title: An ABC transporter with a secondary-active multidrug translocator domain.
abstract: Multidrug resistance, by which cells become resistant to multiple unrelated pharmaceuticals, is due to the extrusion of drugs from the cell's interior by active transporters such as the human multidrug resistance P-glycoprotein. Two major classes of transporters mediate this extrusion. Primary-active transporters are dependent on ATP hydrolysis, whereas secondary-active transporters are driven by electrochemical ion gradients that exist across the plasma membrane. The ATP-binding cassette (ABC) transporter LmrA is a primary drug transporter in Lactococcus lactis that can functionally substitute for P-glycoprotein in lung fibroblast cells. Here we have engineered a truncated LmrA protein that lacks the ATP-binding domain. Surprisingly, this truncated protein mediates a proton-ethidium symport reaction without the requirement for ATP. In other words, it functions as a secondary-active multidrug uptake system. These findings suggest that the evolutionary precursor of LmrA was a secondary-active substrate translocator that acquired an ATP-binding domain to enable primary-active multidrug efflux in L. lactis.
authors.affiliation: Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK.
authors.forename: Henrietta
authors.initials: H
authors.lastname: Venter
authors.forename: Richard A
authors.initials: RA
authors.lastname: Shilling
authors.forename: Saroj
authors.initials: S
authors.lastname: Velamakanni
authors.forename: Lekshmy
authors.initials: L
authors.lastname: Balakrishnan
authors.forename: Hendrik W
authors.initials: HW
authors.lastname: Van Veen
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D001693:Biological Transport, Active; D018432:Drug Resistance, Multiple; D004996:Ethidium / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D013294:Lactococcus lactis / Q000235:genetics / Q000378:metabolism*; D008564:Membrane Potentials; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D018892:Proton-Motive Force; D011522:Protons; D017384:Sequence Deletion / Q000235:genetics
chemical_list: D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate; D001426:Bacterial Proteins; D004996:Ethidium; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011522:Protons; C101824:LmrA protein, Lactococcus lactis