CLONING AND CHARACTERIZATION OF A MAMMALIAN PROTON-COUPLED METAL-ION TRANSPORTER

Metal ions are essential cofactors for a wealth of biological processe s, including oxidative phosphorylation, gene regulation and free-radic al homeostasis. Failure to maintain appropriate levels of metal ions i n humans is a feature of hereditary haemoduomatosis(1), disorders of m etal-ion deficiency, and certain neurodegenerative diseases(2). Despit e their pivotal physiological roles, however, there is no molecular in formation on how metal ions are actively absorbed by mammalian cells. We have now identified a new metal-ion transporter in the rat, DCT1, w hich has an unusually broad substrate range that includes Fe2+ Zn2+, M n2+, 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 k ey mediator of intestinal iron absorption. DCT1 is a member of the 'na tural-resistance-associated macrophage protein' (Nramp) family(3-5) an d thus its properties provide insight into how these proteins confer r esistance to pathogens.