Mining copper transport genes

Abstract

Copper is not only a ubiquitous metal in our modern, technological environment, it is also essential for the function of most living organisms. Just as it allows for the movement of electrons through wires, it helps catalyze the movement of electrons within biological molecules. Making up only 0.01% of the Earth's crust, it is relatively scarce in the environment and must be actively scavenged. Until recently, little was known about how trace amounts of dietary copper are assimilated by intestinal absorptive cells to enter the body. In this issue of PNAS, three groups report genetic studies that may give insight into this process. Kuo et al. (1) and Lee et al. (2) report targeted gene disruption of a putative copper uptake molecule, Ctr1. In an accompanying report, Hamza and colleagues (3) report disruption of the gene encoding a copper chaperone, which escorts copper to sites of use and export within the cell. The story begins in yeast. For copper, more than any other essential metal, Saccharomyces cerevisiae has proven to be a model model system. Ironically, insights into copper metabolism initially came from experiments aimed at understanding how cells take up iron. Dancis, Kaplan, Klausner, and colleagues (4, 5) set up genetic screens to find mutations that protected yeast cells from excess environmental iron, hoping to identify components of the high-affinity iron uptake system. One of the first genes they found encoded a putative transmembrane transport protein that, to their surprise, had no affinity for iron, but rather transported copper. This protein, designated Ctr1p, supplies the metal for a multicopper ferroxidase needed for high affinity iron transport. Until that time, little was known about how copper enters eukaryotic cells, although some details of copper export had been elucidated through studies of human patients with Menkes disease and Wilson disease …