Manipulating the drug/proton antiport stoichiometry of the secondary multidrug transporter MdfA
- 16 July 2012
- journal article
- Published by National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 109 (31) , 12473-12478
Abstract
Multidrug transporters are integral membrane proteins that use cellular energy to actively extrude antibiotics and other toxic compounds from cells. The multidrug/proton antiporter MdfA from Escherichia coli exchanges monovalent cationic substrates for protons with a stoichiometry of 1, meaning that it translocates only one proton per antiport cycle. This may explain why transport of divalent cationic drugs by MdfA is energetically unfavorable. Remarkably, however, we show that MdfA can be easily converted into a divalent cationic drug/≥ 2 proton-antiporter, either by random mutagenesis or by rational design. The results suggest that exchange of divalent cationi c drugs with two (or more) protons requires an additional acidic residue in the multidrug recognition pocket of MdfA. This outcome further illustrates the exceptional promiscuous capabilities of multidrug transporters.Keywords
This publication has 27 references indexed in Scilit:
- Dissection of Mechanistic Principles of a Secondary Multidrug Efflux ProteinMolecular Cell, 2012
- Alkalitolerance: A biological function for a multidrug transporter in pH homeostasisProceedings of the National Academy of Sciences, 2004
- Determinants of Substrate Recognition by the Escherichia coli Multidrug Transporter MdfA Identified on Both Sides of the MembraneJournal of Biological Chemistry, 2004
- Role of a Conserved Membrane-Embedded Acidic Residue in the Multidrug Transporter MdfABiochemistry, 2003
- The Escherichia coli multidrug transporter MdfA catalyzes both electrogenic and electroneutral transport reactionsProceedings of the National Academy of Sciences, 2003
- Evidence for Simultaneous Binding of Dissimilar Substrates by the Escherichia coli Multidrug Transporter MdfABiochemistry, 2001
- Phylogeny of multidrug transportersSeminars in Cell & Developmental Biology, 2001
- Functional expression of mouse Mdr1 in an outer membrane permeability mutant of Escherichia coli.Proceedings of the National Academy of Sciences, 1996
- Multidrug resistance proteins QacA and QacB from Staphylococcus aureus: membrane topology and identification of residues involved in substrate specificity.Proceedings of the National Academy of Sciences, 1996
- Functional expression of mouse mdr1 in Escherichia coli.Proceedings of the National Academy of Sciences, 1993