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

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) family^3,4,5 and thus its properties provide insight into how these proteins confer resistance to pathogens.