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MarA DNA-binding transcriptional dual regulator

Synonyms: MarA
Summary:
MarA, multiple antibiotic resistance [21] participates in controlling several genes involved in resistance to antibiotics, oxidative stress [22] organic solvents [22, 23, 24] and heavy metals [22]
MarA, SoxS, and Rob are paralogous transcriptional regulators that show 45% amino acid identity between them [21] the crystal structures for Rob [11]and MarA [25]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 [26, 27], and the transcription of MarA and SoxS is increased by the aromatic weak acid salicylate [28]and oxidative stress [29] 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     nd nd
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, dctR, decR, fpr, fumC, hdeA, hdeB, inaA, marA, marB, marR, micF, nfo, nfsA, nfsB, poxB, pqiA, pqiB, purA, putA, rimK, rob, slp, sodA, tolC, waaY, waaZ, 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)
drug resistance/sensitivity (7)
Transcription related (5)
pH (4)
repressor (4)
detoxification (4)
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Regulated operon(s) acnA, acrAB, acrZ, decR, fpr, fumAC, hdeAB-yhiD, inaA, marRAB, micF, nfo, nfsB, poxB-ltaE-ybjT, pqiAB, purA, putA, rob, slp-dctR, sodA, tolC-ygiABC, waaQGPSBOJYZU, ybjC-nfsA-rimK-ybjN, yncE, zwf
First gene in the operon(s) acnA, acrA, acrZ, decR, fpr, fumC, hdeA, inaA, marR, micF, nfo, nfsB, poxB, pqiA, purA, putA, rob, slp, sodA, tolC, tolC, waaY, 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,FNR,Fur,IHF,MarA,Rob,SoxS
Read more >
Simple and complex regulatory phrases Regulatory phrase (List of promoters regulated by the phrase)
[MarA,-](4)
[MarA,+](20)


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
  MarA activator acnAp2 Sigma70 -51.5 -101.5 acnA
aaggtttctcCTCTTTTATCAATTTGGGTTgttatcaaat
1335720 1335739 [BPP], [GEA], [HIBSCS] [1], [2]
  MarA activator acrAp Sigma70 -72.5 -151.5 acrA, acrB
ttgcgcttctTGTTTGGTTTTTCGTGCCATatgttcgtga
485761 485780 [AIBSCS], [BPP], [GEA], [HIBSCS] [2], [3], [4]
  MarA activator acrZp Sigma70 -40.5 -62.5 acrZ
cgcaaagctgACCGCACAAAAGGGGAGTGCttttctgtgc
794701 794720 [GEA], [IHBCE] [5]
  MarA activator fprp Sigma70 -58.5 -85.5 fpr
atcctctgatTGATTTGATCGATTGAGCCTtccagtcctt
4114548 4114567 [AIBSCS], [BPP], [GEA], [HIBSCS] [2], [4], [6]
  MarA activator fumCp Sigma38 -46.5 -167.5 fumC
ttccagcagaTACAACTCACACAATGCACCcgctgtgtga
1686746 1686765 [BPP], [GEA] [6], [7]
  MarA repressor hdeAp Sigma38 -39.0 -89.5 hdeA, hdeB, yhiD
tgattttgatATTTTCCATCAACATGACATatacagaaaa
3656820 3656839 [APPH], [GEA], [HIBSCS], [SM] [8]
  MarA activator inaAp Sigma70 -41.5 -68.5 inaA
attcattaatACGACACGTTTCATTAAGATtttcctcagg
2349531 2349550 [BPP], [GEA], [HIBSCS] [2], [3], [7]
  MarA activator marRp Sigma70 -61.5 -88.5 marR, marA, marB
acttgaaccgATTTAGCAAAACGTGGCATCggtcaattca
1619022 1619041 [AIBSCS], [BPP], [GEA], [HIBSCS] [2], [3], [4], [6], [7], [9]
  MarA activator micFp Sigma70 -40.0 -40.5 micF
aagtatttgaCAGCACTGAATGTCAAAACAaaaccttcac
2313034 2313053 [AIBSCS], [BPP], [GEA], [HIBSCS] [4], [6], [10], [11]
  MarA activator nfop Sigma70 -38.5 -72.5 nfo
tcaaagcgtcATCGCATAAACCACTACATCttgctcctgt
2250758 2250777 [AIBSCS], [GEA], [HIBSCS] [3], [4], [12]
  MarA activator nfsBp Sigma70 -43.5 -72.5 nfsB
gcggaaatctATAGCGCATTTTTCTCGCTTaccatttctc
605487 605506 [BPP], [GEA], [HIBSCS] [1], [13]
  MarA activator poxBp Sigma38 -60.5 -87.5 poxB
ttcatcgggcTATTTAACCGTTAGTGCCTCctttctctcc
911127 911146 [GEA], [HIBSCS] [3]
  MarA activator pqiAp1 Sigma70 -42.5 -377.5 pqiA, pqiB
cgccgcggcaAAAGCAGAAACTGTAAAACGcagcagtagc
1011614 1011633 [BPP], [GEA], [HIBSCS] [2], [3]
  MarA repressor purAp Sigma70 -43.0 -66.5 purA
cgaggtcattTTTGAGTGCAAAAAGTGCTGtaactctgaa
4404611 4404630 [BPP], [GEA], [HIBSCS], [SM] [8]
  MarA activator putAp Sigma70 nd nd putA nd nd [GEA] [7]
  MarA activator rfaYp Sigma70 -43.0 -213.5 waaY, waaZ
gcaactaaacCGTGGCACAAATGGGCAATTtatccatcgg
3801169 3801188 [GEA], [HIBSCS] [14]
  MarA repressor robp nd -20.0 -62.5 rob
actgaatgctAAAACAGCAAAAAATGCTATtatccaatta
4635363 4635382 [BPP], [GEA], [HIBSCS], [SM] [15]
  MarA repressor slpp Sigma70 39.0 12.5 slp, dctR
tagtaacatgAACATGACAAAAGGTGCACTcatcctcagc
3653964 3653983 [GEA], [HIBSCS] [16], [17]
  MarA activator sodAp Sigma70 -40.5 -91.5 sodA
tacgaaaagtACGGCATTGATAATCATTTTcaatatcatt
4100709 4100728 [BPP], [HIBSCS] [2], [3], [12]
  MarA activator tolCp3 nd -40.5 -93.5 tolC, ygiA, ygiB, ygiC
ttaacgccctATGGCACGTAACGCCAACCTtttgcggtag
3178012 3178031 [AIBSCS], [GEA] [4], [18], [19]
  MarA activator tolCp4 Sigma38 -52.5 -93.5 tolC, ygiA, ygiB, ygiC
ttaacgccctATGGCACGTAACGCCAACCTtttgcggtag
3178012 3178031 [AIBSCS], [GEA] [4], [18], [19]
  MarA activator ybaOp Sigma70 -65.0 -96.5 decR
tttttgcgttGAATTTGTCATTTTGTGCCGtggtgtttaa
468277 468296 [AIBSCS] [4]
  MarA activator ybjCp Sigma70 -40.5 -61.5 ybjC, nfsA, rimK, ybjN
ttaattgctaAAAGCTATAACTGTTAAACAcaatacagtg
890842 890861 [BPP], [GEA], [HIBSCS] [1], [2]
  MarA activator yncEp nd -41.5 -121.5 yncE
tgtagtcgtaACGGCAAGAAATGCTCCACAtttgagaaaa
1523176 1523195 [GEA], [HIBSCS] [1]
  MarA activator zwfp Sigma70 -54.0 -115.5 zwf
gcttttcccgTAATCGCACGGGTGGATAAGcgtttacagt
1936420 1936439 [BPP], [GEA], [HIBSCS] [2], [3], [6], [12], [20]


Alignment and PSSM for MarA TFBSs    

Aligned TFBS of MarA   
  Sequence
 

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    

 [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



Reference(s)    

 [1] 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

 [2] 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

 [3] 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

 [4] 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

 [5] 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

 [6] 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

 [7] 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

 [8] 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

 [9] 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

 [10] 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

 [11] 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

 [12] 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

 [13] 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

 [14] 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

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

 [16] 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

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

 [18] 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

 [19] 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

 [20] 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

 [21] 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

 [22] Alekshun MN., Levy SB., 1999, The mar regulon: multiple resistance to antibiotics and other toxic chemicals., Trends Microbiol. 7(10):410-3

 [23] White DG., Goldman JD., Demple B., Levy SB., 1997, Role of the acrAB locus in organic solvent tolerance mediated by expression of marA, soxS, or robA in Escherichia coli., J Bacteriol. 179(19):6122-6

 [24] Asako H., Nakajima H., Kobayashi K., Kobayashi M., Aono R., 1997, Organic solvent tolerance and antibiotic resistance increased by overexpression of marA in Escherichia coli., Appl Environ Microbiol. 63(4):1428-33

 [25] Rhee S., Martin RG., Rosner JL., Davies DR., 1998, A novel DNA-binding motif in MarA: the first structure for an AraC family transcriptional activator., Proc Natl Acad Sci U S A. 95(18):10413-8

 [26] Rosner JL., Dangi B., Gronenborn AM., Martin RG., 2002, Posttranscriptional activation of the transcriptional activator Rob by dipyridyl in Escherichia coli., J Bacteriol. 184(5):1407-16

 [27] 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

 [28] Martin RG., Gillette WK., Martin NI., Rosner JL., 2002, Complex formation between activator and RNA polymerase as the basis for transcriptional activation by MarA and SoxS in Escherichia coli., Mol Microbiol. 43(2):355-70

 [29] Demple B., 1996, Redox signaling and gene control in the Escherichia coli soxRS oxidative stress regulon--a review., Gene. 179(1):53-7

 [30] 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

 [31] 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

 [32] Martin RG., Bartlett ES., Rosner JL., Wall ME., 2008, Activation of the Escherichia coli marA/soxS/rob regulon in response to transcriptional activator concentration., J Mol Biol. 380(2):278-84

 [33] Wall ME., Markowitz DA., Rosner JL., Martin RG., 2009, Model of transcriptional activation by MarA in Escherichia coli., PLoS Comput Biol. 5(12):e1000614

 [34] 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

 [35] 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

 [36] Griffith KL., Shah IM., Myers TE., O'Neill MC., Wolf RE., 2002, Evidence for pre-recruitment as a new mechanism of transcription activation in Escherichia coli: the large excess of SoxS binding sites per cell relative to the number of SoxS molecules per cell., Biochem Biophys Res Commun. 291(4):979-86

 [37] 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

 [38] 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

 [39] Koulechova DA., Tripp KW., Horner G., Marqusee S., 2015, When the Scaffold Cannot Be Ignored: The Role of the Hydrophobic Core in Ligand Binding and Specificity., J Mol Biol. 427(20):3316-26

 [40] Griffith KL., Shah IM., Wolf RE., 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. 51(6):1801-16

 [41] Shah IM., Wolf RE., 2006, Inhibition of Lon-dependent degradation of the Escherichia coli transcription activator SoxS by interaction with 'soxbox' DNA or RNA polymerase., Mol Microbiol. 60(1):199-208

 [42] Bhaskarla C., Das M., Verma T., Kumar A., Mahadevan S., Nandi D., 2016, Roles of Lon protease and its substrate MarA during sodium salicylate-mediated growth reduction and antibiotic resistance in Escherichia coli., Microbiology

 [43] Shultzaberger RK., Maerkl SJ., Kirsch JF., Eisen MB., 2012, Probing the informational and regulatory plasticity of a transcription factor DNA-binding domain., PLoS Genet. 8(3):e1002614

 [44] Randall LP., Woodward MJ., 2002, The multiple antibiotic resistance (mar) locus and its significance., Res Vet Sci. 72(2):87-93



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