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Escherichia coli K-12 substr. MG1655 Protein: TolC outer membrane channel



Gene: tolC Accession Numbers: EG11009 (EcoCyc), b3035, ECK3026

Synonyms: weeA, colE1-i, mtcB, mukA, refI, toc

Regulation Summary Diagram: ?

Component of:
MdtABC-TolC multidrug efflux system (extended summary available)
EntS-TolC Enterobactin Efflux Transport System (summary available)
EmrKY-TolC multidrug efflux transport system (summary available)
EmrAB-TolC multidrug efflux transport system (summary available)
AcrEF-TolC multidrug efflux system (summary available)
AcrAD-TolC multidrug efflux system (extended summary available)
AcrAB-TolC multidrug efflux system (extended summary available)
MdtEF-TolC multidrug efflux transport system (extended summary available)
MacAB-TolC macrolide efflux transport system (extended summary available)

Subunit composition of TolC outer membrane channel = [TolC]3
         TolC monomer = TolC

Summary:
TolC is an outer membrane porin involved in the efflux of several hydrophobic and amphipathic molecules. TolC functions as a trimer and is a common outer membrane component of several multi-drug efflux systems.

The tolC gene product localises to the outer membrane [Morona83]. TolC was purified from the Escherichia coli outer membrane as a trimer and its structure was determined by two dimensional projection at a resolution of 12 Å. TolC was found to be an outer membrane protein with each monomer comprising a membrane domain, predicted to be beta-barrel, and a C-terminal periplasmic domain [Koronakis97]. Targeting of TolC to the Sec-translocase for transport across the inner membrane is SecB-dependent [Baars06]. The three dimensional crystal structure of TolC has been determined in an unbound state to a 2.1 Å resolution and in a ligand-bound complex to a 2.75 Å resolution. Each protomer of TolC contributes four β strands to the outer membrane β-barrel structure and four alpha helices to a contiguous α-helical barrel that extends into the periplasm [Koronakis00, Higgins04a].

Reconstitution studies suggest that TolC is an outer membrane channel for peptides [Benz93]. TolC is required for the function of the AcrAB multidrug efflux system [Fralick96] and its homologs AcrEF [Kobayashi01] and YhiUV [Nishino02], the EmrAB drug efflux system [BorgesWalmsley03], the EmrAB homolog, EmrKY [Tanabe97], the MdtABC drug efflux system [Nagakubo02] and the MacAB macrolide extrusion system [Kobayashi01a]. Crystal structures of TolC mutants reveal partially open states of the porin and indicate regions which appear to be involved in binding the periplasmic component of ArcAB [Bavro08].

The mutant phenotype from growth assays suggest TolC is involved in export of thymine when thymidine is the sole carbon source, though an inner membrane export system has not yet been identified [Reed06].

Gene expression analyses indicate that tolC is essential for L-cysteine tolerance and that tolC overexpression is effective for L-cysteine production in E. coli cells [Wiriyathanawudh09].

Mutations in tolC result in a reduction in the synthesis of OmpF porin and an increase in the level of OmpC porin synthesis [Misra87]. Down regulation of tolC is observed under starvation conditions [Muela08]. TolC deficient E.coli cells show decreased growth rates and altered morphology when grown in glucose minimal media. This phenotype is exacerbated by lack of ybiBC and/or yjfMC [Dhamdhere10]. ΔtolC cells are morphologically abnormal - they are often longer and exhibit coccoid shaped bulges. The observed growth impairment and abnormal morhology can be complemented by tolC expressed in trans, by the addition of iron to the culture medium or by deleting any of the genes involved in enterobactin synthesis (entC, entA, entB, entE or entF). The morphological defects and growth impairment of ΔtolC cells grown in glucose minimal medium are due to the accumulation of enterobactin in the periplasm of E. coli K-12 [Vega13].

Reviews: [Koronakis04, Zgurskaya11]

Citations: [Vaccaro08, Lin08a, Zhang08c]

Locations: outer membrane

Map Position: [3,176,137 -> 3,177,618] (68.46 centisomes)
Length: 1482 bp / 493 aa

Molecular Weight of Polypeptide: 53.741 kD (from nucleotide sequence)

Unification Links: ASAP:ABE-0009965 , CGSC:97 , DIP:DIP-11007N , EchoBASE:EB1002 , EcoGene:EG11009 , EcoliWiki:b3035 , ModBase:P02930 , OU-Microarray:b3035 , PortEco:tolC , PR:PRO_000024080 , Protein Model Portal:P02930 , RefSeq:NP_417507 , RegulonDB:EG11009 , SMR:P02930 , String:511145.b3035 , UniProt:P02930

Relationship Links: InterPro:IN-FAMILY:IPR003423 , InterPro:IN-FAMILY:IPR010130 , PDB:Structure:1EK9 , PDB:Structure:1TQQ , PDB:Structure:2VDD , PDB:Structure:2VDE , PDB:Structure:2WMZ , PDB:Structure:2XMN , Pfam:IN-FAMILY:PF02321

Gene-Reaction Schematic: ?

Genetic Regulation Schematic: ?

GO Terms:

Biological Process: GO:0014070 - response to organic cyclic compound Inferred from experiment [Aono98]
GO:0042930 - enterobactin transport Inferred from experiment [Bleuel05]
GO:0055085 - transmembrane transport Inferred from experiment [Benz93, Wandersman90]
GO:0006810 - transport Inferred by computational analysis [UniProtGOA11, GOA01]
GO:0015031 - protein transport Inferred by computational analysis [GOA01]
GO:0046677 - response to antibiotic Inferred by computational analysis [UniProtGOA11]
Molecular Function: GO:0015288 - porin activity Inferred from experiment [Benz93]
GO:0015562 - efflux transmembrane transporter activity Inferred from experiment [Wandersman90]
GO:0005215 - transporter activity Inferred by computational analysis [GOA01]
Cellular Component: GO:0009279 - cell outer membrane Inferred from experiment Inferred by computational analysis [UniProtGOA11a, UniProtGOA11, DiazMejia09, Han12a, Zhang07, Molloy00, LopezCampistrou05, Morona83]
GO:0016020 - membrane Inferred by computational analysis [UniProtGOA11]
GO:0016021 - integral component of membrane Inferred by computational analysis [UniProtGOA11]
GO:0019867 - outer membrane Inferred by computational analysis [GOA01]

MultiFun Terms: cell processes cell division
transport Channel-type Transporters Beta barrel porins (The Outer Membrane Porin (OMP) Functional Superfamily)

Essentiality data for tolC 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:
Created 09-Jan-2012 by Mackie A , Macquarie University


Subunit of: MdtABC-TolC multidrug efflux system

Subunit composition of MdtABC-TolC multidrug efflux system = [(TolC)3][MdtC][MdtB]2[MdtA]
         TolC outer membrane channel = (TolC)3 (extended summary available)
                 TolC monomer = TolC
         MdtABC-TolC multidrug efflux system - membrane subunit = MdtC (summary available)
         MdtABC-TolC multidrug efflux system - membrane subunit = MdtB (summary available)
         MdtABC-TolC multidrug efflux transport system - putative membrane fusion protein = MdtA (summary available)

Summary:
In response regulator overproduction studies and deletion mutation experiments [Nagakubo02], [Baranova02] the mdtABC (yegMNO) genes were found to constitute a multidrug resistance cluster which is regulated by the response regulator BaeR. These genes code for an RND-type drug export complex, MdtABC, which confers resistance against bile salt derivatives, sodium dodecyl sulfate (SDS) and novobiocin. The complex is unusual in that the MdtBC subunits comprise a heteromultimeric transmembrane complex whereas typical RND transporters in E.coli are homotrimers. Sequence homology suggests that mdtA encodes a membrane fusion protein [Nagakubo02]. MdtABC also has an absolute requirement for the multifunctional outer membrane channel TolC for its function [Nagakubo02].

Purified, active trimers contain MdtB and MdtC in a 2:1 ratio [Kim10h]. Mutagenesis of residues predicted to be involved in the proton translocation pathway and in ligand binding in both subunits suggests potentially different functions for each subunit and indicates that the complex is unlikely to function using a similar mechanism to that proposed for homotrimeric RND type transporters [Kim10h, Kim12b].

MdtAC was shown to confer bile salt, but not novobiocin, resistance [Nagakubo02] suggesting that the MdtC homomultimeric RND exporter may represent an evolutionally earlier version of the exporter which, with the addition of MdtB gained an increased range of resistance.

GO Terms:

Biological Process: GO:0006855 - drug transmembrane transport Inferred by computational analysis Inferred from experiment [Baranova02, Nagakubo02]
Molecular Function: GO:0015307 - drug:proton antiporter activity Inferred by computational analysis Inferred from experiment [Kim10h, Nagakubo02]

Credits:
Last-Curated ? 19-Jun-2012 by Mackie A , Macquarie University


Enzymatic reaction of: multidrug efflux


Subunit of: EntS-TolC Enterobactin Efflux Transport System

Subunit composition of EntS-TolC Enterobactin Efflux Transport System = [EntS][(TolC)3]
         enterobactin efflux transporter EntS = EntS (summary available)
         TolC outer membrane channel = (TolC)3 (extended summary available)
                 TolC monomer = TolC

Summary:
The EntS protein is a member of the major facilitator superfamily (MFS) of transporters [Pao98]. Based on sequence similarity, it functions as a proton-driven efflux system. Siderophore nutrition assays have shown that an entS mutant is unable to export enterobactin efficiently to alleviate iron deprivation [Furrer02], though some export does still occur through another mechanism. Deletion of tolC abolishes enterobactin export completely. Enterobactin appears to have more than one mechanism for export to the periplasm, one involving EntS, but TolC is the only outer membrane channel that can export enterobactin from the periplasm [Bleuel05].


Enzymatic reaction of: EntS-TolC Enterobactin Efflux Transport System


Subunit of: EmrKY-TolC multidrug efflux transport system

Subunit composition of EmrKY-TolC multidrug efflux transport system = [EmrK][EmrY][(TolC)3]
         EmrKY-TolC multidrug efflux transport system - membrane fusion protein = EmrK (summary available)
         EmrKY putative multidrug efflux transporter - membrane subunit = EmrY (summary available)
         TolC outer membrane channel = (TolC)3 (extended summary available)
                 TolC monomer = TolC

Summary:
EmrK and EmrY show sequence similarity to EmrA and EmrB respectively. Cloning of the promoter along with the creation of an emrK-lacZ fusion revealed that expression was increased in the prescence of a sub inhibitory concentration of tetracyclin, chloramphenicol, or salicylate but not by carbonylcyanide m-chlorophenylhydrazone, nalidixic acid, or kanamycin [Tanabe97]

Locations: outer membrane, inner membrane, periplasmic space

GO Terms:

Cellular Component: GO:0005886 - plasma membrane
GO:0009279 - cell outer membrane
GO:0030288 - outer membrane-bounded periplasmic space


Enzymatic reaction of: multidrug efflux


Subunit of: EmrAB-TolC multidrug efflux transport system

Subunit composition of EmrAB-TolC multidrug efflux transport system = [EmrA][EmrB][(TolC)3]
         EmrAB-TolC multidrug efflux transport system - membrane fusion protein = EmrA (summary available)
         EmrAB-TolC multidrug efflux transport system - membrane subunit = EmrB (extended summary available)
         TolC outer membrane channel = (TolC)3 (extended summary available)
                 TolC monomer = TolC

Summary:
The EmrAB-TolC Drug Efflux System consists of the EmrA membrane fusion protein, the EmrB drug efflux pump (a member of the major facilitator superfamily), and TolC, the outer membrane protein that extrudes the drugs to the extracellular environment. One possible model of transport might be one in which EmrA and EmrB form a stable complex, possibly via their membrane-spanning leucine zipper motifs. The β-sheet domain of EmrA may be positioned above EmrB at the membrane surface with the α-helices of EmrA radiating across the periplasm to interact with TolC when triggered by the binding of drugs to the β-sheet domain of EmrA [BorgesWalmsley03]. Electron microscopy of reconstituted EmrAB complex suggests that the physiological form of EmrAB is a dimer [Tanabe09].

Locations: outer membrane, inner membrane, periplasmic space

GO Terms:

Cellular Component: GO:0005886 - plasma membrane
GO:0009279 - cell outer membrane
GO:0030288 - outer membrane-bounded periplasmic space


Enzymatic reaction of: multidrug efflux


Subunit of: AcrEF-TolC multidrug efflux system

Subunit composition of AcrEF-TolC multidrug efflux system = [AcrE][AcrF]3[(TolC)3]
         AcrEF-TolC multidrug efflux system - membrane fusion protein = AcrE (summary available)
         AcrEF-TolC multidrug efflux system - permease subunit = AcrF (summary available)
         TolC outer membrane channel = (TolC)3 (extended summary available)
                 TolC monomer = TolC

Summary:
The AcrEF proteins share high amino acid sequence identity with the AcrAB multidrug efflux proteins of Escherichia coli K-12 [Klein91, Ma93a]. Plasmid overexpression of acrEF suppresses the hyper-drug sensitivity of acrAB deletion mutants [KawamuraSato99] however the AcrEF system is not thought to play a large role in drug resistance as acrEF deletion mutants do not display a drug sensitive phenotype. The level of expression of acrEF is thought to be low under laboratory conditions [Nikaido96]. Complementation studies have shown that plasmid-expressed acrF is able to complement an acrB deletion mutation. AcrEF plasmid complementation is dependent on TolC, strongly suggesting that AcrEF, like AcrAB, forms a complex with the outer membrane protein [Kobayashi01].


Enzymatic reaction of: multidrug efflux


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 [Saier94a]. 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 [Nishino03a]. 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 [Hirakawa03a], 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, Yamada06a]

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) [Nishino03a].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 [Lee00d, 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: [Xu11c, 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)


Subunit of: MdtEF-TolC multidrug efflux transport system

Subunit composition of MdtEF-TolC multidrug efflux transport system = [(TolC)3][MdtE]3[MdtF]3
         TolC outer membrane channel = (TolC)3 (extended summary available)
                 TolC monomer = TolC
         MdtEF-TolC multidrug efflux transport system - membrane fusion protein = MdtE (summary available)
         MdtEF-TolC multidrug efflux transport system - permease subunit = MdtF (summary available)

Summary:
Studies performed using overexpression of the response regulator EvgA conferred multiple drug resistance (MDR) to Escherichia coli cells lacking the AcrAB MDR transporter [Nishino01]. The plasmid-containing cells showed drug resistance against deoxycholate (>32-fold compared with control level), doxorubicin (64-fold), rhodamine 6G (16-fold), erythromycin (8-fold), crystal violet (8-fold), benzalkonium (8-fold), and sodium dodecyl sulfate (SDS) (4-fold). EvgA is known to positively regulate the gene expression of the drug resistance system EmrKY, but cells in which only EmrKY is overproduced acquire resistance only to deoxycholate (8-fold) [Nishino01a]. Deletion mutation studies were conducted [Nishino02] in which mdtEF was removed by chromosomal in-frame mutation. The mdtEF deletion strain showed no increased drug resistance (except for deoxycholate) when evgA was overexpressed. Since overexpression of EvgA normally confers an MDR phenotype, these results strongly suggest that the EvgA-induced MDR is due to stimulation of mdtEF gene expression.

Sequence similarity indicate that MdtF belongs to the resistance-nodulation-cell division (RND) transporter family and that MdtE belongs to the membrane fusion protein family [Nishino02]. The outer membrane channel TolC is also required for proper MdtEF transporter function [Zgurskaya00].

MdtE and MdtF were found as homotrimers within the inner membrane and assemble with trimeric TolC to form the efflux pump [Stenberg05].


Enzymatic reaction of: multidrug efflux


Subunit of: MacAB-TolC macrolide efflux transport system

Synonyms: YbjYZ

Subunit composition of MacAB-TolC macrolide efflux transport system = [(TolC)3][MacB]2[MacA]6
         TolC outer membrane channel = (TolC)3 (extended summary available)
                 TolC monomer = TolC
         MacAB-TolC macrolide efflux transport system - membrane subunit = MacB (summary available)
         MacAB-TolC macrolide efflux transport system - membrane fusion protein = MacA (summary available)

Summary:
MacAB, also known as YbjYZ, probably forms a complex with outer membrane protein TolC to confer macrolide resistance via active drug efflux. The macAB genes form an operon with a single promoter and sequence analysis suggests that MacA is a peripheral membrane protein of the MFP family and MacB is a half-type ABC protein with four putative TM segments and an N-terminal nucleotide binding region with both Walker motifs and a characteristic ABC signature sequence. Expression of macAB in a drug-sensitive E. coli strain lacking the multidrug efflux transporter genes acrAB resulted in an eight-fold increased level of resistance to the macrolide erythromycin [Kobayashi01a]. Similar macAB mediated resistance was found to other macrolides with 14-and 15- membered rings, though not for 16-membered lactones. Deletion studies indicate that macAB mediated macrolide resistance is dependent on the tolC outer membrane channel protein. Fractionation studies indicate that MacA and MacB both sequester into the membrane and that MacA is released from the membrane upon treatment with urea, suggesting that MacA is a peripheral membrane protein [Yamanaka01b].

Citations: [Xu11d]

GO Terms:

Biological Process: GO:0046618 - drug export Inferred from experiment [Kobayashi01a]
Molecular Function: GO:0008559 - xenobiotic-transporting ATPase activity Inferred from experiment Inferred by computational analysis [Kobayashi01a, Tikhonova07]
Cellular Component: GO:0030313 - cell envelope Inferred from experiment [Kobayashi01a]


Enzymatic reaction of: transport of a macrolide antibiotic (MacAB-TolC macrolide efflux transport system)


Sequence Features

Feature Class Location Citations Comment
Signal-Sequence 1 -> 22
[Molloy98, Link97, UniProt11]
.
Repeat 23 -> 230
[UniProt09]
UniProt: 1;
Chain 23 -> 493
[UniProt09]
UniProt: Outer membrane protein tolC;
Transmembrane-Region 63 -> 74
[UniProt10a]
UniProt: Beta stranded; Name=S1;
Transmembrane-Region 83 -> 96
[UniProt10a]
UniProt: Beta stranded; Name=S2;
Sequence-Conflict 178
[Hackett83, UniProt14]
Alternate sequence: N → K; UniProt: (in Ref. 1; CAA24914).
Sequence-Conflict 191
[Niki90, Hackett83, UniProt10a]
Alternate sequence: V → L; UniProt: (in Ref. 1; CAA37982);
Sequence-Conflict 203 -> 204
[Hackett83, UniProt14]
Alternate sequence: QL → HV; UniProt: (in Ref. 1; CAA24914).
Sequence-Conflict 214 -> 215
[Hackett83, UniProt14]
Alternate sequence: EL → GT; UniProt: (in Ref. 1; CAA24914).
Repeat 231 -> 446
[UniProt09]
UniProt: 2;
Sequence-Conflict 258 -> 270
[Hackett83, UniProt14]
Alternate sequence: QIRQAQDGHLPTL → KFARRRMVTYRLW; UniProt: (in Ref. 1; CAA24914).
Transmembrane-Region 269 -> 279
[UniProt10a]
UniProt: Beta stranded; Name=S4;
Sequence-Conflict 278 -> 295
[Hackett83, UniProt14]
Alternate sequence: ISDTSYSGSKTRGAAGTQ → FLTPLIAVRKPCAAVP; UniProt: (in Ref. 1; CAA24914).
Transmembrane-Region 301 -> 311
[UniProt10a]
UniProt: Beta stranded; Name=S5;
Sequence-Conflict 325
[Hackett83, UniProt14]
Alternate sequence: K → T; UniProt: (in Ref. 1; CAA24914).
Sequence-Conflict 335 -> 354
[Hackett83, UniProt14]
Alternate sequence: SEQLESAHRSVVQTVRSSFN → ASTWKVPIVASCQRAFCFS; UniProt: (in Ref. 1; CAA24914).
Sequence-Conflict 365 -> 370
[Hackett83, UniProt14]
Alternate sequence: AYKQAV → RYTQAA; UniProt: (in Ref. 1; CAA24914).
Sequence-Conflict 400 -> 411
[Hackett83, UniProt14]
Alternate sequence: TLYNAKQELANA → SCTAQARAGNP; UniProt: (in Ref. 1; CAA24914).
Sequence-Conflict 445
[Hackett83, UniProt14]
Alternate sequence: V → I; UniProt: (in Ref. 1; CAA24914).


Gene Local Context (not to scale): ?

Transcription Units:

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 b3035 from Blattner lab Genbank (v. M52) entry merged into EcoCyc gene EG11009; 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

Aono98: 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. PMID: 9473050

Baars06: Baars L, Ytterberg AJ, Drew D, Wagner S, Thilo C, van Wijk KJ, de Gier JW (2006). "Defining the role of the Escherichia coli chaperone SecB using comparative proteomics." J Biol Chem 281(15);10024-34. PMID: 16352602

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

Baranova02: Baranova N, Nikaido H (2002). "The baeSR two-component regulatory system activates transcription of the yegMNOB (mdtABCD) transporter gene cluster in Escherichia coli and increases its resistance to novobiocin and deoxycholate." J Bacteriol 184(15);4168-76. PMID: 12107134

Bavro08: Bavro VN, Pietras Z, Furnham N, Perez-Cano L, Fernandez-Recio J, Pei XY, Misra R, Luisi B (2008). "Assembly and channel opening in a bacterial drug efflux machine." Mol Cell 30(1);114-21. PMID: 18406332

Benz93: Benz R, Maier E, Gentschev I (1993). "TolC of Escherichia coli functions as an outer membrane channel." Zentralbl Bakteriol 278(2-3);187-96. PMID: 7688606

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

BorgesWalmsley03: Borges-Walmsley MI, Beauchamp J, Kelly SM, Jumel K, Candlish D, Harding SE, Price NC, Walmsley AR (2003). "Identification of oligomerization and drug-binding domains of the membrane fusion protein EmrA." J Biol Chem 278(15);12903-12. PMID: 12482849

Dhamdhere10: Dhamdhere G, Zgurskaya HI (2010). "Metabolic shutdown in Escherichia coli cells lacking the outer membrane channel TolC." Mol Microbiol 77(3);743-54. PMID: 20545840

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

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

Furrer02: Furrer JL, Sanders DN, Hook-Barnard IG, McIntosh MA (2002). "Export of the siderophore enterobactin in Escherichia coli: involvement of a 43 kDa membrane exporter." Mol Microbiol 44(5);1225-34. PMID: 12068807

Furukawa93: Furukawa H, Tsay JT, Jackowski S, Takamura Y, Rock CO (1993). "Thiolactomycin resistance in Escherichia coli is associated with the multidrug resistance efflux pump encoded by emrAB." J Bacteriol 1993;175(12);3723-9. PMID: 8509326

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

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

Hackett83: Hackett J, Reeves P (1983). "Primary structure of the tolC gene that codes for an outer membrane protein of Escherichia coli K12." Nucleic Acids Res 11(18);6487-95. PMID: 6312426

Han12a: Han MJ, Lee SY, Hong SH (2012). "Comparative analysis of envelope proteomes in Escherichia coli B and K-12 strains." J Microbiol Biotechnol 22(4);470-8. PMID: 22534293

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

Higgins04a: Higgins MK, Eswaran J, Edwards P, Schertler GF, Hughes C, Koronakis V (2004). "Structure of the ligand-blocked periplasmic entrance of the bacterial multidrug efflux protein TolC." J Mol Biol 342(3);697-702. PMID: 15342230

Hirakawa03a: 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

KawamuraSato99: Kawamura-Sato K, Shibayama K, Horii T, Iimuma Y, Arakawa Y, Ohta M (1999). "Role of multiple efflux pumps in Escherichia coli in indole expulsion." FEMS Microbiol Lett 179(2);345-52. PMID: 10518736

Kim10h: Kim HS, Nagore D, Nikaido H (2010). "Multidrug efflux pump MdtBC of Escherichia coli is active only as a B2C heterotrimer." J Bacteriol 192(5);1377-86. PMID: 20038594

Kim12b: Kim HS, Nikaido H (2012). "Different Functions of MdtB and MdtC Subunits in the Heterotrimeric Efflux Transporter MdtB(2)C Complex of Escherichia coli." Biochemistry 51(20);4188-97. PMID: 22559837

Klein91: Klein JR, Henrich B, Plapp R (1991). "Molecular analysis and nucleotide sequence of the envCD operon of Escherichia coli." Mol Gen Genet 1991;230(1-2);230-40. PMID: 1720861

Kobayashi01: Kobayashi K, Tsukagoshi N, Aono R (2001). "Suppression of hypersensitivity of Escherichia coli acrB mutant to organic solvents by integrational activation of the acrEF operon with the IS1 or IS2 element." J Bacteriol 183(8);2646-53. PMID: 11274125

Kobayashi01a: Kobayashi N, Nishino K, Yamaguchi A (2001). "Novel macrolide-specific ABC-type efflux transporter in Escherichia coli." J Bacteriol 2001;183(19);5639-44. PMID: 11544226

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

Koronakis00: Koronakis V, Sharff A, Koronakis E, Luisi B, Hughes C (2000). "Crystal structure of the bacterial membrane protein TolC central to multidrug efflux and protein export." Nature 405(6789);914-9. PMID: 10879525

Koronakis04: Koronakis V, Eswaran J, Hughes C (2004). "Structure and function of TolC: the bacterial exit duct for proteins and drugs." Annu Rev Biochem 73;467-89. PMID: 15189150

Koronakis97: Koronakis V, Li J, Koronakis E, Stauffer K (1997). "Structure of TolC, the outer membrane component of the bacterial type I efflux system, derived from two-dimensional crystals." Mol Microbiol 23(3);617-26. PMID: 9044294

Lee00d: 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

Lin08a: Lin XM, Li H, Wang C, Peng XX (2008). "Proteomic analysis of nalidixic acid resistance in Escherichia coli: identification and functional characterization of OM proteins." J Proteome Res 7(6);2399-405. PMID: 18438992

Link97: Link AJ, Robison K, Church GM (1997). "Comparing the predicted and observed properties of proteins encoded in the genome of Escherichia coli K-12." Electrophoresis 18(8);1259-313. PMID: 9298646

Lomovskaya92: Lomovskaya O, Lewis K (1992). "Emr, an Escherichia coli locus for multidrug resistance." Proc Natl Acad Sci U S A 1992;89(19);8938-42. PMID: 1409590

LopezCampistrou05: Lopez-Campistrous A, Semchuk P, Burke L, Palmer-Stone T, Brokx SJ, Broderick G, Bottorff D, Bolch S, Weiner JH, Ellison MJ (2005). "Localization, annotation, and comparison of the Escherichia coli K-12 proteome under two states of growth." Mol Cell Proteomics 4(8);1205-9. PMID: 15911532

Ma93a: 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

Misra87: Misra R, Reeves PR (1987). "Role of micF in the tolC-mediated regulation of OmpF, a major outer membrane protein of Escherichia coli K-12." J Bacteriol 169(10);4722-30. PMID: 2443485

Molloy00: Molloy MP, Herbert BR, Slade MB, Rabilloud T, Nouwens AS, Williams KL, Gooley AA (2000). "Proteomic analysis of the Escherichia coli outer membrane." Eur J Biochem 267(10);2871-81. PMID: 10806384

Molloy98: Molloy MP, Herbert BR, Walsh BJ, Tyler MI, Traini M, Sanchez JC, Hochstrasser DF, Williams KL, Gooley AA (1998). "Extraction of membrane proteins by differential solubilization for separation using two-dimensional gel electrophoresis." Electrophoresis 19(5);837-44. PMID: 9629924

Morona83: Morona R, Manning PA, Reeves P (1983). "Identification and characterization of the TolC protein, an outer membrane protein from Escherichia coli." J Bacteriol 153(2);693-9. PMID: 6337123

Muela08: Muela A, Seco C, Camafeita E, Arana I, Orruno M, Lopez JA, Barcina I (2008). "Changes in Escherichia coli outer membrane subproteome under environmental conditions inducing the viable but nonculturable state." FEMS Microbiol Ecol 64(1);28-36. PMID: 18318713

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

Nagakubo02: Nagakubo S, Nishino K, Hirata T, Yamaguchi A (2002). "The putative response regulator BaeR stimulates multidrug resistance of Escherichia coli via a novel multidrug exporter system, MdtABC." J Bacteriol 184(15);4161-7. PMID: 12107133

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

Niki90: Niki H, Imamura R, Ogura T, Hiraga S (1990). "Nucleotide sequence of the tolC gene of Escherichia coli." Nucleic Acids Res 18(18);5547. PMID: 2216730

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

Nishino01a: Nishino K, Yamaguchi A (2001). "Overexpression of the response regulator evgA of the two-component signal transduction system modulates multidrug resistance conferred by multidrug resistance transporters." J Bacteriol 183(4);1455-8. PMID: 11157960

Nishino02: Nishino K, Yamaguchi A (2002). "EvgA of the two-component signal transduction system modulates production of the yhiUV multidrug transporter in Escherichia coli." J Bacteriol 184(8);2319-23. PMID: 11914367

Nishino03a: 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

Pao98: Pao SS, Paulsen IT, Saier MH (1998). "Major facilitator superfamily." Microbiol Mol Biol Rev 1998;62(1);1-34. PMID: 9529885

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

Reed06: Reed JL, Patel TR, Chen KH, Joyce AR, Applebee MK, Herring CD, Bui OT, Knight EM, Fong SS, Palsson BO (2006). "Systems approach to refining genome annotation." Proc Natl Acad Sci U S A 103(46);17480-4. PMID: 17088549

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

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

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

Saier94a: 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

Tanabe09: Tanabe M, Szakonyi G, Brown KA, Henderson PJ, Nield J, Byrne B (2009). "The multidrug resistance efflux complex, EmrAB from Escherichia coli forms a dimer in vitro." Biochem Biophys Res Commun 380(2);338-42. PMID: 19171121

Tanabe97: Tanabe H, Yamasak K, Furue M, Yamamoto K, Katoh A, Yamamoto M, Yoshioka S, Tagami H, Aiba HA, Utsumi R (1997). "Growth phase-dependent transcription of emrKY, a homolog of multidrug efflux emrAB genes of Escherichia coli, is induced by tetracycline." J Gen Appl Microbiol 43(5);257-263. PMID: 12501312

Thanabalu98: Thanabalu T, Koronakis E, Hughes C, Koronakis V (1998). "Substrate-induced assembly of a contiguous channel for protein export from E.coli: reversible bridging of an inner-membrane translocase to an outer membrane exit pore." EMBO J 17(22);6487-96. PMID: 9822594

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

Tikhonova07: Tikhonova EB, Devroy VK, Lau SY, Zgurskaya HI (2007). "Reconstitution of the Escherichia coli macrolide transporter: the periplasmic membrane fusion protein MacA stimulates the ATPase activity of MacB." Mol Microbiol 63(3);895-910. PMID: 17214741

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.

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

UniProt11: UniProt Consortium (2011). "UniProt version 2011-06 released on 2011-06-30 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 manual assignment of UniProtKB keywords in UniProtKB/Swiss-Prot entries."

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

Vaccaro08: Vaccaro L, Scott KA, Sansom MS (2008). "Gating at both ends and breathing in the middle: conformational dynamics of TolC." Biophys J 95(12);5681-91. PMID: 18835894

Vega13: Vega DE, Young KD (2013). "Accumulation of periplasmic enterobactin impairs the growth and morphology of Escherichia coli tolC mutants." Mol Microbiol. PMID: 24330203

Wandersman90: Wandersman C, Delepelaire P (1990). "TolC, an Escherichia coli outer membrane protein required for hemolysin secretion." Proc Natl Acad Sci U S A 87(12);4776-80. PMID: 2112747

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

Wiriyathanawudh09: Wiriyathanawudhiwong N, Ohtsu I, Li ZD, Mori H, Takagi H (2009). "The outer membrane TolC is involved in cysteine tolerance and overproduction in Escherichia coli." Appl Microbiol Biotechnol 81(5);903-13. PMID: 18828007

Xu11c: 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

Xu11d: Xu Y, Song S, Moeller A, Kim N, Piao S, Sim SH, Kang M, Yu W, Cho HS, Chang I, Lee K, Ha NC (2011). "Functional implications of an intermeshing cogwheel-like interaction between TolC and MacA in the action of macrolide-specific efflux pump MacAB-TolC." J Biol Chem 286(15);13541-9. PMID: 21325274

Yamada06a: 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

Yamanaka01b: Yamanaka N, Yamamoto Y, Kuki K (2001). "Engraftment of tonsillar mononuclear cells in human skin/SCID mouse chimera--validation of a novel xenogeneic transplantation model for autoimmune diseases." Microbiol Immunol 2001;45(7);507-14. PMID: 11529556

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

Zgurskaya11: Zgurskaya HI, Krishnamoorthy G, Ntreh A, Lu S (2011). "Mechanism and Function of the Outer Membrane Channel TolC in Multidrug Resistance and Physiology of Enterobacteria." Front Microbiol 2;189. PMID: 21954395

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

Zhang07: Zhang N, Chen R, Young N, Wishart D, Winter P, Weiner JH, Li L (2007). "Comparison of SDS- and methanol-assisted protein solubilization and digestion methods for Escherichia coli membrane proteome analysis by 2-D LC-MS/MS." Proteomics 7(4);484-93. PMID: 17309111

Zhang08c: Zhang DF, Jiang B, Xiang ZM, Wang SY (2008). "Functional characterisation of altered outer membrane proteins for tetracycline resistance in Escherichia coli." Int J Antimicrob Agents 32(4);315-9. PMID: 18620846

Other References Related to Gene Regulation

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

Huerta03: Huerta AM, Collado-Vides J (2003). "Sigma70 promoters in Escherichia coli: specific transcription in dense regions of overlapping promoter-like signals." J Mol Biol 333(2);261-78. PMID: 14529615

Masuda02: Masuda N, Church GM (2002). "Escherichia coli gene expression responsive to levels of the response regulator EvgA." J Bacteriol 184(22);6225-34. PMID: 12399493

Nishino03: Nishino K, Inazumi Y, Yamaguchi A (2003). "Global analysis of genes regulated by EvgA of the two-component regulatory system in Escherichia coli." J Bacteriol 185(8);2667-72. PMID: 12670992

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

Rosner09: Rosner JL, Martin RG (2009). "An excretory function for the Escherichia coli outer membrane pore TolC: upregulation of marA and soxS transcription and Rob activity due to metabolites accumulated in tolC mutants." J Bacteriol 191(16);5283-92. PMID: 19502391

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

Zhang08: 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. PMID: 18673442


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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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