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discounted EARLY registration ends Dec 31, 2014
BioCyc websites MAYBE down
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for maintenance.
Metabolic Modeling Tutorial
discounted EARLY registration ends Dec 31, 2014
BioCyc websites MAYBE down
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Metabolic Modeling Tutorial
discounted EARLY registration ends Dec 31, 2014
BioCyc websites MAYBE down
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Escherichia coli K-12 substr. MG1655 Protein: CRP-cAMP DNA-binding transcriptional dual regulator



Gene: crp Accession Numbers: EG10164 (EcoCyc), b3357, ECK3345

Synonyms: cap, csm, gurB, CRP-cAMP

Regulation Summary Diagram: ?

Subunit composition of CRP-cAMP DNA-binding transcriptional dual regulator = [(Crp)2][cyclic-AMP]
         CRP transcriptional dual regulator = (Crp)2 (summary available)
                 CRP transcriptional dual regulator = Crp

Summary:
The transcriptional dual regulator CRP, "cAMP receptor protein," also called CAP, "catabolite gene activator protein," regulates the expression of over 180 genes [Grainger05, Robison98, Zheng04] in E. coli. Many of these genes are involved in the catabolism of secondary carbon sources (for reviews, see [Fic08, Deutscher08, Gorke08, Kolb93]. In addition, CRP is involved in many other processes, such as osmoregulation [Landis99, Balsalobre06], stringent response [Johansson00], biofilm formation [Jackson02], virulence [Balsalobre06], nitrogen assimilation [Mao07, Paul07, Tian01], iron uptake [Zhang05], competence [Sinha09], multidrug resistance to antibiotics [Nishino08, Hirakawa06], and expression of CyaR sRNA [De09]. Transcriptome analyses have been performed [Khankal09, GutierrezRios07, Zheng04, Gosset04]. Expression of crp is positively and negatively autoregulated [Aiba83, Hanamura92]; repression of crp requires Fis [GonzalezGil98]. CRP activates a gene potentially related to persistence [Uppal14].

CRP was the first purified transcriptional regulator and the first for which the structure was solved [Zubay70, Emmer70, McKay81, Aiba82, Goldberg88]. CRP is activated as a DNA-binding protein by binding of its allosteric effector, cAMP [Zubay70, McKay81, Blaszczyk01].

Protein structure and allosteric activation

CRP belongs to the CRP-FNR superfamily of transcription factors [Korner03, Green01]. The crystal structures of cAMP-CRP [McKay82, Weber87, Passner00], cAMP-CRP bound to DNA [Schultz91a, Parkinson96, Passner97, Huang13], the cAMP-CRP-α-CTD-DNA complex [Benoff02], and the solution structure [Popovych09], as well as the crystal structure of apo-CRP [Sharma09], have been solved. CRP is a homodimer and consists of two domains connected by a short hinge region. The C-terminal α-helical DNA-binding domain carries a characteristic helix-turn-helix motif. It dimerizes in apo-CRP, with the DNA recognition helix F buried within its core [Sharma09]. The N-terminal dimerization domain mainly consists of β-sheets and carries a hydrophobic pocket for binding of cAMP. A long α-helix, termed the C-helix, forms an intersubunit coiled-coil. This helix plays a central role in the allosteric activation of CRP. Allostery arises as a natural consequence of changes in global low-frequency protein fluctuations on ligand binding, and there are conserved residues crucial for allosteric control [Rodgers13]. After binding of cAMP, the signal is propagated through a lengthening and reorientation of the C-helix to the DNA-binding domain, resulting in the liberation of the DNA recognition helix [Popovych09, Sharma09].

Mechanism of transcriptional regulation

CRP binds to a 22-bp symmetrical site [Ebright89] and induces a severe bend upon binding, with an angle of ∼80° [Schultz91a, Parkinson96, Wu, Chen01c]. Two regions of CRP, AR1 ("activation region 1"), located in the C-terminal domain [Zhou93a, Niu94], and AR2 [Niu96], located in the N-terminal domain, are known to interact with RNA polymerase (RNAP).

Promoters that are activated by cAMP-CRP can be grouped into three classes, termed class I, class II, and class III promoters [Busby99]. Class I- and class II-dependent promoters require one cAMP-CRP for activation and have a single DNA-binding site located upstream of the RNAP-binding site, centered near position -93, -83, -72, or -62 of class I promoters [Ushida90, Gaston90, Tebbutt02] and overlapping the RNAP-binding site of class II promoters [Busby99]. At class I promoters, AR1 of the downstream subunit of the CRP dimer interacts with the α-CTD of RNAP [Zhou94a], thereby increasing the affinity of RNAP for the promoter DNA [Igarashi91, Savery96, Ebright93].

Class II-dependent promoters require AR1 of the upstream subunit and AR2 of the downstream subunit of CRP. AR1 recruits α-CTD to the DNA region upstream of the bound CRP dimer, while AR2 interacts with α-NTD of RNAP [Savery96, Niu96, Savery98]. Class III promoters require multiple activator molecules, that is, either two or more CAP dimers or one CRP dimer and additional activator proteins synergistically activate transcription [Barnard04, Beatty03]. Dependent on the localization of its binding site, CRP functions by a class I or class II mechanism at class III promoters or by a more complex mechanism which can involve direct interactions with the second activator [Belyaeva00, Wade01, Wickstrum05], or CRP exerts its function by DNA bending [Savery96, Busby99, Lobell91].

CRP represses transcription by promoter occlusion [Kolb93], by exclusion of an activator protein [Polayes88], through the interaction with a repressor protein in an antiactivation mechanism [Mollegaard93, ValentinHansen96, McNeill07, Perini96] or by hindering promoter clearance [Liu04a, Rostoks00].

Catabolite repression and inducer exclusion

Catabolite repression in E. coli is mediated by the interplay of CRP, adenylate cyclase, cAMP, and the glucose-specific enzyme IIA (EIIAGlc) of the phosphoenolpyruvate:sugar phosphotransferase system [Deutscher08, Deutscher06, Gorke08]. In the absence of rapidly metabolizable carbon sources, such as glucose, EIIAGlc is phosphorylated [Hogema98] and activates adenylate cyclase [Feucht80, Reddy98], resulting in an elevated level of cAMP [Park06a, Bettenbrock07]. Due to the autoregulation of crp [Aiba83, Ishizuka94, Hanamura92], cAMP-CRP levels increase. In addition, in the presence of unphosphorylated EIIAGlc, inducer is transported into the cell, leading to the inactivation of the corresponding repressor molecules [Saier89][Magasanik70*]. Therefore, transcription of catabolic genes is switched on by cAMP-CRP.

If glucose is available, EIIAGlc is predominantly dephosphorylated [Hogema98]. As a consequence, adenylate cyclase is not activated, resulting in a reduced level of cAMP. Due to the autoregulation of crp, cAMP-CRP levels decrease [Hanamura91]. In addition, EIIAGlc blocks the uptake of inducer by blocking the transport systems ("inducer exclusion") [Nelson83, Osumi82, Dills82, Sondej02]. Thus, transcription of catabolic genes is switched off. cAMP not only mediates carbon metabolism but also plays a physiological role to ensure that proteomic resources are spent on distinct metabolic pathways as needed in different nutrient environments [You13]. α-Keto-acids inhibit cAMP production [You13].

CRP has been adapted to respond to different external and internal stimuli according to the particular ecological niches occupied by the bacterium [Green14].

Mutants

CRP was engineered to prove the enhanced strain osmotolerance phenotype based on several random mutagenesis studies. All variants showed much higher osmotolerance towards NaCl and others osmotic stressors, such as KCl, glucose, and sucrose, than the wild type [Zhang12]. Using DNA microarray analysis, genes involved in colonic acid biosynthesis were identified as upregulated in the absence of salt stress, whereas carbohydrate metabolism genes were differentially expressed under NaCl stress in an MT6 (CRP mutant with the best osmotolerance towards NaCl) mutant compared to the wild type [Zhang12].

Magasanik: doi:10.1101/087969100.1.189

*Magasanik, 1970. B. Magasanik, Glucose effects: inducer exclusion and repression. In: J. Beckwith and D. Zipser, Editors, The Lactose Operon, Cold Spring Harbor Laboratory, New York (1970), pp. 189-219.

Map Position: [3,484,142 -> 3,484,774] (75.09 centisomes)
Length: 633 bp / 210 aa

Unification Links: ASAP:ABE-0010970 , CGSC:906 , EchoBASE:EB0162 , EcoGene:EG10164 , OU-Microarray:b3357 , PortEco:crp , RegulonDB:EG10164

In Paralogous Gene Group: 278 (2 members)

In Reactions of unknown directionality:

Not in pathways:
Crp + cyclic-AMP = CRP-cAMP DNA-binding transcriptional dual regulator

Gene-Reaction Schematic: ?

Genetic Regulation Schematic: ?

GO Terms:

Biological Process: GO:0045893 - positive regulation of transcription, DNA-templated Inferred from experiment [Zubay70]
Molecular Function: GO:0043565 - sequence-specific DNA binding Inferred from experiment [Ebright89]

MultiFun Terms: information transfer RNA related Transcription related
regulation genetic unit regulated global
regulation type of regulation transcriptional level activator
regulation type of regulation transcriptional level repressor

DNA binding site length: 22 base-pairs

Symmetry: Inverted Repeat

Consensus DNA Binding Sequence: AAATGTGAtctagaTCACATTT

Regulated Transcription Units (276 total): ?

Notes:


Subunit of CRP-cAMP DNA-binding transcriptional dual regulator: CRP transcriptional dual regulator

Synonyms: cap, csm, gurB

Gene: crp Accession Numbers: EG10164 (EcoCyc), b3357, ECK3345

Locations: cytosol

Subunit composition of CRP transcriptional dual regulator = [Crp]2
         CRP transcriptional dual regulator = Crp

Map Position: [3,484,142 -> 3,484,774] (75.09 centisomes)
Length: 633 bp / 210 aa

Molecular Weight of Polypeptide: 23.64 kD (from nucleotide sequence)

pI: 8.25

GO Terms:

Biological Process: GO:0006351 - transcription, DNA-templated Inferred from experiment Inferred by computational analysis [UniProtGOA11a, Shaw83, Wade01, Belyaeva00, Wickstrum05, Beatty03, Williams96, Ramseier95, Zheng04]
GO:0045013 - carbon catabolite repression of transcription Inferred from experiment [Cirino06]
GO:0045892 - negative regulation of transcription, DNA-templated Inferred from experiment [Zheng04]
GO:0045893 - positive regulation of transcription, DNA-templated Inferred from experiment [Zheng04]
GO:0006355 - regulation of transcription, DNA-templated Inferred by computational analysis [UniProtGOA11a, GOA01a]
Molecular Function: GO:0005515 - protein binding Inferred from experiment [Rajagopala14, Butland05]
GO:0000166 - nucleotide binding Inferred by computational analysis [UniProtGOA11a]
GO:0003677 - DNA binding Inferred by computational analysis [UniProtGOA11a, GOA01a]
GO:0003700 - sequence-specific DNA binding transcription factor activity Inferred by computational analysis [GOA01a]
GO:0030552 - cAMP binding Inferred by computational analysis [UniProtGOA11a]
Cellular Component: GO:0005829 - cytosol Inferred from experiment Inferred by computational analysis [DiazMejia09, Ishihama08]
GO:0005622 - intracellular Inferred by computational analysis [GOA01a]

MultiFun Terms: information transfer RNA related Transcription related
regulation genetic unit regulated global
regulation type of regulation transcriptional level activator
regulation type of regulation transcriptional level repressor

Unification Links: DIP:DIP-29232N , EcoliWiki:b3357 , Mint:MINT-1249660 , ModBase:P0ACJ8 , PR:PRO_000022333 , Pride:P0ACJ8 , Protein Model Portal:P0ACJ8 , RefSeq:NP_417816 , SMR:P0ACJ8 , String:511145.b3357 , UniProt:P0ACJ8

Relationship Links: InterPro:IN-FAMILY:IPR000595 , InterPro:IN-FAMILY:IPR001808 , InterPro:IN-FAMILY:IPR011991 , InterPro:IN-FAMILY:IPR012318 , InterPro:IN-FAMILY:IPR014710 , InterPro:IN-FAMILY:IPR018335 , InterPro:IN-FAMILY:IPR018488 , InterPro:IN-FAMILY:IPR018490 , PDB:Structure:1CGP , PDB:Structure:1G6N , PDB:Structure:1HW5 , PDB:Structure:1I5Z , PDB:Structure:1I6X , PDB:Structure:1J59 , PDB:Structure:1LB2 , PDB:Structure:1O3Q , PDB:Structure:1O3R , PDB:Structure:1O3S , PDB:Structure:1O3T , PDB:Structure:1RUN , PDB:Structure:1RUO , PDB:Structure:1ZRC , PDB:Structure:1ZRD , PDB:Structure:1ZRE , PDB:Structure:1ZRF , PDB:Structure:2CGP , PDB:Structure:2GAP , PDB:Structure:2GZW , PDB:Structure:2WC2 , PDB:Structure:3FWE , PDB:Structure:3HIF , PDB:Structure:3IYD , PDB:Structure:3KCC , PDB:Structure:3N4M , PDB:Structure:3QOP , PDB:Structure:3RDI , PDB:Structure:3ROU , PDB:Structure:3RPQ , PDB:Structure:3RYP , PDB:Structure:3RYR , PDB:Structure:4BH9 , PDB:Structure:4BHP , Pfam:IN-FAMILY:PF00027 , Pfam:IN-FAMILY:PF00325 , Prints:IN-FAMILY:PR00034 , Prosite:IN-FAMILY:PS00042 , Prosite:IN-FAMILY:PS00888 , Prosite:IN-FAMILY:PS00889 , Prosite:IN-FAMILY:PS50042 , Prosite:IN-FAMILY:PS51063 , Smart:IN-FAMILY:SM00100 , Smart:IN-FAMILY:SM00419

In Reactions of unknown directionality:

Not in pathways:
Crp + cyclic-AMP = CRP-cAMP DNA-binding transcriptional dual regulator

Summary:

Citations: [Hanamura92, Ramseier95]

Gene Citations: [Hanamura91, Ishizuka94]


Gene Local Context (not to scale): ?

Transcription Units:

Notes:

History:
3/2/1998 (pkarp) Merged genes G51/b3357 and EG10164/crp
10/20/97 Gene b3357 from Blattner lab Genbank (v. M52) entry merged into EcoCyc gene EG10164.


References

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Other References Related to Gene Regulation

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Please cite the following article in publications resulting from the use of EcoCyc: Nucleic Acids Research 41:D605-12 2013
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