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MarA DNA-binding transcriptional dual regulator

Synonyms: MarA
Summary:
MarA, "multiple antibiotic resistance" [1] participates in controlling several genes involved in resistance to antibiotics, oxidative stress [] organic solvents [] and heavy metals [] MarA, SoxS, and Rob are paralogous transcriptional regulators that show 45% amino acid identity between them [1] the crystal structures for Rob [14]and MarA []confirm this similarity between them. They activate a common set of genes, but the expression and activity of each one of these proteins are induced by different signals: the activity of Rob is increased with dipyridyl, bile salts, or decanoate [24], and the transcription of MarA and SoxS is increased by the aromatic weak acid salicylate []and oxidative stress [] respectively. Many genes are regulated by all three proteins; however, some genes are regulated only by one of them.
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Transcription factor      
TF conformation(s):
Name Conformation Type TF-Effector Interaction Type Apo/Holo Conformation Evidence (Confirmed, Strong, Weak) References
MarA Functional   [IE] [1], [2], [3]
Evolutionary Family: AraC/XylS
Connectivity class: Local Regulator
Gene name: marA
  Genome position: 1619574-1619957
  Length: 384 bp / 127 aa
Operon name: marRAB
TU(s) encoding the TF:
Transcription unit        Promoter
marRAB
marRp


Regulon       
Regulated gene(s) acnA, acrA, acrB, acrZ, aldA, dctR, decR, fpr, fumC, hdeA, hdeB, inaA, marA, marB, marR, micF, mlaB, mlaC, mlaD, mlaE, mlaF, nfo, nfsA, nfsB, poxB, pqiA, pqiB, pqiC, purA, putA, rimK, rob, slp, sodA, tolC, waaY, waaZ, xseA, ybjC, ybjN, ygiA, ygiB, ygiC, yhiD, yncE, zwf
Multifun term(s) of regulated gene(s) MultiFun Term (List of genes associated to the multifun term)
membrane (9)
drug resistance/sensitivity (7)
transport (6)
Transcription related (5)
pH (4)
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Regulated operon(s) acnA, acrAB, acrZ, aldA, decR, fpr, fumAC, hcp-hcr-poxB-ltaE-ybjT, hdeAB-yhiD, inaA, marRAB, micF, mlaFEDCB, nfo, nfsB, pqiABC, purA, putA, rirA-waaQGPSBOJYZU, rob, slp-dctR, sodA, tolC-ygiABC, xseA, ybjC-nfsA-rimK-ybjN, yncE, zwf
First gene in the operon(s) acnA, acrA, acrZ, aldA, decR, fpr, fumC, hdeA, inaA, marR, micF, mlaF, nfo, nfsB, poxB, pqiA, purA, putA, rob, slp, sodA, tolC, tolC, waaY, xseA, ybjC, yncE, zwf
Simple and complex regulons AcrR,CRP,CpxR,Cra,Fis,MarA,MarR,Rob,SoxS
AcrR,EnvR,MarA,MprA,PhoP,Rob,SoxS
AcrR,H-NS,HU,IHF,Lrp,MarA,OmpR,Rob,SoxS
ArcA,CRP,Cra,FNR,MarA,Rob,SoxS
ArcA,CRP,DnaA,FNR,MarA,Rob,SoxS
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Simple and complex regulatory phrases Regulatory phrase (List of promoters regulated by the phrase)
[MarA,-](4)
[MarA,+](23)


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 Growth Conditions Evidence (Confirmed, Strong, Weak) References
  MarA activator acnAp2 Sigma70 -51.5 -101.0 acnA
aaggtttctcCTCTTTTATCAATTTGGGTTgttatcaaat
1335720 1335740 nd [BPP], [GEA], [HIBSCS] [4], [5]
  MarA activator acrAp Sigma70 -72.5 -151.5 acrA, acrB
tcacgaacatATGGCACGAAAAACCAAACAagaagcgcaa
485761 485780 nd [AIBSCS], [BPP], [GEA], [HIBSCS] [5], [6], [7]
  MarA activator acrZp Sigma70 -40.5 -62.5 acrZ
cgcaaagctgACCGCACAAAAGGGGAGTGCttttctgtgc
794701 794720 nd [GEA], [IHBCE] [8]
  MarA activator aldAp Sigma70 -161.0 -203.5 aldA
gcgatggaaaGTCGCTCGTTACGTTAAAAAttgcccgttt
1488019 1488038 nd [AIBSCS], [GEA] [4]
  MarA activator fprp Sigma70 -58.5 -85.5 fpr
aaggactggaAGGCTCAATCGATCAAATCAatcagaggat
4114548 4114567 nd [AIBSCS], [BPP], [GEA], [HIBSCS] [5], [7], [9]
  MarA activator fumCp Sigma38 -46.5 -167.5 fumC
tcacacagcgGGTGCATTGTGTGAGTTGTAtctgctggaa
1686746 1686765 nd [BPP], [GEA] [9], [10]
  MarA repressor hdeAp Sigma38, Sigma70, Sigma70, Sigma38 -39.0 -89.5 hdeA, hdeB, yhiD
ttttctgtatATGTCATGTTGATGGAAAATatcaaaatca
3656820 3656839 nd [APPH], [GEA], [HIBSCS], [SM] [11]
  MarA activator inaAp Sigma70 -41.5 -68.5 inaA
cctgaggaaaATCTTAATGAAACGTGTCGTattaatgaat
2349531 2349550 nd [BPP], [GEA], [HIBSCS] [5], [6], [10]
  MarA activator marRp Sigma70 -61.5 -88.5 marR, marA, marB
acttgaaccgATTTAGCAAAACGTGGCATCggtcaattca
1619022 1619041 nd [AIBSCS], [BPP], [GEA], [HIBSCS] [5], [6], [7], [9], [10], [12]
  MarA activator micFp Sigma70 -40.0 -40.5 micF
aagtatttgaCAGCACTGAATGTCAAAACAaaaccttcac
2313034 2313053 nd [AIBSCS], [BPP], [GEA], [HIBSCS] [7], [9], [13], [14]
  MarA activator mlaFp2 nd -41.5 -97.5 mlaF, mlaE, mlaD, mlaC, mlaB
acccgccgtgGTTAGCGAAAGCTGGcatttgtttt
3340155 3340170 nd [BPP], [GEA], [ICWHO] [15]
  MarA activator nfop Sigma70 -38.5 -72.5 nfo
tcaaagcgtcATCGCATAAACCACTACATCttgctcctgt
2250758 2250777 nd [AIBSCS], [GEA], [HIBSCS] [3], [6], [7]
  MarA activator nfsBp Sigma70 -43.5 -73.0 nfsB
gagaaatggtAAGCGAGAAAAATGCGCTATagatttccgc
605487 605507 nd [BPP], [GEA], [HIBSCS] [4], [16]
  MarA activator poxBp Sigma38, Sigma70 -60.5 -87.5 poxB
ggagagaaagGAGGCACTAACGGTTAAATAgcccgatgaa
911127 911146 nd [GEA], [HIBSCS] [6]
  MarA activator pqiAp1 Sigma70, Sigma38 -42.5 -377.5 pqiA, pqiB, pqiC
cgccgcggcaAAAGCAGAAACTGTAAAACGcagcagtagc
1011614 1011633 nd [BPP], [GEA], [HIBSCS] [5], [6]
  MarA repressor purAp Sigma70 -43.0 -66.5 purA
cgaggtcattTTTGAGTGCAAAAAGTGCTGtaactctgaa
4404611 4404630 nd [BPP], [GEA], [HIBSCS], [SM] [11]
  MarA activator putAp Sigma70 nd 1078882.0 putA nd nd nd [GEA] [10]
  MarA repressor robp nd -20.0 -62.5 rob
taattggataATAGCATTTTTTGCTGTTTTagcattcagt
4635363 4635382 nd [BPP], [GEA], [HIBSCS], [SM] [17]
  MarA repressor slpp Sigma70 39.0 12.5 slp, dctR
tagtaacatgAACATGACAAAAGGTGCACTcatcctcagc
3653964 3653983 nd [GEA], [HIBSCS] [18], [19]
  MarA activator sodAp Sigma70 -40.5 -91.5 sodA
tacgaaaagtACGGCATTGATAATCATTTTcaatatcatt
4100709 4100728 nd [BPP], [HIBSCS] [3], [5], [6]
  MarA activator tolCp3 nd -40.5 -93.0 tolC, ygiA, ygiB, ygiC
ttaacgccctATGGCACGTAACGCCAACCTtttgcggtag
3178012 3178032 [a] [AIBSCS], [GEA] [7], [20], [21]
  MarA activator tolCp4 Sigma38 -52.5 -93.0 tolC, ygiA, ygiB, ygiC
ttaacgccctATGGCACGTAACGCCAACCTtttgcggtag
3178012 3178032 [a] [AIBSCS], [GEA] [7], [20], [21]
  MarA activator waaYp Sigma70 -43.0 -213.5 waaY, waaZ
ccgatggataAATTGCCCATTTGTGCCACGgtttagttgc
3801169 3801188 nd [GEA], [HIBSCS] [22]
  MarA activator xseAp Sigma70 -42.0 -76.5 xseA
atctacccctTTTTGCAAAAAATGCttgctatccc
2634148 2634163 nd [BPP], [GEA], [ICWHO] [15]
  MarA activator ybaOp Sigma70 -65.0 -96.5 decR
tttttgcgttGAATTTGTCATTTTGTGCCGtggtgtttaa
468277 468296 nd [AIBSCS] [7]
  MarA activator ybjCp Sigma70 -40.5 -61.5 ybjC, nfsA, rimK, ybjN
ttaattgctaAAAGCTATAACTGTTAAACAcaatacagtg
890842 890861 nd [BPP], [GEA], [HIBSCS] [4], [5]
  MarA activator yncEp nd -41.5 -121.0 yncE
tgtagtcgtaACGGCAAGAAATGCTCCACAtttgagaaaa
1523176 1523196 nd [GEA], [HIBSCS] [4]
  MarA activator zwfp Sigma70 -54.0 -115.5 zwf
actgtaaacgCTTATCCACCCGTGCGATTAcgggaaaagc
1936420 1936439 nd [BPP], [GEA], [HIBSCS] [3], [5], [6], [9], [23]



High-throughput Transcription factor binding sites (TFBSs)
      

  Functional conformation Function Object name Object type Distance to first Gene Sequence LeftPos RightPos Evidence (Confirmed, Strong, Weak) References
  MarA activator yhbW nd nd 3303372 3303391 [ICWHO] nd
  MarA activator map-glnD-dapD nd nd 189597 189616 [ICWHO] nd
  MarA activator mdaB nd nd 3172452 3172471 [ICWHO] nd


Growth Condition    

 [a] Salicylate treatment



Alignment and PSSM for MarA TFBSs    

Position weight matrix (PWM).   
A	10	4	5	0	9	8	0	12	7	4	4	5	2	3	0	2	0	7	1
C	2	2	1	0	3	2	18	6	0	1	3	6	1	1	1	17	10	1	2
G	6	4	3	5	8	9	0	3	5	1	1	0	16	1	20	2	6	10	0
T	5	13	14	18	3	4	5	2	11	17	15	12	4	18	2	2	7	5	20

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    

 [IE] Inferred from experiment

 [BPP] Binding of purified proteins

 [GEA] Gene expression analysis

 [HIBSCS] Human inference based on similarity to consensus sequences

 [AIBSCS] Automated inference based on similarity to consensus sequences

 [IHBCE] Inferred by a human based on computational evidence

 [APPH] Assay of protein purified to homogeneity

 [SM] Site mutation

 [ICWHO] Inferred computationally without human oversight



Reference(s)    

 [1] Cohen SP., Hachler H., Levy SB., 1993, Genetic and functional analysis of the multiple antibiotic resistance (mar) locus in Escherichia coli., J Bacteriol 175(5):1484-92

 [2] Gambino L., Gracheck SJ., Miller PF., 1993, Overexpression of the MarA positive regulator is sufficient to confer multiple antibiotic resistance in Escherichia coli., J Bacteriol 175(10):2888-94

 [3] Jair KW., Martin RG., Rosner JL., Fujita N., Ishihama A., Wolf RE., 1995, Purification and regulatory properties of MarA protein, a transcriptional activator of Escherichia coli multiple antibiotic and superoxide resistance promoters., J Bacteriol 177(24):7100-4

 [4] Martin RG., Rosner JL., 2002, Genomics of the marA/soxS/rob regulon of Escherichia coli: identification of directly activated promoters by application of molecular genetics and informatics to microarray data., Mol Microbiol 44(6):1611-24

 [5] Martin RG., Rosner JL., 2011, Promoter discrimination at class I MarA regulon promoters mediated by glutamic acid 89 of the MarA transcriptional activator of Escherichia coli., J Bacteriol 193(2):506-15

 [6] Martin RG., Gillette WK., Rhee S., Rosner JL., 1999, Structural requirements for marbox function in transcriptional activation of mar/sox/rob regulon promoters in Escherichia coli: sequence, orientation and spatial relationship to the core promoter., Mol Microbiol 34(3):431-41

 [7] Rodionov DA., Gelfand MS., Mironov AA., Rakhmaninova AB., 2001, Comparative approach to analysis of regulation in complete genomes: multidrug resistance systems in gamma-proteobacteria., J Mol Microbiol Biotechnol 3(2):319-24

 [8] Hobbs EC., Yin X., Paul BJ., Astarita JL., Storz G., 2012, Conserved small protein associates with the multidrug efflux pump AcrB and differentially affects antibiotic resistance., Proc Natl Acad Sci U S A 109(41):16696-701

 [9] Gillette WK., Martin RG., Rosner JL., 2000, Probing the Escherichia coli transcriptional activator MarA using alanine-scanning mutagenesis: residues important for DNA binding and activation., J Mol Biol 299(5):1245-55

 [10] Pomposiello PJ., Bennik MH., Demple B., 2001, Genome-wide transcriptional profiling of the Escherichia coli responses to superoxide stress and sodium salicylate., J Bacteriol 183(13):3890-902

 [11] Schneiders T., Barbosa TM., McMurry LM., Levy SB., 2004, The Escherichia coli transcriptional regulator MarA directly represses transcription of purA and hdeA., J Biol Chem 279(10):9037-42

 [12] Martin RG., Jair KW., Wolf RE., Rosner JL., 1996, Autoactivation of the marRAB multiple antibiotic resistance operon by the MarA transcriptional activator in Escherichia coli., J Bacteriol 178(8):2216-23

 [13] Delihas N., Forst S., 2001, MicF: an antisense RNA gene involved in response of Escherichia coli to global stress factors., J Mol Biol 313(1):1-12

 [14] Kwon HJ., Bennik MH., Demple B., Ellenberger T., 2000, Crystal structure of the Escherichia coli Rob transcription factor in complex with DNA., Nat Struct Biol 7(5):424-30

 [15] Sharma P., Haycocks JRJ., Middlemiss AD., Kettles RA., Sellars LE., Ricci V., Piddock LJV., Grainger DC., 2017, The multiple antibiotic resistance operon of enteric bacteria controls DNA repair and outer membrane integrity., Nat Commun 8(1):1444

 [16] Barbosa TM., Levy SB., 2002, Activation of the Escherichia coli nfnB gene by MarA through a highly divergent marbox in a class II promoter., Mol Microbiol 45(1):191-202

 [17] Schneiders T., Levy SB., 2006, MarA mediated transcriptional repression of the rob promoter., J Biol Chem 281(15):10049-51

 [18] Price GP., St John AC., 2000, Purification and analysis of expression of the stationary phase-inducible slp lipoprotein in Escherichia coli: role of the Mar system., FEMS Microbiol Lett 193(1):51-6

 [19] Seoane AS., Levy SB., 1995, Identification of new genes regulated by the marRAB operon in Escherichia coli., J Bacteriol 177(3):530-5

 [20] Aono R., Tsukagoshi N., Yamamoto M., 1998, Involvement of outer membrane protein TolC, a possible member of the mar-sox regulon, in maintenance and improvement of organic solvent tolerance of Escherichia coli K-12., J Bacteriol 180(4):938-44

 [21] Zhang A., Rosner JL., Martin RG., 2008, Transcriptional activation by MarA, SoxS and Rob of two tolC promoters using one binding site: a complex promoter configuration for tolC in Escherichia coli., Mol Microbiol 69(6):1450-5

 [22] Lee JH., Lee KL., Yeo WS., Park SJ., Roe JH., 2009, SoxRS-mediated lipopolysaccharide modification enhances resistance against multiple drugs in Escherichia coli., J Bacteriol 191(13):4441-50

 [23] Jair KW., Yu X., Skarstad K., Thony B., Fujita N., Ishihama A., Wolf RE., 1996, Transcriptional activation of promoters of the superoxide and multiple antibiotic resistance regulons by Rob, a binding protein of the Escherichia coli origin of chromosomal replication., J Bacteriol 178(9):2507-13

 [24] Rosenberg EY., Bertenthal D., Nilles ML., Bertrand KP., Nikaido H., 2003, Bile salts and fatty acids induce the expression of Escherichia coli AcrAB multidrug efflux pump through their interaction with Rob regulatory protein., Mol Microbiol 48(6):1609-19

 [25] 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

 [26] Wood TI., Griffith KL., Fawcett WP., Jair KW., Schneider TD., Wolf RE., 1999, Interdependence of the position and orientation of SoxS binding sites in the transcriptional activation of the class I subset of Escherichia coli superoxide-inducible promoters., Mol Microbiol 34(3):414-30

 [27] Dangi B., Pelupessey P., Martin RG., Rosner JL., Louis JM., Gronenborn AM., 2001, Structure and dynamics of MarA-DNA complexes: an NMR investigation., J Mol Biol 314(1):113-27

 [28] Griffith KL., Wolf RE., 2001, Systematic mutagenesis of the DNA binding sites for SoxS in the Escherichia coli zwf and fpr promoters: identifying nucleotides required for DNA binding and transcription activation., Mol Microbiol 40(5):1141-54

 [29] Gallegos MT., Schleif R., Bairoch A., Hofmann K., Ramos JL., 1997, Arac/XylS family of transcriptional regulators., Microbiol Mol Biol Rev 61(4):393-410

 [30] Griffith KL., Wolf RE., 2002, A comprehensive alanine scanning mutagenesis of the Escherichia coli transcriptional activator SoxS: identifying amino acids important for DNA binding and transcription activation., J Mol Biol 322(2):237-57



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