholesterol statin response. Combined with suggestions in the literature that APOE also leads to differential statin benefit in Alzheimer's, the APOE locus warrants further investigation for potential genetic effects on healthcare with statin treatment.

Humans↗
PubMed1979

[Enhanced UV sensitivity of Escherichia coli strain uvrA crp].

UV-sensitivity and UV-induced mutability to tryptophan independence has been studied in isogenic crp, cya, crp+, uvrA crp and uvrA crp+ strains of Escherichia coli. crp and cya strains are found to have the same UV-sensitivity as an isogenic wild type strain. UV-sensitivity of uvrA crp strain seems to be one-two orders increased as compared with the sensitivity exhibited by the uvrA - crp+ strain. The yield of UV-induced revertants is slightly higher in crp, cya and uvrA crp strains than in the wild type cells. The existence of cap-dependent inducible error-free repair pathway is supposed due to the data obtained.

DNA Repair↗
PubMed1977

Mediation of CRP-dependent phagocytosis through mouse macrophage Fc-receptors.

The purified acute phase serum constituent, C-reactive protein (CRP), was examined for its ability to interact with mouse macrophage Fc-receptors when serving as an opsonin for C-polysaccharide (CPS)-coated erythrocytes (E.CPS). The ingestion of E.CPS-CRP by macrophage monolayers was dependent on the presence of CRP on the erythrocyte surface and on the treatment of the CRP-sensitized cells with human complement (C). The ingestion of E.CPS-CRP-C was inhibited by exposing the macrophages to either 2-deoxyglucose, a selective inhibitor of Fc-receptor activity, or to aggregated gamma-globulin. Inhibition was also brought about by plating macrophages on glass-bound immune complexes of BSA/anti-BSA (IgG) but not on complexes formed with the F(ab')2 fragment of the anti-BSA. Substrate-bound complexes of CPS-CRP selectively inhibited the uptake of IgG-coated E, EA(IgG); the inhibition was proportional to the concentration of CRP used to form the complex. The opsonin-independent ingestion of latex particles was not altered by these Fc-receptor blocking procedures. These findings coupled with the recent demonstration of a sequence homology between CRP and the CH3 domain of human IgG lead us to propose shared opsonic functions for antibody and CRP.

Animals↗
PubMed1976

Effects of C-reactive protein on platelet function. II. Inhibition by CRP of platelet reactivities stimulated by poly-L-lysine, ADP, epinephrine, and collagen.

It was recently demonstrated that C-reactive protein (CRP)4 inhibits the response of human platelets to heataggregated human gamma-globulin and thrombin and that this inhibition is characterized by a dose-dependent reduction in aggregation, activation of platelet factor 3 (PF3), and release of beta-glucuronidase. In the present experiments, CRP was found also to inhibit the ability of washed human platelets to aggregate in response to poly-L-lysine (PLL); in these experiments, the magnitude of the inhibitory effect was dependent upon the m.w. of PLL used as the stimulating agent, and was more effective with low (15,000 daltons) than with high (400,000 daltons) m.w. polymers. CRP similarly inhibited ADP- and epinephrine-stimulated platelet aggregation in platelet-rich plasma (PRP), and this was characterized by relatively minimal suppression of the primary wave of aggregation. CRP also inhibited the platelet aggregation induced by collagen in PRP, although it had no effect upon the adherence of platelets to collagen. Finally, CRP inhibited the activation of PF3 and the release of serotonin during stimulation of platelets with ADP, and this inhibition was temporally related to the onset of the secondary wave of aggregation. These experiments extend the platelet reactivities inhibited by CRP, show that CRP expresses its inhibitory capacity in platelet-rich plasma as well as upon isolated platelets, raise the possibility that CRP exercises its effects by inhibiting or interfering with the release and/or utilization of endogenous platelet ADP, and support the concept that CRP plays an important role in the control of platelet responsiveness to a variety of stimuli during acute inflammatory reactions.

Adenosine Triphosphate↗
PubMed1992

Human serum amyloid P-component (SAP) selectively binds to immobilized or bound forms of C-reactive protein (CRP).

The two homologous human pentraxins, C-reactive protein (CRP) and serum amyloid P-component (SAP), specifically bind to each other only when the CRP is in an immobilized form bound to one of its ligands or to an antibody. CRP did not bind to immobilized SAP. The binding of SAP to immobilized forms of CRP was Ca(2+)-dependent and of sufficient affinity to occur in the presence of serum or purified serum proteins. SAP bound preferentially to a synthetic peptide corresponding to the Ca(2+)-binding region of CRP. Monoclonal antibodies to a synthetic peptide corresponding to the Ca(2+)-binding region selectively inhibited the binding interaction. Proteolytic cleavage of CRP between residues 146 and 147 within the Ca2+ binding region abolished the SAP-binding site; however, the intact subunits of the pentameric CRP were capable of binding SAP. The significance of the binding interaction is that it may serve as the basis for localization of SAP to sites of tissue damage or repair, sites where CRP is selectively deposited.

Amino Acid Sequence↗
PubMed1992

Rapid C-reactive protein (CRP) measurements in the diagnosis of acute appendicitis.

C-reactive protein (CRP) has been measured in plasma of patients with acute appendicitis and in controls without appendicitis to test the accuracy and diagnostic performance of a new rapid test kit for CRP (NycoCard CRP). The values obtained for CRP by the rapid test correlated well (Rs = 0.92) with the reference method for measuring CRP. The sensitivity, specificity and predictive values were calculated at different cut-off values. At values > 10 mg l-1 a sensitivity of 58% and a negative predictive value of 72% were found. Higher values of sensitivity were observed for men than for women, 69% and 44% respectively. Patients with acute appendicitis who had had symptoms for more than 24 h, had elevated CRP values (cut-off > 10 mg l-1) in more than 80% of cases. Our study shows that the rapid CRP test and the reference CRP test gave an almost identical result.

Acute Disease↗
PubMed1975

Interactions of C-reactive protein with the complement system. III. Complement-dependent passive hemolysis initiated by CRP.

Interactions of CRP with various substrates in the presence of human serum have been shown to result in efficient activation of C components C1-C5. We now report the ability of CRP to initiate C-dependent hemolysis. For this purpose CRP was isolated by affinity chromatography using pneumococcal CPS and gel filtration; its purity was established by several criteria. Erythrocytes were coated with CPS (E-CPS) and passively sensitized with CRP. C-dependent lysis of these cells was observed upon the addition of suitably absorbed human serum, and the efficiency of hemolysis compared favorably with that initiated by rabbit IgG anti-CPS antibody. CRP also sensitized E-CPS for lysis by guinea pig C; partial lysis was seen when C4-deficient guinea pig serum was used, suggesting that CRP also shares with antibody the ability of CRP to fully activate the C system and provide further evidence for a role for CRP similar to that of antibody in the initiation and modulation of inflammatory reactions via the complete system.

Animals↗
PubMed1992

Reactivity of anti-human C-reactive protein (CRP) and serum amyloid P component (SAP) monoclonal antibodies with limulin and pentraxins of other species.

Limulus polyphemus C-reactive protein (CRP) (limulin) has approximately 30% amino acid sequence homology and shares at least one idiotypic determinant associated with ligand-binding activity with human CRP (hCRP); limulin also shares amino acid sequence homology and lectin activity with human serum amyloid P component (hSAP). In the present study panels of 14 anti-hCRP monoclonal antibodies (mAb) directed to distinct hCRP epitopes and 11 anti-hSAP mAb directed to distinct epitopes of hSAP were tested for reactivity with limulin and pentraxins of other species including rabbit CRP (raCRP), rat CRP and hamster female protein (FP) by ELISA and Western blot analyses. None of the anti-human pentraxin mAb showed strong cross-reactivity with limulin; only five mAb reacted with limulin at all, and cross-reactivities of these mAb with the other pentraxins, when present, also were weak. Cross-reactivity of limulin with hCRP and hSAP was similar, and in light of comparable amino acid sequence homology, suggests this molecule can be considered the limulus SAP as well as the limulus CRP. Several anti-hCRP mAb cross-reacted strongly with rabbit CRP and rat CRP; a few anti-hSAP cross-reacted strongly with FP; and weak cross-reactions were observed between hCRP and hSAP, but cross-reactivities between the pentraxins generally were limited and weak. A rabbit polyclonal antibody raised to highly conserved limulin peptide 141-156 and strongly reactive with limulin reacted weakly with hCRP and raCRP but failed to react with rat CRP, hSAP or FP. These studies emphasize a limited but distinct antigenic similarity between limulin, hCRP and other pentraxins, and identify mAb reactive with potential regions of shared structure and/or function between pentraxins of different species.

Alpha-Globulins↗