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Escherichia coli K-12 substr. MG1655 Protein: MarR-salicylate



Gene: marR Accession Numbers: EG11435 (EcoCyc), b1530, ECK1523

Synonyms: cfxB, inaR, soxQ

Regulation Summary Diagram: ?

Subunit composition of MarR-salicylate = [MarR][salicylate]
         MarR transcriptional repressor = MarR (extended summary available)

Summary:

Gene Citations: [Cohen93, Seoane95]

Map Position: [1,617,144 -> 1,617,578] (34.85 centisomes)
Length: 435 bp / 144 aa

Molecular Weight: 13.898 kD (from nucleotide sequence)

Unification Links: ASAP:ABE-0005110 , CGSC:30935 , EchoBASE:EB1405 , EcoGene:EG11435 , OU-Microarray:b1530 , PortEco:marR , RegulonDB:EG11435

Relationship Links: PDB:Structure:1JGS , Pfam:IN-FAMILY:PF01047

In Paralogous Gene Group: 323 (2 members)

In Reactions of unknown directionality:

Not in pathways:
MarR + salicylate = MarR-salicylate

Gene-Reaction Schematic: ?

Genetic Regulation Schematic: ?

MultiFun Terms: cell processes protection drug resistance/sensitivity
information transfer RNA related Transcription related
regulation genetic unit regulated operon
regulation type of regulation transcriptional level repressor


Subunit of MarR-salicylate: MarR transcriptional repressor

Synonyms: SoxQ, InaR, CfxB, MarR

Gene: marR Accession Numbers: EG11435 (EcoCyc), b1530, ECK1523

Locations: cytosol

Sequence Length: 144 AAs

Molecular Weight: 16.065 kD (from nucleotide sequence)

pI: 8.25

GO Terms:

Biological Process: GO:0009408 - response to heat Inferred from experiment [Krisko14]
GO:0045892 - negative regulation of transcription, DNA-templated Inferred from experiment [Cohen93]
GO:0071236 - cellular response to antibiotic Inferred from experiment [Cohen93]
GO:0006351 - transcription, DNA-templated Inferred by computational analysis [UniProtGOA11]
GO:0006355 - regulation of transcription, DNA-templated Inferred by computational analysis [UniProtGOA11, GOA01]
GO:0046677 - response to antibiotic Inferred by computational analysis [UniProtGOA11]
Molecular Function: GO:0003677 - DNA binding Inferred from experiment Inferred by computational analysis [UniProtGOA11, Martin95]
GO:0005515 - protein binding Inferred from experiment [Domain09]
GO:0003700 - sequence-specific DNA binding transcription factor activity Inferred by computational analysis [GOA01]
Cellular Component: GO:0005622 - intracellular Inferred by computational analysis [GOA01]
GO:0005829 - cytosol Inferred by computational analysis [DiazMejia09]

MultiFun Terms: cell processes protection drug resistance/sensitivity
information transfer RNA related Transcription related
regulation genetic unit regulated operon
regulation type of regulation transcriptional level repressor

Unification Links: DIP:DIP-10164N , EcoliWiki:b1530 , ModBase:P27245 , PR:PRO_000023167 , Protein Model Portal:P27245 , RefSeq:NP_416047 , SMR:P27245 , String:511145.b1530 , UniProt:P27245

Relationship Links: InterPro:IN-FAMILY:IPR000835 , InterPro:IN-FAMILY:IPR011991 , InterPro:IN-FAMILY:IPR023187 , PDB:Structure:1JGS , PDB:Structure:3VB2 , PDB:Structure:3VOD , PDB:Structure:3VOE , Pfam:IN-FAMILY:PF01047 , Prints:IN-FAMILY:PR00598 , Prosite:IN-FAMILY:PS01117 , Prosite:IN-FAMILY:PS50995 , Smart:IN-FAMILY:SM00347

In Reactions of unknown directionality:

Not in pathways:
MarR + salicylate = MarR-salicylate

Summary:
MarA, "Multiple antibiotic resistance" [Cohen93], participates in controlling several genes involved in resistance to antibiotics, multidrug efflux [Ruiz10, Warner10, Keeney08], oxidative stress [Alekshun99], organic solvents [White97], and heavy metals [Alekshun99].

MarR is part of the marRAB operon and negatively autoregulates its own expression [Alekshun97]. The marA gene encodes a transcriptional activator that autoactivates expression of the marRAB operon and that regulates the expression of a global network of at least 80 chromosomal genes [Pomposiello01, Barbosa00, Alekshun97, Alekshun01], as well as expression of the marB gene, whose product has an unknown function [Domain07].

Under laboratory conditions, the marRAB operon can be induced by tetracycline, chloramphenicol, or salicylate [Seoane95, Cohen93a, Hachler91, Sulavik95, Martin95], plumbagin, dinitrophenol, and menadione [Alekshun99a], and other chemicals with phenolic rings [Alekshun99a]. All these compounds attenuate the ability of MarR homodimers to bind their cognate DNA sequences [Wilkinson06]. They also antagonize the effects of MarR repressing activity and induce transcription of marRAB. However, the way in which environmental conditions affect transcriptional expression of the marRAB operon is currently unknown [Domain07]. Cross talk between the mar and rob systems plays an important role in the response to salicylate [Chubiz12]. TktA, "transketolase A," an enzyme of central metabolism, interacts with MarR and reduces MarR repression of marRAB [Domain07]. In addition, subunit A of gyrase, GyrA, interacts with MarR and interferes with the binding of MarR to its operator, leading to a decreased repression of the marRAB operon [Domain09].

Based on the crystal structure, it was reported that there are two possible salicylate sites, SAL-A and SAL-B, in MarR [Alekshun01]. However, these are not the physiological regulatory sites [Duval13]. On the other hand, based on mutational analysis of the MarR homologue MTH313 from Methanobacterium thermautotrophicum, residues P57, R86, M74, and R77 were found important for DNA binding; residues R16, D26, and K44 significantly reduced binding to either salicylate or 2,4-dinitrophenol, and residue H19 impaired the binding to 2,4-dinitrophenol. These findings indicate, as with MTH313, the presence of a ligand-binding pocket located between the dimerization and DNA-binding domains [Duval13]. For inactivation of MarR by salicylate, 2-4-dinitrophenol, or plumbagin, most of the residues important for ligand effectiveness lie in the α1 and α2 helices of MarR, between the putative DNA-binding domain and the dimerization domain of MarR [McMurry13].

2,3-Dihydroxybenzoate (DHB), anthranilate, and 4-hydroxybenzoate (in the absence of TolC), which are involved in enterobactin, tryptophan, and ubiquinone biosynthesis, respectively, can activate marRAB transcription. However, only DHB directly binds to MarR, affecting its activity [Chubiz10]. More studies to determine whether DHB is the MarR effector under physiological conditions are needed [Chubiz10].

Based on footprinting experiments and crystal structure analysis, MarR binds as a dimer to two direct repeat elements in the mar operator (marO) [Martin96, Martin95, Alekshun01, Cohen93]. Each dimer subunit consists of six helical regions and a winged helix DNA-binding motif [Alekshun01], organized in such a way that the terminal parts of each monomer contribute to an extensive protein-protein interface in the dimer. Both direct repeat elements are required for full transcriptional repression, but either site alone permits partial repression [Martin04]. N-terminal and central regions of MarR are responsible for the specific interactions with the two binding sites in marO [Alekshun97], and the C-terminal domain is also necessary for proper repressor function [Linde00, Notka02]. Biochemical and crystal structure analyses have demonstrated that the N- and C-terminal regions of MarR contribute to dimer formation [Notka02].

The MarR regulator from Escherichia coli belongs to the MarR family, and it has two helix-turn-helix domains involved mainly in the development of antibiotic resistance [Hulo04, Alekshun00]. The marR-type helix-turn-helix domain is well distributed among eubacteria and archaea, with at least 10 proteins from a variety of bacteria [Alekshun01]. MarR plays an important role in the control of biological functions, including resistance to multiple antibiotics, organic solvents, household disinfectants, and oxidative stress agents. It also regulates synthesis of the virulence factor in pathogens of humans and plants, and it also responds to aromatic compounds [Alekshun01, Alekshun99, Egland99, Wu03]. The DNA-binding domains of MarR adopt a conserved winged helix (or winged helix-turn-helix) fold [Wilkinson06].

Homologs of MarR are found in both bacterial and archaeal domains. The MarR family is one of nine families of transcription factors that evolved before divergence of these domains, over 3 billion years ago [PerezRueda01, PerezRueda04].

The Mar locus in Escherichia coli consists of two divergently transcribed operons, marC and marRAB, which control an adaptation response to antibiotics and other environmental hazards [Alekshun97].

Organic solvent tolerance levels are greatly increased in double mutants of the proV and marR genes [Doukyu12]. An increase of organic solvent tolerances (OSTs) was shown by using the fadR and marR double mutant of those two transcriptional regulators [Oh12].

marR shows differential codon adaptation, resulting in differential translation efficiency signatures, in thermophilic microbes. It was therefore predicted to play a role in the heat shock response. A marR deletion mutant was shown to be more sensitive than wild-type specifically to heat shock, but not other stresses [Krisko14].

Citations: [Ariza94]

Essentiality data for marR knockouts: ?

Growth Medium Growth? T (°C) O2 pH Osm/L Growth Observations
LB enriched Yes 37 Aerobic 6.95   Yes [Gerdes03, Comment 1]
LB Lennox Yes 37 Aerobic 7   Yes [Baba06, Comment 2]
M9 medium with 1% glycerol Yes 37 Aerobic 7.2 0.35 Yes [Joyce06, Comment 3]
MOPS medium with 0.4% glucose Yes 37 Aerobic 7.2 0.22 Yes [Baba06, Comment 2]

Gene Local Context (not to scale): ?

Transcription Unit:

Notes:

History:
Peter D. Karp on Wed Jan 18, 2006:
Gene left-end position adjusted based on analysis performed in the 2005 E. coli annotation update [Riley06 ].
10/20/97 Gene b1530 from Blattner lab Genbank (v. M52) entry merged into EcoCyc gene EG11435; confirmed by SwissProt match.


References

Alekshun00: Alekshun MN, Kim YS, Levy SB (2000). "Mutational analysis of MarR, the negative regulator of marRAB expression in Escherichia coli, suggests the presence of two regions required for DNA binding." Mol Microbiol 35(6);1394-404. PMID: 10760140

Alekshun01: Alekshun MN, Levy SB, Mealy TR, Seaton BA, Head JF (2001). "The crystal structure of MarR, a regulator of multiple antibiotic resistance, at 2.3 A resolution." Nat Struct Biol 8(8);710-4. PMID: 11473263

Alekshun97: Alekshun MN, Levy SB (1997). "Regulation of chromosomally mediated multiple antibiotic resistance: the mar regulon." Antimicrob Agents Chemother 41(10);2067-75. PMID: 9333027

Alekshun99: Alekshun MN, Levy SB (1999). "The mar regulon: multiple resistance to antibiotics and other toxic chemicals." Trends Microbiol 7(10);410-3. PMID: 10498949

Alekshun99a: Alekshun MN, Levy SB (1999). "Alteration of the repressor activity of MarR, the negative regulator of the Escherichia coli marRAB locus, by multiple chemicals in vitro." J Bacteriol 181(15);4669-72. PMID: 10419969

Ariza94: Ariza RR, Cohen SP, Bachhawat N, Levy SB, Demple B (1994). "Repressor mutations in the marRAB operon that activate oxidative stress genes and multiple antibiotic resistance in Escherichia coli." J Bacteriol 1994;176(1);143-8. PMID: 8282690

Baba06: Baba T, Ara T, Hasegawa M, Takai Y, Okumura Y, Baba M, Datsenko KA, Tomita M, Wanner BL, Mori H (2006). "Construction of Escherichia coli K-12 in-frame, single-gene knockout mutants: the Keio collection." Mol Syst Biol 2;2006.0008. PMID: 16738554

Barbosa00: Barbosa TM, Levy SB (2000). "Differential expression of over 60 chromosomal genes in Escherichia coli by constitutive expression of MarA." J Bacteriol 182(12);3467-74. PMID: 10852879

Chubiz10: Chubiz LM, Rao CV (2010). "Aromatic acid metabolites of Escherichia coli K-12 can induce the marRAB operon." J Bacteriol. PMID: 20639340

Chubiz12: Chubiz LM, Glekas GD, Rao CV (2012). "Transcriptional cross talk within the mar-sox-rob regulon in Escherichia coli is limited to the rob and marRAB operons." J Bacteriol 194(18);4867-75. PMID: 22753060

Cohen93: Cohen SP, Hachler H, Levy SB (1993). "Genetic and functional analysis of the multiple antibiotic resistance (mar) locus in Escherichia coli." J Bacteriol 1993;175(5);1484-92. PMID: 8383113

Cohen93a: Cohen SP, Levy SB, Foulds J, Rosner JL (1993). "Salicylate induction of antibiotic resistance in Escherichia coli: activation of the mar operon and a mar-independent pathway." J Bacteriol 175(24);7856-62. PMID: 7504664

DiazMejia09: Diaz-Mejia JJ, Babu M, Emili A (2009). "Computational and experimental approaches to chart the Escherichia coli cell-envelope-associated proteome and interactome." FEMS Microbiol Rev 33(1);66-97. PMID: 19054114

Domain07: Domain F, Bina XR, Levy SB (2007). "Transketolase A, an enzyme in central metabolism, derepresses the marRAB multiple antibiotic resistance operon of Escherichia coli by interaction with MarR." Mol Microbiol 66(2);383-94. PMID: 17850260

Domain09: Domain F, Levy SB (2009). "GyrA Interacts with MarR to Reduce Repression of the marRAB Operon in E. coli." J Bacteriol. PMID: 19933356

Doukyu12: Doukyu N, Ishikawa K, Watanabe R, Ogino H (2012). "Improvement in organic solvent tolerance by double disruptions of proV and marR genes in Escherichia coli." J Appl Microbiol 112(3);464-74. PMID: 22257006

Egland99: Egland PG, Harwood CS (1999). "BadR, a new MarR family member, regulates anaerobic benzoate degradation by Rhodopseudomonas palustris in concert with AadR, an Fnr family member." J Bacteriol 181(7);2102-9. PMID: 10094687

Gerdes03: Gerdes SY, Scholle MD, Campbell JW, Balazsi G, Ravasz E, Daugherty MD, Somera AL, Kyrpides NC, Anderson I, Gelfand MS, Bhattacharya A, Kapatral V, D'Souza M, Baev MV, Grechkin Y, Mseeh F, Fonstein MY, Overbeek R, Barabasi AL, Oltvai ZN, Osterman AL (2003). "Experimental determination and system level analysis of essential genes in Escherichia coli MG1655." J Bacteriol 185(19);5673-84. PMID: 13129938

GOA01: GOA, DDB, FB, MGI, ZFIN (2001). "Gene Ontology annotation through association of InterPro records with GO terms."

Hachler91: Hachler H, Cohen SP, Levy SB (1991). "marA, a regulated locus which controls expression of chromosomal multiple antibiotic resistance in Escherichia coli." J Bacteriol 173(17);5532-8. PMID: 1715857

Hulo04: Hulo N, Sigrist CJ, Le Saux V, Langendijk-Genevaux PS, Bordoli L, Gattiker A, De Castro E, Bucher P, Bairoch A (2004). "Recent improvements to the PROSITE database." Nucleic Acids Res 32(Database issue);D134-7. PMID: 14681377

Joyce06: Joyce AR, Reed JL, White A, Edwards R, Osterman A, Baba T, Mori H, Lesely SA, Palsson BO, Agarwalla S (2006). "Experimental and computational assessment of conditionally essential genes in Escherichia coli." J Bacteriol 188(23);8259-71. PMID: 17012394

Keeney08: Keeney D, Ruzin A, McAleese F, Murphy E, Bradford PA (2008). "MarA-mediated overexpression of the AcrAB efflux pump results in decreased susceptibility to tigecycline in Escherichia coli." J Antimicrob Chemother 61(1);46-53. PMID: 17967850

Krisko14: Krisko A, Copi T, Gabaldon T, Lehner B, Supek F (2014). "Inferring gene function from evolutionary change in signatures of translation efficiency." Genome Biol 15(3);R44. PMID: 24580753

Linde00: Linde HJ, Notka F, Metz M, Kochanowski B, Heisig P, Lehn N (2000). "In vivo increase in resistance to ciprofloxacin in Escherichia coli associated with deletion of the C-terminal part of MarR." Antimicrob Agents Chemother 44(7);1865-8. PMID: 10858345

Martin04: Martin RG, Rosner JL (2004). "Transcriptional and translational regulation of the marRAB multiple antibiotic resistance operon in Escherichia coli." Mol Microbiol 53(1);183-91. PMID: 15225313

Martin95: Martin RG, Rosner JL (1995). "Binding of purified multiple antibiotic-resistance repressor protein (MarR) to mar operator sequences." Proc Natl Acad Sci U S A 1995;92(12);5456-60. PMID: 7777530

Martin96: 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 1996;178(8);2216-23. PMID: 8636021

McMurry13: McMurry LM, Levy SB (2013). "Amino acid residues involved in inactivation of the Escherichia coli multidrug resistance repressor MarR by salicylate, 2,4-dinitrophenol, and plumbagin." FEMS Microbiol Lett 349(1);16-24. PMID: 24111786

Notka02: Notka F, Linde HJ, Dankesreiter A, Niller HH, Lehn N (2002). "A C-terminal 18 amino acid deletion in MarR in a clinical isolate of Escherichia coli reduces MarR binding properties and increases the MIC of ciprofloxacin." J Antimicrob Chemother 49(1);41-7. PMID: 11751765

Oh12: Oh HY, Lee JO, Kim OB (2012). "Increase of organic solvent tolerance of Escherichia coli by the deletion of two regulator genes, fadR and marR." Appl Microbiol Biotechnol 96(6);1619-27. PMID: 23053109

PerezRueda01: Perez-Rueda E, Collado-Vides J (2001). "Common history at the origin of the position-function correlation in transcriptional regulators in archaea and bacteria." J Mol Evol 53(3);172-9. PMID: 11523004

PerezRueda04: Perez-Rueda E, Collado-Vides J, Segovia L (2004). "Phylogenetic distribution of DNA-binding transcription factors in bacteria and archaea." Comput Biol Chem 28(5-6);341-50. PMID: 15556475

Pomposiello01: 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. PMID: 11395452

Riley06: Riley M, Abe T, Arnaud MB, Berlyn MK, Blattner FR, Chaudhuri RR, Glasner JD, Horiuchi T, Keseler IM, Kosuge T, Mori H, Perna NT, Plunkett G, Rudd KE, Serres MH, Thomas GH, Thomson NR, Wishart D, Wanner BL (2006). "Escherichia coli K-12: a cooperatively developed annotation snapshot--2005." Nucleic Acids Res 34(1);1-9. PMID: 16397293

Ruiz10: Ruiz C, Levy SB (2010). "Many chromosomal genes modulate MarA-mediated multidrug resistance in Escherichia coli." Antimicrob Agents Chemother 54(5);2125-34. PMID: 20211899

Seoane95: Seoane AS, Levy SB (1995). "Characterization of MarR, the repressor of the multiple antibiotic resistance (mar) operon in Escherichia coli." J Bacteriol 1995;177(12);3414-9. PMID: 7768850

Sulavik95: Sulavik MC, Gambino LF, Miller PF (1995). "The MarR repressor of the multiple antibiotic resistance (mar) operon in Escherichia coli: prototypic member of a family of bacterial regulatory proteins involved in sensing phenolic compounds." Mol Med 1995;1(4);436-46. PMID: 8521301

UniProtGOA11: UniProt-GOA (2011). "Gene Ontology annotation based on manual assignment of UniProtKB keywords in UniProtKB/Swiss-Prot entries."

Warner10: Warner DM, Levy SB (2010). "Different effects of transcriptional regulators MarA, SoxS and Rob on susceptibility of Escherichia coli to cationic antimicrobial peptides (CAMPs): Rob-dependent CAMP induction of the marRAB operon." Microbiology 156(Pt 2);570-8. PMID: 19926649

White97: 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. PMID: 9324261

Wilkinson06: Wilkinson SP, Grove A (2006). "Ligand-responsive transcriptional regulation by members of the MarR family of winged helix proteins." Curr Issues Mol Biol 8(1);51-62. PMID: 16450885

Wu03: Wu RY, Zhang RG, Zagnitko O, Dementieva I, Maltzev N, Watson JD, Laskowski R, Gornicki P, Joachimiak A (2003). "Crystal structure of Enterococcus faecalis SlyA-like transcriptional factor." J Biol Chem 278(22);20240-4. PMID: 12649270

Other References Related to Gene Regulation

Bennik00: Bennik MH, Pomposiello PJ, Thorne DF, Demple B (2000). "Defining a rob regulon in Escherichia coli by using transposon mutagenesis." J Bacteriol 182(13);3794-801. PMID: 10850996

Gillette00: 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. PMID: 10873449

Martin11: 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. PMID: 21097628

Martin97: Martin RG, Rosner JL (1997). "Fis, an accessorial factor for transcriptional activation of the mar (multiple antibiotic resistance) promoter of Escherichia coli in the presence of the activator MarA, SoxS, or Rob." J Bacteriol 1997;179(23);7410-9. PMID: 9393706

Martin99: 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 1999;34(3);431-41. PMID: 10564485

Rodionov01: 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. PMID: 11321589

Shimada11: Shimada T, Yamamoto K, Ishihama A (2011). "Novel Members of the Cra Regulon Involved in Carbon Metabolism in Escherichia coli." J Bacteriol 193(3);649-59. PMID: 21115656

Viveiros07: Viveiros M, Dupont M, Rodrigues L, Couto I, Davin-Regli A, Martins M, Pages JM, Amaral L (2007). "Antibiotic stress, genetic response and altered permeability of E. coli." PLoS ONE 2;e365. PMID: 17426813

Wright13: Wright PR, Richter AS, Papenfort K, Mann M, Vogel J, Hess WR, Backofen R, Georg J (2013). "Comparative genomics boosts target prediction for bacterial small RNAs." Proc Natl Acad Sci U S A 110(37);E3487-96. PMID: 23980183

Zheng04: Zheng D, Constantinidou C, Hobman JL, Minchin SD (2004). "Identification of the CRP regulon using in vitro and in vivo transcriptional profiling." Nucleic Acids Res 32(19);5874-93. PMID: 15520470


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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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