Document Detail

On the role of TolC in multidrug efflux: the function and assembly of AcrAB-TolC tolerate significant depletion of intracellular TolC protein.
MedLine Citation:
PMID:  23331412     Owner:  NLM     Status:  MEDLINE    
TolC channel provides a route for the expelled drugs and toxins to cross the outer membrane of Escherichia coli. The puzzling feature of TolC structure is that the periplasmic entrance of the channel is closed by dense packing of 12 α-helices. Efflux pumps exemplified by AcrAB are proposed to drive the opening of TolC channel. How interactions with AcrAB promote the close-to-open transition in TolC remains unclear. In this study, we investigated in vivo the functional and physical interactions of AcrAB with the closed TolC and its conformer opened by mutations in the periplasmic entrance. We found that the two conformers of TolC are readily distinguishable in vivo by characteristic drug susceptibility, thiol modification and proteolytic profiles. However, these profiles of TolC variants respond neither to the in vivo stoichiometry of AcrAB:TolC nor to the presence of vancomycin, which is used often to assess the permeability of TolC channel. We further found that the activity and assembly of AcrAB-TolC tolerates significant changes in amounts of TolC and that only a small fraction of intracellular TolC is likely used to support efflux needs of E. coli. Our findings explain why TolC is not a good target for inhibition of multidrug efflux.
Ganesh Krishnamoorthy; Elena B Tikhonova; Girija Dhamdhere; Helen I Zgurskaya
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2013-01-21
Journal Detail:
Title:  Molecular microbiology     Volume:  87     ISSN:  1365-2958     ISO Abbreviation:  Mol. Microbiol.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-02-25     Completed Date:  2013-08-23     Revised Date:  2014-03-06    
Medline Journal Info:
Nlm Unique ID:  8712028     Medline TA:  Mol Microbiol     Country:  England    
Other Details:
Languages:  eng     Pagination:  982-97     Citation Subset:  IM    
Copyright Information:
© 2013 Blackwell Publishing Ltd.
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MeSH Terms
Anti-Bacterial Agents / metabolism,  pharmacology
Bacterial Outer Membrane Proteins / genetics,  metabolism*
Biological Transport
Escherichia coli / drug effects,  genetics,  metabolism*
Escherichia coli Proteins / genetics,  metabolism*
Lipoproteins / genetics,  metabolism*
Membrane Transport Proteins / genetics,  metabolism*
Multidrug Resistance-Associated Proteins / genetics,  metabolism*
Protein Binding
Vancomycin / metabolism,  pharmacology
Grant Support
Reg. No./Substance:
0/AcrA protein, E coli; 0/AcrB protein, E coli; 0/Anti-Bacterial Agents; 0/Bacterial Outer Membrane Proteins; 0/Escherichia coli Proteins; 0/Lipoproteins; 0/Membrane Transport Proteins; 0/Multidrug Resistance-Associated Proteins; 0/tolC protein, E coli; 6Q205EH1VU/Vancomycin

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