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Escherichia coli K-12 substr. MG1655 Polypeptide: AcrAB-TolC multidrug efflux system - membrane fusion protein



Gene: acrA Accession Numbers: EG11703 (EcoCyc), b0463, ECK0457

Synonyms: sipB, Mb, lir, mbl, mtcA, nbsA, acridine efflux pump, AcrA membrane fusion protein

Regulation Summary Diagram: ?

Component of:
AcrAD-TolC multidrug efflux system (extended summary available)
AcrAB-TolC multidrug efflux system (extended summary available)

Summary:
AcrA is the periplasmic lipoprotein component of the AcrAB-TolC multidrug efflux pump in Escherichia coli and can function in chimeric constructions with three other RND-family pumps, AcrD, AcrF and MdtF(YhiV). The C-terminal domain of AcrA is functionally significant [Ge09a] and a small region located near the C-terminus has been shown to be necessary for interaction with AcrB [Elkins03]. A stable fragment of AcrA has been crystallized and its three-dimensional structure determined [Mikolosko06].

The structure of E.coli AcrA has been modelled on the basis of crystallographic data from Pseudomonas aeruginosa [Higgins04, Symmons09]. The intermolecular contacts between AcrA and AcrB have been mapped using an in vivo cross-linking approach and the AcrAB complex has been modelled [Symmons09].

acrA is one of a network of genes believed to play a role in promoting the stress-induced mutagenesis (SIM) response of E. coli K-12 [Al12].

Gene Citations: [Ma93, Rand02, Rosenberg03, Linde00]

Locations: periplasmic space, inner membrane

Map Position: [483,650 <- 484,843] (10.42 centisomes)
Length: 1194 bp / 397 aa

Molecular Weight of Polypeptide: 42.197 kD (from nucleotide sequence)

Unification Links: ASAP:ABE-0001603 , CGSC:1045 , DIP:DIP-29039N , EchoBASE:EB1654 , EcoGene:EG11703 , EcoliWiki:b0463 , ModBase:P0AE06 , OU-Microarray:b0463 , PortEco:acrA , PR:PRO_000022048 , Pride:P0AE06 , Protein Model Portal:P0AE06 , RefSeq:NP_414996 , RegulonDB:EG11703 , SMR:P0AE06 , String:511145.b0463 , Swiss-Model:P0AE06 , UniProt:P0AE06

Relationship Links: InterPro:IN-FAMILY:IPR006143 , PDB:Structure:2F1M , Pfam:IN-FAMILY:PF00529 , Prosite:IN-FAMILY:PS51257

In Paralogous Gene Group: 132 (13 members)

Gene-Reaction Schematic: ?

Genetic Regulation Schematic: ?

GO Terms:

Biological Process: GO:0006855 - drug transmembrane transport Inferred from experiment [Okusu96]
GO:0015721 - bile acid and bile salt transport Inferred from experiment [Thanassi97]
GO:0006810 - transport Inferred by computational analysis [UniProtGOA11a]
GO:0046677 - response to antibiotic Inferred by computational analysis [UniProtGOA11a]
GO:0055085 - transmembrane transport Inferred by computational analysis [GOA01a]
Molecular Function: GO:0015238 - drug transmembrane transporter activity Inferred from experiment [Ma93]
GO:0042802 - identical protein binding Inferred from experiment [Rajagopala14, Yum09, Stenberg05]
Cellular Component: GO:0005886 - plasma membrane Inferred from experiment Inferred by computational analysis [UniProtGOA11, UniProtGOA11a, Stenberg05]
GO:0016020 - membrane Inferred by computational analysis [UniProtGOA11a, GOA01a]
GO:0030288 - outer membrane-bounded periplasmic space

MultiFun Terms: cell processes protection drug resistance/sensitivity
cell structure membrane
transport Electrochemical potential driven transporters Porters (Uni-, Sym- and Antiporters)

Essentiality data for acrA 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]

Credits:
Last-Curated ? 30-Jun-2009 by Mackie A , Macquarie University


Subunit of: AcrAD-TolC multidrug efflux system

Subunit composition of AcrAD-TolC multidrug efflux system = [AcrD]3[AcrA][(TolC)3]
         AcrAD-TolC multidrug efflux system - permease subunit = AcrD (summary available)
         AcrAB-TolC multidrug efflux system - membrane fusion protein = AcrA (extended summary available)
         TolC outer membrane channel = (TolC)3 (extended summary available)
                 TolC monomer = TolC

Summary:
AcrD is a member of the resistance-nodulation-division (RND) family [Saier94]. RND family transporters interact with membrane fusion proteins (MFPs) and outer membrane channels for transport of their substrates into the external medium. AcrD is believed to form a tripartite complex with AcrA (an MFP) and TolC for multidrug transport. AcrD shows amino acid sequence similarity with the E. coli RND multidrug efflux proteins AcrB and AcrF.

AcrD was shown to require AcrA for aminoglycoside transport when reconstituted into proteoliposomes [Aires05]. AcrAD are believed to form a complex with TolC for multidrug export [Aires05]. Experiments using proteoliposomes show the AcrAD-TolC complex is able to transport drugs from both the cytoplasm and the periplasm to the extracellular space [Aires05]. AcrD was shown to export streptomycin, but only from the periplasm [Aires05]. AcrD was also shown to bind cisplatin [Will08]. Linear α-helical cathelicidin LL-37 and β-sheet defensins HNP-1-3, hBD-2/-3 and HD-5 are not substrates for AcrAB [Rieg09].

Disruption of the acrD gene did not result in hypersusceptibility to lipophilic and amphiphilic drugs, but did result in hypersusceptibility to a variety of aminoglycosides including amikacin, gentamicin, tobramycin, kanamycin, neomycin, erythromycin, and polymyxin B [Rosenberg00]. The mutants also accumulated more dihydrostreptomycin and gentamicin than the parental strain [Rosenberg00]. Treatment with CCCP increased aminoglycoside accumulation suggesting that efflux of aminoglycosides is energized by the proton-motive force [Rosenberg00]. Expression of acrD on a multicopy plasmid from native or IPTG inducible promoters in an acrAB mutant resulted in increased resistance to deoxycholate, SDS, novobiocin, kanamycin, tetracycline, nalidixic acid, norfloxacin, fosfomycin [Nishino01], bile acids, fusidic acid [Elkins02], and progesterone [Elkins06]. AcrADTolC confers stronger resistance to anionic β-lactams (aztreonam, carbenicillin, sulbenicillin) than AcrABTolC [Nishino03]. The two large periplasmic loops of AcrD are implicated in substrate specificity [Elkins02, Kobayashi14].

In one study, disruption of acrA or tolC did not result in hypersensitivity to aminoglycosides [Rosenberg00]. Since aminoglycosides do not cross the inner membrane spontaneously, it was suggested that AcrD simply transports the hydrophilic molecules to the periplasm and does not require other proteins for aminoglycoside transport across the outer membrane [Rosenberg00]. Later studies showed AcrA was required for transport of cholic acid, taurocholic acid, and novobiocin by AcrD [Elkins02], and that acrA mutants were as susceptible to aminoglycosides as acrD mutants [Aires05]. AcrD and AcrA have also been shown to interact through chemical crosslinking studies [Elkins02]. These results suggest that AcrD interacts with AcrA and TolC for transport of at least some substrates [Elkins02].

BaeR is responsible for activation of acrD transcription [Hirakawa03], and this activation is enhanced by CpxR [Hirakawa05]. Indole was shown to activate BaeR and CpxR leading to acrD transcription [Hirakawa05]. Iron depletion led to reduced expression of acrD [Bleuel05].

Citations: [Nakamura79, Ma94, Fralick96, Nikaido96, Yamada06]

Credits:
Last-Curated ? 12-May-2008 by Johnson A , JCVI


Enzymatic reaction of: multidrug transport (AcrAD-TolC multidrug efflux system)

Summary:
AcrADTolC exports substrates from the periplasm and from the cytoplasm according to the following reactions:
drug(periplasmic space) + H+(periplasmic space) ===> drug(extracellular) + H+(cytoplasm)

drug(cytoplasm) + H+(periplasmic space) ===> drug(extracellular) + H+(cytoplasm)


Subunit of: AcrAB-TolC multidrug efflux system

Subunit composition of AcrAB-TolC multidrug efflux system = [AcrA]6[(TolC)3][AcrB]3
         AcrAB-TolC multidrug efflux system - membrane fusion protein = AcrA (extended summary available)
         TolC outer membrane channel = (TolC)3 (extended summary available)
                 TolC monomer = TolC
         AcrAB-TolC multidrug efflux system - permease subunit = AcrB (extended summary available)

Summary:
AcrAB and TolC make up a three-component proton motive force-dependent multidrug efflux system which confers resistance to multiple antimicrobial agents. The complex is the major contributor to the intrinsic resistance of E. coli to organic solvents [Tsukagoshi00], dyes and detergents as well as lipophilic antibiotics including novobiocin, erythromycin, fusidic acid and cloxacillin. The AcrAB-TolC system is a significant contributor to the intrinsic resistance of E. coli to bile acids [Thanassi97].The AcrAB-TolC complex confers only weak reistance to anionic β-lactams (aztreonam, carbenicillin, sulbenicillin) [Nishino03].The acrAB locus encodes for two of the complex proteins, AcrA and AcrB. AcrA is a periplasmic lipoprotein component which is a member of the membrane fusion protein (MFP) family and is anchored to the inner membrane's outer surface by its lipid moiety. AcrB is an RND-type inner-membrane associated efflux pump. Reconstitution studies suggest that AcrB is a proton-substrate antiporter [Zgurskaya99]. The crystal structure of the AcrB trimer reveals an asymmetric assembly of the monomers and suggests a functionally rotating, three step (access, binding, and extrusion), peristaltic pump mechanism for the export of substrates [Seeger06, Murakami06, Pos09]. The small membrane protein AcrZ associates with AcrAB-TolC and may affect the specificity of drug export [Hobbs12].

AcrABTolC provides minimal reistance to ethidium and acriflavine in an emrE mdfA double null background [Tal09] suggesting that tripartite pumps may act cooperatively with single component major facilitator superfamily (MFS) and small multidrug resistance (SMR) transporters to export hydrophobic drugs/toxins from the cytoplasm in a two step process [Lee00b, Tal09].

Expression of the complex is constitutive and does not require the presence of substrate [Touze04]. Overexpression of the complex components results in significant levels of resistance to other common antibiotics such as tetracycline and chloramphenicol [Okusu96].

AcrA and AcrB were found as homotrimers within the inner membrane and assemble with trimeric TolC to form the efflux pump [Stenberg05]. Genetic, cross-linking, and protein purification studies suggest that the TolC channel associates with AcrAB to form a tri-partite complex spanning the entire cell envelope [Fralick96, Gerken04, Tikhonova04, Touze04]. Cross-linking studies [Zgurskaya00] suggest that AcrA interacts with AcrB as an oligomeric trimer or dimer and that the AcrA/AcrB complex can exist in a stable state associated with the inner membrane independently of the TolC outer membrane channel. A small region of AcrA located near its C-terminus has been shown to be necessary for interaction with AcrB [Elkins03]. Cross-linking and titration calorimetry studies reveal interaction between AcrB and AcrA as well as interaction between AcrA and TolC, suggesting a role for AcrA as an adaptor between AcrB and TolC [Touze04, Husain04]. Interaction between AcrA and TolC is important for export [Stegmeier06a]. Cross-linking studies have also suggested a direct interaction between TolC and AcrB [Touze04, Tamura05].

The structure of E.coli AcrA has been modelled on the basis of crystallographic data from Pseudomonas aeruginosa [Higgins04, Symmons09]. The intermolecular contacts between AcrA and AcrB have been mapped using an in vivo cross-linking approach and the AcrAB complex has been modelled [Symmons09]. A complete assembly of the AcrAB-TolC complex has been modelled [Symmons09].

Fusion proteins of AcrA-AcrB, AcrA-AcraZ and TolC remain associated during purification and the purified complex retains partial activity. A pseudo-atomic model of the complex has been constructed which comprises an AcrB trimer, an AcrA hexamer and TolC trimer. In the model no direct interaction between AcrB and TolC is observed, rather AcrA acts as a bridge between them [Du14].

Review: [Eicher09]

Citations: [Xu11, Kobayashi14]

Credits:
Last-Curated ? 30-Jun-2009 by Mackie A , Macquarie University


Enzymatic reaction of: multidrug efflux transporter (AcrAB-TolC multidrug efflux system)

Summary:
Kinetic behaviour of the complex has been investigated for various cephalosporins [Nagano09].
Nitrocefin Km: 5 μM
Cephalothin Km: 91.2 μM
Cefamandole Km: 19.6 μM
Cephaloridine Km: 288 μM
The latter three compounds showed strong positive cooperativity with Hill coefficients of 1.9, 3.2 and 1.75 respectively.

Please note: AcrABTolC exports substrates from the periplasm and from the cytoplasm according to the following reactions:
drug(periplasmic space) + H+(periplasmic space) ===> drug(extracellular) + H+(cytoplasm)

drug(cytoplasm) + H+(periplasmic space) ===> drug(extracellular) + H+(cytoplasm)


Enzymatic reaction of: chenodeoxycholate efflux (AcrAB-TolC multidrug efflux system)


Sequence Features

Feature Class Location Citations Comment
Mutagenesis-Variant 1 -> 25
[Mikolosko06, UniProt14]
Alternate sequence: MNKNRGFTPLAVVLMLSGSLALTGC → MKKTAIAIAVALAGFATVAQA; UniProt: Fully functional (replaces endogenous signal and lipid anchor with periplasmic signal for OmpA).
Signal-Sequence 1 -> 24
[UniProt10a]
Lipid-Binding-Site 25
[UniProt10]
UniProt: N-palmitoyl cysteine; Non-Experimental Qualifier: potential;
Chain 25 -> 397
[UniProt09]
UniProt: Acriflavine resistance protein A;
Protein-Segment 172 -> 397
[UniProt14]
UniProt: Interacts with AcrB; Sequence Annotation Type: region of interest.
Mutagenesis-Variant 223 -> 224
[Mikolosko06, UniProt14]
Alternate sequence: FL → MM; UniProt: Wild-type resistance to efflux substrates. Protein unstable; when associated with 287-M-M-288.
Mutagenesis-Variant 287 -> 288
[Mikolosko06, UniProt14]
Alternate sequence: LL → MM; UniProt: Wild-type resistance to efflux substrates. Protein unstable; when associated with 223-M-M-224.
Protein-Segment 313 -> 397
[UniProt14]
UniProt: Required for growth on efflux drugs; Sequence Annotation Type: region of interest.


Gene Local Context (not to scale): ?

Transcription Units:

Notes:

History:
10/20/97 Gene b0463 from Blattner lab Genbank (v. M52) entry merged into EcoCyc gene EG11703; confirmed by SwissProt match.


References

Aires05: Aires JR, Nikaido H (2005). "Aminoglycosides are captured from both periplasm and cytoplasm by the AcrD multidrug efflux transporter of Escherichia coli." J Bacteriol 187(6);1923-9. PMID: 15743938

Al12: Al Mamun AA, Lombardo MJ, Shee C, Lisewski AM, Gonzalez C, Lin D, Nehring RB, Saint-Ruf C, Gibson JL, Frisch RL, Lichtarge O, Hastings PJ, Rosenberg SM (2012). "Identity and function of a large gene network underlying mutagenic repair of DNA breaks." Science 338(6112);1344-8. PMID: 23224554

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

Bleuel05: Bleuel C, Grosse C, Taudte N, Scherer J, Wesenberg D, Krauss GJ, Nies DH, Grass G (2005). "TolC is involved in enterobactin efflux across the outer membrane of Escherichia coli." J Bacteriol 187(19);6701-7. PMID: 16166532

Du14: Du D, Wang Z, James NR, Voss JE, Klimont E, Ohene-Agyei T, Venter H, Chiu W, Luisi BF (2014). "Structure of the AcrAB-TolC multidrug efflux pump." Nature. PMID: 24747401

Eicher09: Eicher T, Brandstatter L, Pos KM (2009). "Structural and functional aspects of the multidrug efflux pump AcrB." Biol Chem 390(8);693-9. PMID: 19453279

Elkins02: Elkins CA, Nikaido H (2002). "Substrate specificity of the RND-type multidrug efflux pumps AcrB and AcrD of Escherichia coli is determined predominantly by two large periplasmic loops." J Bacteriol 184(23);6490-8. PMID: 12426336

Elkins03: Elkins CA, Nikaido H (2003). "Chimeric analysis of AcrA function reveals the importance of its C-terminal domain in its interaction with the AcrB multidrug efflux pump." J Bacteriol 185(18);5349-56. PMID: 12949086

Elkins06: Elkins CA, Mullis LB (2006). "Mammalian steroid hormones are substrates for the major RND- and MFS-type tripartite multidrug efflux pumps of Escherichia coli." J Bacteriol 188(3);1191-5. PMID: 16428427

Fralick96: Fralick JA (1996). "Evidence that TolC is required for functioning of the Mar/AcrAB efflux pump of Escherichia coli." J Bacteriol 1996;178(19);5803-5. PMID: 8824631

Ge09a: Ge Q, Yamada Y, Zgurskaya H (2009). "The C-terminal domain of AcrA is essential for the assembly and function of the multidrug efflux pump AcrAB-TolC." J Bacteriol 191(13);4365-71. PMID: 19411330

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

Gerken04: Gerken H, Misra R (2004). "Genetic evidence for functional interactions between TolC and AcrA proteins of a major antibiotic efflux pump of Escherichia coli." Mol Microbiol 54(3);620-31. PMID: 15491355

GOA01a: GOA, DDB, FB, MGI, ZFIN (2001). "Gene Ontology annotation through association of InterPro records with GO terms."

Higgins04: Higgins MK, Bokma E, Koronakis E, Hughes C, Koronakis V (2004). "Structure of the periplasmic component of a bacterial drug efflux pump." Proc Natl Acad Sci U S A 101(27);9994-9. PMID: 15226509

Hirakawa03: Hirakawa H, Nishino K, Yamada J, Hirata T, Yamaguchi A (2003). "Beta-lactam resistance modulated by the overexpression of response regulators of two-component signal transduction systems in Escherichia coli." J Antimicrob Chemother 52(4);576-82. PMID: 12951338

Hirakawa05: Hirakawa H, Inazumi Y, Masaki T, Hirata T, Yamaguchi A (2005). "Indole induces the expression of multidrug exporter genes in Escherichia coli." Mol Microbiol 55(4);1113-26. PMID: 15686558

Hobbs12: 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. PMID: 23010927

Husain04: Husain F, Humbard M, Misra R (2004). "Interaction between the TolC and AcrA proteins of a multidrug efflux system of Escherichia coli." J Bacteriol 186(24);8533-6. PMID: 15576805

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

Kobayashi14: Kobayashi N, Tamura N, van Veen HW, Yamaguchi A, Murakami S (2014). "β-Lactam Selectivity of Multidrug Transporters AcrB and AcrD Resides in the Proximal Binding Pocket." J Biol Chem. PMID: 24558035

Lee00b: Lee A, Mao W, Warren MS, Mistry A, Hoshino K, Okumura R, Ishida H, Lomovskaya O (2000). "Interplay between efflux pumps may provide either additive or multiplicative effects on drug resistance." J Bacteriol 182(11);3142-50. PMID: 10809693

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

Ma93: Ma D, Cook DN, Alberti M, Pon NG, Nikaido H, Hearst JE (1993). "Molecular cloning and characterization of acrA and acrE genes of Escherichia coli." J Bacteriol 1993;175(19);6299-313. PMID: 8407802

Ma94: Ma D, Cook DN, Hearst JE, Nikaido H (1994). "Efflux pumps and drug resistance in gram-negative bacteria." Trends Microbiol 2(12);489-93. PMID: 7889326

Mikolosko06: Mikolosko J, Bobyk K, Zgurskaya HI, Ghosh P (2006). "Conformational flexibility in the multidrug efflux system protein AcrA." Structure 14(3);577-87. PMID: 16531241

Murakami06: Murakami S, Nakashima R, Yamashita E, Matsumoto T, Yamaguchi A (2006). "Crystal structures of a multidrug transporter reveal a functionally rotating mechanism." Nature 443(7108);173-9. PMID: 16915237

Nagano09: Nagano K, Nikaido H (2009). "Kinetic behavior of the major multidrug efflux pump AcrB of Escherichia coli." Proc Natl Acad Sci U S A 106(14);5854-8. PMID: 19307562

Nakamura79: Nakamura H (1979). "Novel acriflavin resistance genes, acrC and acrD, in Escherichia coli K-12." J Bacteriol 139(1);8-12. PMID: 378962

Nikaido96: Nikaido H (1996). "Multidrug efflux pumps of gram-negative bacteria." J Bacteriol 178(20);5853-9. PMID: 8830678

Nishino01: Nishino K, Yamaguchi A (2001). "Analysis of a complete library of putative drug transporter genes in Escherichia coli." J Bacteriol 2001;183(20);5803-12. PMID: 11566977

Nishino03: Nishino K, Yamada J, Hirakawa H, Hirata T, Yamaguchi A (2003). "Roles of TolC-dependent multidrug transporters of Escherichia coli in resistance to beta-lactams." Antimicrob Agents Chemother 47(9);3030-3. PMID: 12937021

Okusu96: Okusu H, Ma D, Nikaido H (1996). "AcrAB efflux pump plays a major role in the antibiotic resistance phenotype of Escherichia coli multiple-antibiotic-resistance (Mar) mutants." J Bacteriol 1996;178(1);306-8. PMID: 8550435

Pos09: Pos KM (2009). "Drug transport mechanism of the AcrB efflux pump." Biochim Biophys Acta 1794(5);782-93. PMID: 19166984

Rajagopala14: Rajagopala SV, Sikorski P, Kumar A, Mosca R, Vlasblom J, Arnold R, Franca-Koh J, Pakala SB, Phanse S, Ceol A, Hauser R, Siszler G, Wuchty S, Emili A, Babu M, Aloy P, Pieper R, Uetz P (2014). "The binary protein-protein interaction landscape of Escherichia coli." Nat Biotechnol 32(3);285-90. PMID: 24561554

Rand02: Rand JD, Danby SG, Greenway DL, England RR (2002). "Increased expression of the multidrug efflux genes acrAB occurs during slow growth of Escherichia coli." FEMS Microbiol Lett 207(1);91-5. PMID: 11886757

Rieg09: Rieg S, Huth A, Kalbacher H, Kern WV (2009). "Resistance against antimicrobial peptides is independent of Escherichia coli AcrAB, Pseudomonas aeruginosa MexAB and Staphylococcus aureus NorA efflux pumps." Int J Antimicrob Agents 33(2);174-6. PMID: 18945595

Rosenberg00: Rosenberg EY, Ma D, Nikaido H (2000). "AcrD of Escherichia coli is an aminoglycoside efflux pump." J Bacteriol 2000;182(6);1754-6. PMID: 10692383

Rosenberg03: 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. PMID: 12791142

Saier94: Saier MH, Tam R, Reizer A, Reizer J (1994). "Two novel families of bacterial membrane proteins concerned with nodulation, cell division and transport." Mol Microbiol 1994;11(5);841-7. PMID: 8022262

Seeger06: Seeger MA, Schiefner A, Eicher T, Verrey F, Diederichs K, Pos KM (2006). "Structural asymmetry of AcrB trimer suggests a peristaltic pump mechanism." Science 313(5791);1295-8. PMID: 16946072

Stegmeier06a: Stegmeier JF, Polleichtner G, Brandes N, Hotz C, Andersen C (2006). "Importance of the adaptor (membrane fusion) protein hairpin domain for the functionality of multidrug efflux pumps." Biochemistry 45(34);10303-12. PMID: 16922505

Stenberg05: Stenberg F, Chovanec P, Maslen SL, Robinson CV, Ilag LL, von Heijne G, Daley DO (2005). "Protein complexes of the Escherichia coli cell envelope." J Biol Chem 280(41);34409-19. PMID: 16079137

Symmons09: Symmons MF, Bokma E, Koronakis E, Hughes C, Koronakis V (2009). "The assembled structure of a complete tripartite bacterial multidrug efflux pump." Proc Natl Acad Sci U S A 106(17);7173-8. PMID: 19342493

Tal09: Tal N, Schuldiner S (2009). "A coordinated network of transporters with overlapping specificities provides a robust survival strategy." Proc Natl Acad Sci U S A 106(22);9051-6. PMID: 19451626

Tamura05: Tamura N, Murakami S, Oyama Y, Ishiguro M, Yamaguchi A (2005). "Direct interaction of multidrug efflux transporter AcrB and outer membrane channel TolC detected via site-directed disulfide cross-linking." Biochemistry 44(33);11115-21. PMID: 16101295

Thanassi97: Thanassi DG, Cheng LW, Nikaido H (1997). "Active efflux of bile salts by Escherichia coli." J Bacteriol 179(8);2512-8. PMID: 9098046

Tikhonova04: Tikhonova EB, Zgurskaya HI (2004). "AcrA, AcrB, and TolC of Escherichia coli Form a Stable Intermembrane Multidrug Efflux Complex." J Biol Chem 279(31);32116-24. PMID: 15155734

Touze04: Touze T, Eswaran J, Bokma E, Koronakis E, Hughes C, Koronakis V (2004). "Interactions underlying assembly of the Escherichia coli AcrAB-TolC multidrug efflux system." Mol Microbiol 53(2);697-706. PMID: 15228545

Tsukagoshi00: Tsukagoshi N, Aono R (2000). "Entry into and release of solvents by Escherichia coli in an organic-aqueous two-liquid-phase system and substrate specificity of the AcrAB-TolC solvent-extruding pump." J Bacteriol 182(17);4803-10. PMID: 10940021

UniProt09: UniProt Consortium (2009). "UniProt version 15.8 released on 2009-10-01 00:00:00." Database.

UniProt10: UniProt Consortium (2010). "UniProt version 2010-07 released on 2010-06-15 00:00:00." Database.

UniProt10a: UniProt Consortium (2010). "UniProt version 2010-11 released on 2010-11-02 00:00:00." Database.

UniProt14: UniProt Consortium (2014). "UniProt version 2014-01 released on 2014-01-01 00:00:00." Database.

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

UniProtGOA11a: UniProt-GOA (2011). "Gene Ontology annotation based on manual assignment of UniProtKB keywords in UniProtKB/Swiss-Prot entries."

Will08: Will J, Sheldrick WS, Wolters D (2008). "Characterisation of cisplatin coordination sites in cellular Escherichia coli DNA-binding proteins by combined biphasic liquid chromatography and ESI tandem mass spectrometry." J Biol Inorg Chem 13(3):421-34. PMID: 18157731

Xu11: Xu Y, Lee M, Moeller A, Song S, Yoon BY, Kim HM, Jun SY, Lee K, Ha NC (2011). "Funnel-like hexameric assembly of the periplasmic adapter protein in the tripartite multidrug efflux pump in gram-negative bacteria." J Biol Chem 286(20);17910-20. PMID: 21454662

Yamada06: Yamada S, Awano N, Inubushi K, Maeda E, Nakamori S, Nishino K, Yamaguchi A, Takagi H (2006). "Effect of drug transporter genes on cysteine export and overproduction in Escherichia coli." Appl Environ Microbiol 72(7);4735-42. PMID: 16820466

Yum09: Yum S, Xu Y, Piao S, Sim SH, Kim HM, Jo WS, Kim KJ, Kweon HS, Jeong MH, Jeon H, Lee K, Ha NC (2009). "Crystal structure of the periplasmic component of a tripartite macrolide-specific efflux pump." J Mol Biol 387(5);1286-97. PMID: 19254725

Zgurskaya00: Zgurskaya HI, Nikaido H (2000). "Cross-linked complex between oligomeric periplasmic lipoprotein AcrA and the inner-membrane-associated multidrug efflux pump AcrB from Escherichia coli." J Bacteriol 2000;182(15);4264-7. PMID: 10894736

Zgurskaya99: Zgurskaya HI, Nikaido H (1999). "Bypassing the periplasm: reconstitution of the AcrAB multidrug efflux pump of Escherichia coli." Proc Natl Acad Sci U S A 1999;96(13);7190-5. PMID: 10377390

Other References Related to Gene Regulation

Dyszel10: Dyszel JL, Soares JA, Swearingen MC, Lindsay A, Smith JN, Ahmer BM (2010). "E. coli K-12 and EHEC genes regulated by SdiA." PLoS One 5(1);e8946. PMID: 20126629

Eguchi03: Eguchi Y, Oshima T, Mori H, Aono R, Yamamoto K, Ishihama A, Utsumi R (2003). "Transcriptional regulation of drug efflux genes by EvgAS, a two-component system in Escherichia coli." Microbiology 149(Pt 10);2819-28. PMID: 14523115

Hirakawa08: Hirakawa H, Takumi-Kobayashi A, Theisen U, Hirata T, Nishino K, Yamaguchi A (2008). "AcrS/EnvR Represses the Expression of the acrAB Multidrug Efflux Genes in Escherichia coli." J Bacteriol 190(18):6276-9. PMID: 18567659

Kobayashi06: Kobayashi A, Hirakawa H, Hirata T, Nishino K, Yamaguchi A (2006). "Growth phase-dependent expression of drug exporters in Escherichia coli and its contribution to drug tolerance." J Bacteriol 188(16);5693-703. PMID: 16885437

Lu03: Lu C, Bentley WE, Rao G (2003). "Comparisons of oxidative stress response genes in aerobic Escherichia coli fermentations." Biotechnol Bioeng 83(7);864-70. PMID: 12889026

Ma96: Ma D, Alberti M, Lynch C, Nikaido H, Hearst JE (1996). "The local repressor AcrR plays a modulating role in the regulation of acrAB genes of Escherichia coli by global stress signals." Mol Microbiol 19(1);101-12. PMID: 8821940

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

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

Monsieurs05: Monsieurs P, De Keersmaecker S, Navarre WW, Bader MW, De Smet F, McClelland M, Fang FC, De Moor B, Vanderleyden J, Marchal K (2005). "Comparison of the PhoPQ regulon in Escherichia coli and Salmonella typhimurium." J Mol Evol 60(4);462-74. PMID: 15883881

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

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

Su07: Su CC, Rutherford DJ, Yu EW (2007). "Characterization of the multidrug efflux regulator AcrR from Escherichia coli." Biochem Biophys Res Commun 361(1);85-90. PMID: 17644067

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


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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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