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SoxR DNA-binding transcriptional dual regulator

Synonyms: SoxR, SoxR-[2Fe-2S]2+ reduced
Summary:
The SoxR protein, for "Superoxide Response protein," is negatively autoregulated and controls the transcription of the regulon involved in defense against redox-cycling drugs [4, 8, 9, 10] and in responses to nitric oxide [2, 11, 12, 13, 14, 15, 16, 17, 18, 19]. SoxR belongs to the MerR family and is a homodimer in solution [3, 20]. SoxR contains two essential [2Fe-2S] clusters for its transcriptional activity [21]. Each SoxR polypeptide contains a [2Fe-2S] cluster that senses the oxidants in the cell. Both Fe-SoxR and apo-SoxR bind to the promoter region, but only Fe-SoxR contributes to the activation in its oxidized form [3, 20, 22, 23, 24]. The redox state of the iron-sulfur cluster regulates SoxR activity [25, 26].
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Transcription factor      
TF conformation(s):
Name Conformation Type TF-Effector Interaction Type Apo/Holo Conformation Evidence (Confirmed, Strong, Weak) References
SoxR Functional   [APPHINH] [1], [2], [3], [4], [5]
SoxR-[2Fe-2S]2+ reduced Non-Functional Covalent Apo [IDA] [3]
Evolutionary Family: MerR
Sensing class: Using internal synthesized signals
Connectivity class: Local Regulator
Gene name: soxR
  Genome position: 4277469-4277933
  Length: 465 bp / 154 aa
Operon name: soxR
TU(s) encoding the TF:
Transcription unit        Promoter
soxR
soxRp


Regulon       
Regulated gene(s) aroF, fumC, sodA, soxR, soxS, tyrA, yjcB, yrbL
Multifun term(s) of regulated gene(s) MultiFun Term (List of genes associated to the multifun term)
detoxification (3)
Transcription related (2)
activator (2)
repressor (2)
other (mechanical, nutritional, oxidative stress) (2)
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Regulated operon(s) aroF-tyrA, fumAC, sodA, soxR, soxS, yjcB, yrbL
First gene in the operon(s) aroF, fumC, sodA, soxR, soxS, yjcB, yrbL
Simple and complex regulons AcrR,FNR,Fur,SoxR
AcrR,FNR,Fur,SoxR,SoxS
ArcA,CRP,FNR,Fur,IHF,MarA,Rob,SoxR,SoxS
ArcA,CRP,FNR,Fur,MarA,SoxR,SoxS
BasR,PhoP,SoxR,SoxS
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Simple and complex regulatory phrases Regulatory phrase (List of promoters regulated by the phrase)
[SoxR,+](6)
[SoxR,-](1)


Transcription factor regulation    


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
  SoxR activator aroFp Sigma70 8.5 -43.5 aroF, tyrA
atcgttacgtCATCCTCGCTGAGGATCAactatcgcaa
2741185 2741202 , [IHBCE], [6]
  SoxR activator fumCp Sigma38 nd nd fumC nd nd [BPP], [GEA] [2]
  SoxR activator sodAp Sigma70 9.0 -43.5 sodA
ataatgaaccAACTGCTTACGCGGCATTaacaatcggc
4100758 4100775 , [IHBCE], [6]
  SoxR repressor soxRp Sigma70 2.5 -20.5 soxR
gagtataattCCTCAAGTTAACTTGAGGtaaagcgatt
4277440 4277457 [BPP], , [CHIP-SV], [GEA], [IHBCE], [MSI], [3], [6], [7]
  SoxR activator soxSp Sigma70 -25.5 -65.5 soxS
aatcgctttaCCTCAAGTTAACTTGAGGaattatactc
4277440 4277457 [BPP], , [GEA], [IHBCE], [3], [6], [7]
  SoxR activator soxSp Sigma70 6.0 -34.5 soxS
tatactccccAACAGATGAATTAACGAActgaacactg
4277409 4277426 , [IHBCE], [6]
  SoxR activator yjcBp nd -4.0 -126.5 yjcB
gtgatatagtTCACAAAATTAATGAAACaaacagagtg
4275159 4275176 , [IHBCE], [6]
  SoxR activator yrbLp nd 36.0 3.5 yrbL
tttccaggagATGGCATGATTCGCTTATctgaacaaag
3348447 3348464 , [IHBCE], [6]


Alignment and PSSM for SoxR TFBSs    

Aligned TFBS of SoxR   
  Sequence
  TACCTCAAGTTAACTTGAGG
  TTCGTTAATTCATCTGTTGG
  TACGTCATCCTCGCTGAGGA
  AATGCCGCGTAAGCAGTTGG
  TTTGTTTCATTAATTTTGTG
  GATGGCATGATTCGCTTATC

Position weight matrix (PWM). SoxR matrix-quality result   
A	1	4	0	0	0	0	4	2	1	1	1	4	2	0	1	0	1	2	0	1
C	0	0	3	1	1	4	0	2	1	1	1	1	1	4	1	0	0	0	0	1
G	1	0	0	5	1	0	1	0	3	0	0	0	2	1	0	3	1	2	4	4
T	4	2	3	0	4	2	1	2	1	4	4	1	1	1	4	3	4	2	2	0

Consensus   
;	consensus.strict             	tacGtCacgttagCtgtgGG
;	consensus.strict.rc          	CCCACAGCTAACGTGACGTA
;	consensus.IUPAC              	twyGtYahgttarCtktdKG
;	consensus.IUPAC.rc           	CMHAMAGYTAACDTRACRWA
;	consensus.regexp             	t[at][ct]Gt[CT]a[act]gtta[ag]Ct[gt]t[agt][GT]G
;	consensus.regexp.rc          	C[AC][ACT]A[AC]AG[CT]TAAC[AGT]T[AG]AC[AG][AT]A

PWM logo   


 


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


Evidence    

 [APPHINH] Assay of protein purified to homogeneity from its native host

 [IDA] Inferred from direct assay

 [CEUMA] ChIP-exo evidence used in manual assertion

 [IHBCE] Inferred by a human based on computational evidence

 [RE] RNA-seq evidence

 [BPP] Binding of purified proteins

 [GEA] Gene expression analysis

 [CHIP-SV] ChIP analysis and statistical validation of TFBSs

 [MSI] Mapping of signal intensities



Reference(s)    

 [1] Amabile-Cuevas CF., Demple B., 1991, Molecular characterization of the soxRS genes of Escherichia coli: two genes control a superoxide stress regulon., Nucleic Acids Res 19(16):4479-84

 [2] Fuentes AM., Diaz-Mejia JJ., Maldonado-Rodriguez R., Amabile-Cuevas CF., 2001, Differential activities of the SoxR protein of Escherichia coli: SoxS is not required for gene activation under iron deprivation., FEMS Microbiol Lett 201(2):271-5

 [3] Hidalgo E., Bollinger JM., Bradley TM., Walsh CT., Demple B., 1995, Binuclear [2Fe-2S] clusters in the Escherichia coli SoxR protein and role of the metal centers in transcription., J Biol Chem 270(36):20908-14

 [4] Nunoshiba T., Hidalgo E., Amabile Cuevas CF., Demple B., 1992, Two-stage control of an oxidative stress regulon: the Escherichia coli SoxR protein triggers redox-inducible expression of the soxS regulatory gene., J Bacteriol 174(19):6054-60

 [5] Wu J., Weiss B., 1991, Two divergently transcribed genes, soxR and soxS, control a superoxide response regulon of Escherichia coli., J Bacteriol 173(9):2864-71

 [6] Seo SW., Kim D., Szubin R., Palsson BO., 2015, Genome-wide Reconstruction of OxyR and SoxRS Transcriptional Regulatory Networks under Oxidative Stress in Escherichia coli K-12 MG1655., Cell Rep 12(8):1289-99

 [7] Hidalgo E., Leautaud V., Demple B., 1998, The redox-regulated SoxR protein acts from a single DNA site as a repressor and an allosteric activator., EMBO J 17(9):2629-36

 [8] Greenberg JT, Monach P, Chou JH, Josephy PD, Demple B, 1990, Positive control of a global antioxidant defense regulon activated by superoxide-generating agents in Escherichia coli., Proc Natl Acad Sci U S A, 1990 Aug

 [9] Vasil'eva SV, Stupakova MV, Lobysheva II, Mikoyan VD, Vanin AF, 2001, Activation of the Escherichia coli SoxRS-regulon by nitric oxide and its physiological donors., Biochemistry (Mosc), 2001 Sep

 [10] Gu M, Imlay JA, 2011, The SoxRS response of Escherichia coli is directly activated by redox-cycling drugs rather than by superoxide., Mol Microbiol, 2011 Mar

 [11] Tsaneva IR, Weiss B, 1990, soxR, a locus governing a superoxide response regulon in Escherichia coli K-12., J Bacteriol, 1990 Aug

 [12] Lu C., Bentley WE., Rao G., 2003, Comparisons of oxidative stress response genes in aerobic Escherichia coli fermentations., Biotechnol Bioeng 83(7):864-70

 [13] Liochev SI, Fridovich I, 1992, Fumarase C, the stable fumarase of Escherichia coli, is controlled by the soxRS regulon., Proc Natl Acad Sci U S A, 1992 Jul 1

 [14] Liochev SI, Hausladen A, Fridovich I, 1999, Nitroreductase A is regulated as a member of the soxRS regulon of Escherichia coli., Proc Natl Acad Sci U S A, 1999 Mar 30

 [15] Demple B, 1999, Genetic responses against nitric oxide toxicity., Braz J Med Biol Res, 1999 Nov

 [16] Demple B, Ding H, Jorgensen M, 2002, Escherichia coli SoxR protein: sensor/transducer of oxidative stress and nitric oxide., Methods Enzymol, 2002

 [17] Lo FC, Chen CL, Lee CM, Tsai MC, Lu TT, Liaw WF, Yu SS, 2008, A study of NO trafficking from dinitrosyl-iron complexes to the recombinant E. coli transcriptional factor SoxR., J Biol Inorg Chem, 2008 Aug

 [18] Manchado M, Michán C, Pueyo C, 2000, Hydrogen peroxide activates the SoxRS regulon in vivo., J Bacteriol, 2000 Dec

 [19] Agnez-Lima LF, Di Mascio P, Demple B, Menck CF, 2001, Singlet molecular oxygen triggers the soxRS regulon of Escherichia coli., Biol Chem, 2001 Jul

 [20] Hidalgo E, Demple B, 1996, Activation of SoxR-dependent transcription in vitro by noncatalytic or NifS-mediated assembly of [2Fe-2S] clusters into apo-SoxR., J Biol Chem, 1996 Mar 29

 [21] Pomposiello PJ, Demple B, 2001, Redox-operated genetic switches: the SoxR and OxyR transcription factors., Trends Biotechnol, 2001 Mar

 [22] Ding H, Demple B, 1996, Glutathione-mediated destabilization in vitro of [2Fe-2S] centers in the SoxR regulatory protein., Proc Natl Acad Sci U S A, 1996 Sep 3

 [23] Gaudu P, Weiss B, 1996, SoxR, a [2Fe-2S] transcription factor, is active only in its oxidized form., Proc Natl Acad Sci U S A, 1996 Sep 17

 [24] Hidalgo E, Demple B, 1994, An iron-sulfur center essential for transcriptional activation by the redox-sensing SoxR protein., EMBO J, 1994 Jan 1

 [25] Hidalgo E, Ding H, Demple B, 1997, Redox signal transduction: mutations shifting [2Fe-2S] centers of the SoxR sensor-regulator to the oxidized form., Cell, 1997 Jan 10

 [26] Gaudu P, Moon N, Weiss B, 1997, Regulation of the soxRS oxidative stress regulon. Reversible oxidation of the Fe-S centers of SoxR in vivo., J Biol Chem, 1997 Feb 21

 [27] Lee KL, Singh AK, Heo L, Seok C, Roe JH, 2015, Factors affecting redox potential and differential sensitivity of SoxR to redox-active compounds., Mol Microbiol, 2015 Sep

 [28] Dietrich LE, Teal TK, Price-Whelan A, Newman DK, 2008, Redox-active antibiotics control gene expression and community behavior in divergent bacteria., Science, 2008 Aug 29

 [29] Demple B, Amábile-Cuevas CF, 1991, Redox redux: the control of oxidative stress responses., Cell, 1991 Nov 29

 [30] Liochev SI, Fridovich I, 2011, Is superoxide able to induce SoxRS?, Free Radic Biol Med, 2011 Jun 15

 [31] Lo FC, Lee JF, Liaw WF, Hsu IJ, Tsai YF, Chan SI, Yu SS, 2012, The metal core structures in the recombinant Escherichia coli transcriptional factor SoxR., Chemistry, 2012 Feb 27

 [32] Fujikawa M, Kobayashi K, Tsutsui Y, Tanaka T, Kozawa T, 2017, Rational Tuning of Superoxide Sensitivity in SoxR, the [2Fe-2S] Transcription Factor: Implications of Species-Specific Lysine Residues., Biochemistry, 2017 Jan 17

 [33] Wu J, Weiss B, 1992, Two-stage induction of the soxRS (superoxide response) regulon of Escherichia coli., J Bacteriol, 1992 Jun

 [34] Nunoshiba T., Hidalgo E., Li Z., Demple B., 1993, Negative autoregulation by the Escherichia coli SoxS protein: a dampening mechanism for the soxRS redox stress response., J Bacteriol 175(22):7492-4

 [35] Michán C, Manchado M, Pueyo C, 2002, SoxRS down-regulation of rob transcription., J Bacteriol, 2002 Sep

 [36] Pomposiello PJ., Koutsolioutsou A., Carrasco D., Demple B., 2003, SoxRS-regulated expression and genetic analysis of the yggX gene of Escherichia coli., J Bacteriol 185(22):6624-32

 [37] Griffith KL, Shah IM, Wolf RE Jr, 2004, Proteolytic degradation of Escherichia coli transcription activators SoxS and MarA as the mechanism for reversing the induction of the superoxide (SoxRS) and multiple antibiotic resistance (Mar) regulons., Mol Microbiol, 2004 Mar

 [38] Giro M., Carrillo N., Krapp AR., 2006, Glucose-6-phosphate dehydrogenase and ferredoxin-NADP(H) reductase contribute to damage repair during the soxRS response of Escherichia coli., Microbiology 152(Pt 4):1119-28

 [39] Touati D, 2000, Sensing and protecting against superoxide stress in Escherichia coli--how many ways are there to trigger soxRS response?, Redox Rep, 2000

 [40] Sakamoto A, Terui Y, Yoshida T, Yamamoto T, Suzuki H, Yamamoto K, Ishihama A, Igarashi K, Kashiwagi K, 2015, Three members of polyamine modulon under oxidative stress conditions: two transcription factors (SoxR and EmrR) and a glutathione synthetic enzyme (GshA)., PLoS One, 2015

 [41] Thomas M, Benov L, 2018, The Contribution of Superoxide Radical to Cadmium Toxicity in E. coli., Biol Trace Elem Res, 2018 Feb

 [42] Wang A, Crowley DE, 2005, Global gene expression responses to cadmium toxicity in Escherichia coli., J Bacteriol, 2005 May

 [43] Watanabe S, Kita A, Kobayashi K, Miki K, 2008, Crystal structure of the [2Fe-2S] oxidative-stress sensor SoxR bound to DNA., Proc Natl Acad Sci U S A, 2008 Mar 18

 [44] Kobayashi K, 2017, Sensing Mechanisms in the Redox-Regulated, [2Fe-2S] Cluster-Containing, Bacterial Transcriptional Factor SoxR., Acc Chem Res, 2017 Jul 18

 [45] Volkert MR, Landini P, 2001, Transcriptional responses to DNA damage., Curr Opin Microbiol, 2001 Apr

 [46] Spiro S, 2006, Nitric oxide-sensing mechanisms in Escherichia coli., Biochem Soc Trans, 2006 Feb

 [47] Lushchak VI, 2008, [Redox-sensors of microorganisms]., Ukr Biokhim Zh (1999), 2008 Jul-Aug

 [48] Demple B, Hidalgo E, Ding H, 1999, Transcriptional regulation via redox-sensitive iron-sulphur centres in an oxidative stress response., Biochem Soc Symp, 1999

 [49] Zheng M, Storz G, 2000, Redox sensing by prokaryotic transcription factors., Biochem Pharmacol, 2000 Jan 1

 [50] Kiley PJ, Beinert H, 2003, The role of Fe-S proteins in sensing and regulation in bacteria., Curr Opin Microbiol, 2003 Apr

 [51] Deng M, Zhu H, Guo J, 2010, [Structure, mechanism and roles of the transcription factor SoxR in bacteria--a review]., Wei Sheng Wu Xue Bao, 2010 Dec

 [52] Chiang SM, Schellhorn HE, 2012, Regulators of oxidative stress response genes in Escherichia coli and their functional conservation in bacteria., Arch Biochem Biophys, 2012 Sep 15

 [53] Kobayashi K, Fujikawa M, Kozawa T, 2014, Oxidative stress sensing by the iron-sulfur cluster in the transcription factor, SoxR., J Inorg Biochem, 2014 Apr



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