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An ABC transporter with a secondary-active multidrug translocator domain

Nature volume 426, pages 866–870 (2003)Cite this article

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-glycoprotein1. Two major classes of transporters mediate this extrusion2,3. 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 LmrA4 is a primary drug transporter in Lactococcus lactis that can functionally substitute for P-glycoprotein in lung fibroblast cells5. 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.

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Figure 1: Structural properties of LmrA are maintained in LmrA-MD.
Figure 2: LmrA-MD mediates multidrug uptake in L. lactis.
Figure 3: Ethidium transport by LmrA-MD is coupled to Δp.
Figure 4: Coupled efflux of ethidium and protons by LmrA in L. lactis cells.

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Acknowledgements

We thank Chris Higgins, Peter McNaughton, Ben Luisi, and Ian Booth for stimulating discussions. This research was funded by Cancer Research UK, the Association of International Cancer Research (AICR), the Biotechnology and Biological Sciences Research Council (BBSRC), the Medical Research Council (MRC), the Royal Society, and Molecular Devices Ltd. S.V. was the recipient of a Cambridge Nehru Scholarship.

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  1. Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1PD, UK

    Henrietta Venter, Richard A. Shilling, Saroj Velamakanni, Lekshmy Balakrishnan & Hendrik W. van Veen

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Correspondence to Hendrik W. van Veen.

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Venter, H., Shilling, R., Velamakanni, S. et al. An ABC transporter with a secondary-active multidrug translocator domain. Nature 426, 866–870 (2003). https://doi.org/10.1038/nature02173

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