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Escherichia coli K-12 substr. MG1655 Transporter: 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]

Gene-Reaction Schematic: ?

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 AcrAD-TolC multidrug efflux system: AcrAD-TolC multidrug efflux system - permease subunit

Synonyms: YffA

Gene: acrD Accession Numbers: EG10014 (EcoCyc), b2470, ECK2465

Locations: inner membrane

Sequence Length: 1037 AAs

Molecular Weight: 113.05 kD (from nucleotide sequence)

GO Terms:

Biological Process: GO:0006855 - drug transmembrane transport Inferred from experiment [Rosenberg00]
GO:0042493 - response to drug Inferred from experiment [Aires05]
GO:0046618 - drug export Inferred from experiment [Aires05]
GO:0006810 - transport Inferred by computational analysis [UniProtGOA11, GOA01]
Molecular Function: GO:0015238 - drug transmembrane transporter activity Inferred from experiment [Rosenberg00]
GO:0015307 - drug:proton antiporter activity Inferred from experiment [Aires05]
GO:0005215 - transporter activity Inferred by computational analysis [GOA01]
Cellular Component: GO:0005886 - plasma membrane Inferred from experiment Inferred by computational analysis [UniProtGOA11a, UniProtGOA11, DiazMejia09, Daley05]
GO:0016020 - membrane Inferred from experiment Inferred by computational analysis [UniProtGOA11, GOA01, Aires05]
GO:0016021 - integral component of membrane Inferred by computational analysis [UniProtGOA11, GOA01]

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

Unification Links: DIP:DIP-9050N , EcoliWiki:b2470 , Mint:MINT-1256458 , ModBase:P24177 , Pride:P24177 , Protein Model Portal:P24177 , RefSeq:NP_416965 , SMR:P24177 , String:511145.b2470 , Swiss-Model:P24177 , UniProt:P24177

Relationship Links: InterPro:IN-FAMILY:IPR001036 , InterPro:IN-FAMILY:IPR004764 , InterPro:IN-FAMILY:IPR027463 , Pfam:IN-FAMILY:PF00873 , Prints:IN-FAMILY:PR00702

Summary:
AcrD is a member of the resistance-nodulation-division (RND) superfamily [Saier14] and a component of the AcrAD-TolC multidrug efflux transport system in E. coli K-12. By analogy with the AcrB RND permease, AcrD is shown as a homotrimer in the complex.

Essentiality data for acrD 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]

Subunit of AcrAD-TolC multidrug efflux system: AcrAB-TolC multidrug efflux system - membrane fusion protein

Synonyms: SipB, Mbl, Lir, NbsA, MtcA, AcrA, acridine efflux pump, AcrA membrane fusion protein

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

Locations: periplasmic space, inner membrane

Sequence Length: 397 AAs

Molecular Weight: 42.197 kD (from nucleotide sequence)

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 [UniProtGOA11]
GO:0046677 - response to antibiotic Inferred by computational analysis [UniProtGOA11]
GO:0055085 - transmembrane transport Inferred by computational analysis [GOA01]
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 [UniProtGOA11a, UniProtGOA11, Stenberg05]
GO:0016020 - membrane Inferred by computational analysis [UniProtGOA11, GOA01]
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)

Unification Links: DIP:DIP-29039N , EcoliWiki:b0463 , ModBase:P0AE06 , PR:PRO_000022048 , Pride:P0AE06 , Protein Model Portal:P0AE06 , RefSeq:NP_414996 , 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

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 [Ge09] 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].

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]

Subunit of AcrAD-TolC multidrug efflux system: TolC outer membrane channel

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

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

Locations: outer membrane

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

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)

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, Han12, 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)

Unification Links: DIP:DIP-11007N , EcoliWiki:b3035 , ModBase:P02930 , PR:PRO_000024080 , Protein Model Portal:P02930 , RefSeq:NP_417507 , 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

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, Lin08, Zhang08]

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]

References

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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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