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CytR DNA-binding transcriptional repressor

Synonyms: CytR, CytR-Cytidine
Summary:
CytR, Cytidine Regulator, is a transcription factor required for transport and utilization of ribonucleosides and deoxyribonucleosides [4, 22, 23, 24, 25, 26, 29]
The repressor CytR and the activator CRP, two dimeric proteins, interact to form a complex repressor nucleoprotein in the intergenic region. When only CRP is bound to this promoter, it functions as an activator, and then, when CytR binds to DNA and to CRP, the activation is repressed because CytR masks an activating region of CRP that otherwise would contact the RNA polymerase to activate transcription [32, 33, 33, 34, 35, 36, 37]
The CytR protein cannot act alone; the synergistic DNA binding is increased by direct interaction with CRP [14, 16, 38] However, footprinting analyses showed that the dimers of CytR are flanked or sandwiched by two dimers of CRP [1, 12, 28, 33] At times CytR also repositions CRP to alternative DNA-binding sites that are not functional for activation [32]
Gavigan et al.
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Transcription factor      
TF conformation(s):
Name Conformation Type TF-Effector Interaction Type Apo/Holo Conformation Evidence (Confirmed, Strong, Weak) References
CytR Functional   Apo [BPP] [1]
CytR-Cytidine Non-Functional Allosteric Holo [BPP] [1]
Evolutionary Family: GalR/LacI
Sensing class: Sensing external and internal signals
Connectivity class: Local Regulator
Gene name: cytR
  Genome position: 4123431-4124456
  Length: 1026 bp / 341 aa
Operon name: cytR
TU(s) encoding the TF:
Transcription unit        Promoter
cytR
cytRp


Regulon       
Regulated gene(s) cdd, cytR, deoA, deoB, deoC, deoD, nupC, nupG, ppiA, rpoH, tsx, udp, ycdZ
Multifun term(s) of regulated gene(s) MultiFun Term (List of genes associated to the multifun term)
nucleotide and nucleoside conversions (10)
Transcription related (2)
Porters (Uni-, Sym- and Antiporters) (2)
membrane (2)
activator (1)
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Regulated operon(s) cdd, cytR, deoCABD, mutY-yggX-mltC-nupG, nupC, ppiA, rpoH, tsx, udp, ycdZ
First gene in the operon(s) cdd, cytR, deoC, nupC, nupG, ppiA, ppiA, ppiA, rpoH, rpoH, rpoH, tsx, udp, ycdZ
Simple and complex regulons CRP,CytR
CRP,CytR,DeoR
CRP,CytR,DeoR,Fis,ModE
CRP,CytR,DnaA
CRP,CytR,Nac
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Simple and complex regulatory phrases Regulatory phrase (List of promoters regulated by the phrase)
[CytR,-](13)


Transcription factor binding sites (TFBSs) arrangements       

  Functional conformation Function Promoter Sigma factor Central Rel-Pos Distance to first Gene Genes Sequence
 LeftPos RightPos Evidence (Confirmed, Strong, Weak) References
  CytR repressor cddp Sigma70 -82.5 -107.5 cdd
tgcgatgcgtCGCGCATTTTTGATGTatgtttcacg
 2231729 2231744 [BPP], [GEA], [HIBSCS] [2], [3], [4]
  CytR repressor cddp Sigma70 -64.0 -89.0 cdd
tttgatgtatGTTTCACGCGTTGCATAattaatgaga
 2231747 2231763 [BPP], [GEA], [HIBSCS], [SM] [2], [3], [4], [5]
  CytR repressor cytRp Sigma70 -59.0 -112.0 cytR
tcgaaaaattCAATATTCATCACACTTTTCATGaaaattctgt
 4124557 4124579 [BPP], [GEA], [HIBSCS], [IC] [6], [7]
  CytR repressor cytRp Sigma70 -43.0 -96.0 cytR
tcacacttttCATGAAAATTCTGTAACcgttttcacg
 4124544 4124560 [BPP], [GEA], [HIBSCS], [IC] [6], [7], [8]
  CytR repressor cytRp Sigma70 -22.0 -75.0 cytR
tctgtaaccgTTTTCACGCGCTATCTGCTAAaaatgttgcc
 4124521 4124541 [BPP], [GEA], [HIBSCS], [IC] [6], [7]
  CytR repressor deoCp2 Sigma70 -87.5 -133.0 deoC, deoA, deoB, deoD
tgaattatttGAACCAGATCGCATTACAGTGatgcaaactt
 4617180 4617200 [BPP], [GEA], [HIBSCS], [SM] [1], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18]
  CytR repressor deoCp2 Sigma70 -70.5 -115.5 deoC, deoA, deoB, deoD
gcattacagtGATGCAAACTTGTAAGtagatttcct
 4617200 4617215 [BPP], [GEA], [HIBSCS], [SM] [1], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20]
  CytR repressor deoCp2 Sigma70 -61.0 -106.0 deoC, deoA, deoB, deoD
gtgatgcaaaCTTGTAAGTAGATTTCCTTaattgtgatg
 4617208 4617226 [BPP], [GEA], [SM] [1], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [21], [22]
  CytR repressor nupCp Sigma70 nd nd nupC
nd
 nd nd [TAS] [23]
  CytR repressor nupGp Sigma70 -76.5 -139.5 nupG
cacatcacaaTTTCGTTTTGCAAAttgggaatgt
 3105568 3105581 [BPP], [HIBSCS] [24]
  CytR repressor nupGp Sigma70 -61.0 -124.5 nupG
cgttttgcaaATTGGGAATGTTTGCAATtatttgccac
 3105581 3105598 [BPP], [HIBSCS] [24]
  CytR repressor nupGp Sigma70 -53.0 -116.0 nupG
aaattgggaaTGTTTGCAATTATTTGCCAcaggtaacaa
 3105589 3105607 [BPP], [HIBSCS] [24]
  CytR repressor ppiAp2 Sigma70 -83.0 -181.0 ppiA
tgatctgtttAAATGTTTTATTGCAATcggttgctaa
 3492470 3492486 [BPP], [GEA], [HIBSCS], [IC] [25]
  CytR repressor ppiAp2 Sigma70 -64.5 -162.5 ppiA
attgcaatcgGTTGCTAAATTGCATTttaagaggtg
 3492452 3492467 [BPP], [GEA], [HIBSCS] [25]
  CytR repressor ppiAp3 Sigma70 -48.0 -181.0 ppiA
tgatctgtttAAATGTTTTATTGCAATcggttgctaa
 3492470 3492486 [BPP], [GEA], [HIBSCS], [IC] [25]
  CytR repressor ppiAp3 Sigma70 -29.5 -162.5 ppiA
attgcaatcgGTTGCTAAATTGCATTttaagaggtg
 3492452 3492467 [BPP], [GEA], [HIBSCS] [25]
  CytR repressor ppiAp4 Sigma70 -29.0 -181.0 ppiA
tgatctgtttAAATGTTTTATTGCAATcggttgctaa
 3492470 3492486 [BPP], [GEA], [HIBSCS], [IC] [25]
  CytR repressor ppiAp4 Sigma70 -10.5 -162.5 ppiA
attgcaatcgGTTGCTAAATTGCATTttaagaggtg
 3492452 3492467 [BPP], [GEA], [HIBSCS] [25]
  CytR repressor rpoHp3 Sigma24 -52.0 -139.0 rpoH
gtcacattttGTGCGTAATTTATTCACAAgcttgcattg
 3600913 3600931 [BPP], [GEA], [HIBSCS] [26]
  CytR repressor rpoHp3 Sigma24 -33.5 -120.5 rpoH
tattcacaagCTTGCATTGAACTTGTggataaaatc
 3600896 3600911 [BPP], [GEA], [HIBSCS] [26]
  CytR repressor rpoHp4 Sigma70 -59.0 -139.0 rpoH
gtcacattttGTGCGTAATTTATTCACAAgcttgcattg
 3600913 3600931 [BPP], [GEA], [HIBSCS] [26]
  CytR repressor rpoHp4 Sigma70 -40.5 -120.5 rpoH
tattcacaagCTTGCATTGAACTTGTggataaaatc
 3600896 3600911 [BPP], [GEA], [HIBSCS] [26]
  CytR repressor rpoHp5 Sigma70 -73.5 -139.0 rpoH
gtcacattttGTGCGTAATTTATTCACAAgcttgcattg
 3600913 3600931 [BPP], [GEA], [HIBSCS] [26]
  CytR repressor rpoHp5 Sigma70 -54.5 -120.5 rpoH
tattcacaagCTTGCATTGAACTTGTggataaaatc
 3600896 3600911 [BPP], [GEA], [HIBSCS] [26]
  CytR repressor tsxp2 Sigma70 -68.5 -146.5 tsx
gtgtaaacgtGAACGCAATCGATTACGTAAatgatagaac
 432150 432169 [BPP], [GEA], [HIBSCS], [IC], [SM] [22]
  CytR repressor tsxp2 Sigma70 -57.5 -135.5 tsx
acgcaatcgaTTACGTAAATGATAGAACtgtgaaacga
 432140 432157 [BPP], [GEA], [IC], [IHBCE] [22], [27]
  CytR repressor tsxp2 Sigma70 -31.5 -109.5 tsx
tagaactgtgAAACGAAACATATTTTTGTGAGCAATgatttttata
 432110 432135 [BPP], [GEA], [IC], [SM] [21], [22]
  CytR repressor udpP Sigma70 -87.0 -127.0 udp
atttatgtgaTTTGCATCACTTTTGGTGGgtaaatttat
 4016295 4016313 [BPP], [GEA], [HIBSCS], [SM] [21], [28], [29]
  CytR repressor udpP Sigma70 -70.5 -110.5 udp
acttttggtgGGTAAATTTATGCAACgcatttgcgt
 4016313 4016328 [BPP], [GEA], [HIBSCS], [SM] [21], [28], [29], [30]
  CytR repressor udpP Sigma70 -61.0 -101.0 udp
tgggtaaattTATGCAACGCATTTGCGTCatggtgatga
 4016321 4016339 [BPP], [GEA], [HIBSCS], [SM] [21], [28], [29], [30]
  CytR repressor ycdZp4 Sigma70 -22.0 -66.5 ycdZ
gtcactcataACTGCAACGGATAATTTGTTGTTGCATAaaatgtgtgc
 1100216 1100243 [AIBSCS] [31]


Alignment and PSSM for CytR TFBSs    

Position weight matrix (PWM).    
A	7	11	3	11	6	6	2	1	0	1	17	5	5	12	13	10	10	3
C	10	5	9	1	4	1	0	3	1	14	0	1	2	3	3	2	0	4
G	1	1	3	3	3	3	2	2	10	3	1	0	6	0	0	1	5	2
T	0	1	3	3	5	8	14	12	7	0	0	12	5	3	2	5	3	9

PWM logo   


 


Evolutionary conservation of regulatory elements    
     Note: Evolutionary conservation of regulatory interactions and promoters is limited to gammaproteobacteria.
TF-target gene evolutionary conservation
Promoter-target gene evolutionary conservation


Evidence    

 [BPP] Binding of purified proteins

 [GEA] Gene expression analysis

 [HIBSCS] Human inference based on similarity to consensus sequences

 [SM] Site mutation

 [IC] Inferred by curator

 [TAS] Traceable author statement

 [IHBCE] Inferred by a human based on computational evidence

 [AIBSCS] Automated inference based on similarity to consensus sequences


Reference(s)    

 [1] Pedersen H., Sogaard-Andersen L., Holst B., Valentin-Hansen P., 1991, Heterologous cooperativity in Escherichia coli. The CytR repressor both contacts DNA and the cAMP receptor protein when binding to the deoP2 promoter., J Biol Chem. 266(27):17804-8

 [2] Holst B., Sogaard-Andersen L., Pedersen H., Valentin-Hansen P., 1992, 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., EMBO J. 11(10):3635-43

 [3] Holt AK., Senear DF., 2010, An unusual pattern of CytR and CRP binding energetics at Escherichia coli cddP suggests a unique blend of class I and class II mediated activation., Biochemistry. 49(3):432-42

 [4] Jorgensen CI., Kallipolitis BH., Valentin-Hansen P., 1998, DNA-binding characteristics of the Escherichia coli CytR regulator: a relaxed spacing requirement between operator half-sites is provided by a flexible, unstructured interdomain linker., Mol Microbiol. 27(1):41-50

 [5] Valentin-Hansen P., Holst B., Josephsen J., Hammer K., Albrechtsen B., 1989, CRP/cAMP- and CytR-regulated promoters in Escherichia coli K12: the cdd promoter., Mol Microbiol. 3(10):1385-90

 [6] Gerlach P., Valentin-Hansen P., Bremer E., 1990, Transcriptional regulation of the cytR repressor gene of Escherichia coli: autoregulation and positive control by the cAMP/CAP complex., Mol Microbiol. 4(3):479-88

 [7] Pedersen H., Sogaard-Andersen L., Holst B., Gerlach P., Bremer E., Valentin-Hansen P., 1992, 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., J Mol Biol. 227(2):396-406

 [8] Pedersen H., Valentin-Hansen P., 1997, Protein-induced fit: the CRP activator protein changes sequence-specific DNA recognition by the CytR repressor, a highly flexible LacI member., EMBO J. 16(8):2108-18

 [9] Chahla M., Wooll J., Laue TM., Nguyen N., Senear DF., 2003, Role of protein-protein bridging interactions on cooperative assembly of DNA-bound CRP-CytR-CRP complex and regulation of the Escherichia coli CytR regulon., Biochemistry. 42(13):3812-25

 [10] Mayes DG., 1977, A comparison of menstrual bleeding patterns associated with three IUD models: an example of reference period analysis., J Biosoc Sci. 9(1):121-35

 [11] Mollegaard NE., Rasmussen PB., Valentin-Hansen P., Nielsen PE., 1993, Characterization of promoter recognition complexes formed by CRP and CytR for repression and by CRP and RNA polymerase for activation of transcription on the Escherichia coli deoP2 promoter., J Biol Chem. 268(23):17471-7

 [12] Perini LT., Doherty EA., Werner E., Senear DF., 1996, Multiple specific CytR binding sites at the Escherichia coli deoP2 promoter mediate both cooperative and competitive interactions between CytR and cAMP receptor protein., J Biol Chem. 271(52):33242-55

 [13] Shin M., Kang S., Hyun SJ., Fujita N., Ishihama A., Valentin-Hansen P., Choy HE., 2001, Repression of deoP2 in Escherichia coli by CytR: conversion of a transcription activator into a repressor., EMBO J. 20(19):5392-9

 [14] Sogaard-Andersen L., Martinussen J., Mollegaard NE., Douthwaite SR., Valentin-Hansen P., 1990, The CytR repressor antagonizes cyclic AMP-cyclic AMP receptor protein activation of the deoCp2 promoter of Escherichia coli K-12., J Bacteriol. 172(10):5706-13

 [15] Sogaard-Andersen L., Mironov AS., Pedersen H., Sukhodelets VV., Valentin-Hansen P., 1991, Single amino acid substitutions in the cAMP receptor protein specifically abolish regulation by the CytR repressor in Escherichia coli., Proc Natl Acad Sci U S A. 88(11):4921-5

 [16] Sogaard-Andersen L., Pedersen H., Holst B., Valentin-Hansen P., 1991, 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., Mol Microbiol. 5(4):969-75

 [17] Sogaard-Andersen L., Valentin-Hansen P., 1991, Restored DNA-binding of the cAMP-CRP activator complex reestablishes negative regulation by the CytR repressor in the deoP2 promoter in Escherichia coli., Mol Gen Genet. 231(1):76-80

 [18] Sogaard-Andersen L., Valentin-Hansen P., 1993, Protein-protein interactions in gene regulation: the cAMP-CRP complex sets the specificity of a second DNA-binding protein, the CytR repressor., Cell. 75(3):557-66

 [19] Valentin-Hansen P., 1982, Tandem CRP binding sites in the deo operon of Escherichia coli K-12., EMBO J. 1(9):1049-54

 [20] Valentin-Hansen P., Larsen JE., Hojrup P., Short SA., Barbier CS., 1986, Nucleotide sequence of the CytR regulatory gene of E. coli K-12., Nucleic Acids Res. 14(5):2215-28

 [21] Brikun I., Suziedelis K., Stemmann O., Zhong R., Alikhanian L., Linkova E., Mironov A., Berg DE., 1996, Analysis of CRP-CytR interactions at the Escherichia coli udp promoter., J Bacteriol. 178(6):1614-22

 [22] Gerlach P., Sogaard-Andersen L., Pedersen H., Martinussen J., Valentin-Hansen P., Bremer E., 1991, The cyclic AMP (cAMP)-cAMP receptor protein complex functions both as an activator and as a corepressor at the tsx-p2 promoter of Escherichia coli K-12., J Bacteriol. 173(17):5419-30

 [23] Craig JE., Zhang Y., Gallagher MP., 1994, Cloning of the nupC gene of Escherichia coli encoding a nucleoside transport system, and identification of an adjacent insertion element, IS 186., Mol Microbiol. 11(6):1159-68

 [24] Pedersen H., Dall J., Dandanell G., Valentin-Hansen P., 1995, Gene-regulatory modules in Escherichia coli: nucleoprotein complexes formed by cAMP-CRP and CytR at the nupG promoter., Mol Microbiol. 17(5):843-53

 [25] Norregaard-Madsen M., Mygind B., Pedersen R., Valentin-Hansen P., Sogaard-Andersen L., 1994, The gene encoding the periplasmic cyclophilin homologue, PPIase A, in Escherichia coli, is expressed from four promoters, three of which are activated by the cAMP-CRP complex and negatively regulated by the CytR repressor., Mol Microbiol. 14(5):989-97

 [26] Kallipolitis BH., Valentin-Hansen P., 1998, Transcription of rpoH, encoding the Escherichia coli heat-shock regulator sigma32, is negatively controlled by the cAMP-CRP/CytR nucleoprotein complex., Mol Microbiol. 29(4):1091-9

 [27] Bremer E., Gerlach P., Middendorf A., 1988, Double negative and positive control of tsx expression in Escherichia coli., J Bacteriol. 170(1):108-16

 [28] Gavigan SA., Nguyen T., Nguyen N., Senear DF., 1999, Role of multiple CytR binding sites on cooperativity, competition, and induction at the Escherichia coli udp promoter., J Biol Chem. 274(23):16010-9

 [29] Zolotukhina M., Ovcharova I., Eremina S., Errais Lopes L., Mironov AS., 2003, Comparison of the structure and regulation of the udp gene of Vibrio cholerae, Yersinia pseudotuberculosis, Salmonella typhimurium, and Escherichia coli., Res Microbiol. 154(7):510-20

 [30] Zolotukhina MA., Ovcharova IV., Eremina SIu., Errais LL., Mironov AS., 2002, [Functional interrelationship between elements of the Escherichia coli udp gene promotor responsible for binding regulatory proteins CytR, CRP, and RNA polymerase], Genetika. 38(9):1223-34

 [31] Sernova NV., Gelfand MS., 2012, Comparative genomics of CytR, an unusual member of the LacI family of transcription factors., PLoS One. 7(9):e44194

 [32] Valentin-Hansen P., Sogaard-Andersen L., Pedersen H., 1996, A flexible partnership: the CytR anti-activator and the cAMP-CRP activator protein, comrades in transcription control., Mol Microbiol. 20(3):461-6

 [33] Meibom KL., Kallipolitis BH., Ebright RH., Valentin-Hansen P., 2000, Identification of the subunit of cAMP receptor protein (CRP) that functionally interacts with CytR in CRP-CytR-mediated transcriptional repression., J Biol Chem. 275(16):11951-6

 [34] Kristensen HH., Valentin-Hansen P., Sogaard-Andersen L., 1997, Design of CytR regulated, cAMP-CRP dependent class II promoters in Escherichia coli: RNA polymerase-promoter interactions modulate the efficiency of CytR repression., J Mol Biol. 266(5):866-76

 [35] Meibom KL., Sogaard-Andersen L., Mironov AS., Valentin-Hansen P., 1999, Dissection of a surface-exposed portion of the cAMP-CRP complex that mediates transcription activation and repression., Mol Microbiol. 32(3):497-504

 [36] Kristensen HH., Valentin-Hansen P., Sogaard-Andersen L., 1996, CytR/cAMP-CRP nucleoprotein formation in E. coli: the CytR repressor binds its operator as a stable dimer in a ternary complex with cAMP-CRP., J Mol Biol. 260(2):113-9

 [37] Rasmussen PB., Holst B., Valentin-Hansen P., 1996, Dual-function regulators: the cAMP receptor protein and the CytR regulator can act either to repress or to activate transcription depending on the context., Proc Natl Acad Sci U S A. 93(19):10151-5

 [38] Sogaard-Andersen L., Mollegaard NE., Douthwaite SR., Valentin-Hansen P., 1990, Tandem DNA-bound cAMP-CRP complexes are required for transcriptional repression of the deoP2 promoter by the CytR repressor in Escherichia coli., Mol Microbiol. 4(9):1595-601

 [39] Kallipolitis BH., Valentin-Hansen P., 2004, A role for the interdomain linker region of the Escherichia coli CytR regulator in repression complex formation., J Mol Biol. 342(1):1-7

 [40] Weickert MJ., Adhya S., 1992, A family of bacterial regulators homologous to Gal and Lac repressors., J Biol Chem. 267(22):15869-74

 [41] Kallipolitis BH., Norregaard-Madsen M., Valentin-Hansen P., 1997, Protein-protein communication: structural model of the repression complex formed by CytR and the global regulator CRP., Cell. 89(7):1101-9

 [42] Moody CL., Tretyachenko-Ladokhina V., Laue TM., Senear DF., Cocco MJ., 2011, Multiple Conformations of the Cytidine Repressor DNA-Binding Domain Coalesce to One upon Recognition of a Specific DNA Surface., Biochemistry. 50(31):6622-32

 [43] Muller-Hill B., 1998, Some repressors of bacterial transcription., Curr Opin Microbiol. 1(2):145-51


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