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Cloning and characterization of a mammalian proton-coupled metal-ion transporter

Nature volume 388, pages 482–488 (1997)Cite this article

Abstract

Metal ions are essential cofactors for a wealth of biological processes, including oxidative phosphorylation, gene regulation and free-radical homeostasis. Failure to maintain appropriate levels of metal ions in humans is a feature of hereditary haemochromatosis1, disorders of metal-ion deficiency, and certain neurodegenerative diseases2. Despite their pivotal physiological roles, however, there is no molecular information on how metal ions are actively absorbed by mammalian cells. We have now identified a new metal-ion transporter in the rat, DCT1, which has an unusually broad substrate range that includes Fe2+, Zn2+, Mn2+, Co2+, Cd2+, Cu2+, Ni2+ and Pb2+. DCT1 mediates active transport that is proton-coupled and depends on the cell membrane potential. It is a 561-amino-acid protein with 12 putative membrane-spanning domains and is ubiquitously expressed, most notably in the proximal duodenum. DCT1 is upregulated by dietary iron deficiency, and may represent a key mediator of intestinal iron absorption. DCT1 is a member of the ‘natural-resistance-associated macrophage protein’ (Nramp) family3,4,5 and thus its properties provide insight into how these proteins confer resistance to pathogens.

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Figure 1: Uptake of 10 µM 55Fe in Xenopus oocytes injected with poly(A)+RNA from normal or iron-de.
Figure 2: Sequence alignment of DCT1 and Nramp-related polypeptides.
Figure 3: High-stringency northern blot analysis of RNA from rat tissues probed with 32P-labelled DCT1 cDNA.
Figure 4: Tissue localization of rat DCT1 mRNA detected by in situ hybridization.
Figure 5: Currents associated with the divalent cation transporter DCT1 expressed in oocytes.

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Acknowledgements

Nramp cDNA was a generous gift from P. Gros. We thank D. Eide for stimulating discussion. This research was supported by the NIH.

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Authors and Affiliations

  1. Renal Division, Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, Boston, 02115, Massachusetts, USA

    Hiromi Gunshin, Bryan Mackenzie, Urs V. Berger, Yoshimi Gunshin, Stephan Nussberger & Matthias A. Hediger

  2. Department of Cellular & Molecular Physiology, Yale University, New Haven, 06510, Connecticut, USA

    Michael F. Romero & Walter F. Boron

  3. Gastroenterology Division, Department of Medicine, Brigham & Women's Hospital, Boston, 02115, Massachusetts, USA

    John L. Gollan

  4. Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Matthias A. Hediger

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Correspondence to Hiromi Gunshin.

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Gunshin, H., Mackenzie, B., Berger, U. et al. Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 388, 482–488 (1997). https://doi.org/10.1038/41343

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