Transition metal ions are essential for life (1). Cells regulate the traffic of transition metal ions (such as copper and iron), maintaining the amount necessary for biological function while avoiding excess levels that are toxic (2). Among the factors required to achieve such metal ion homeostasis are the metallochaperones, proteins that, like chaperones in ordinary life, guide and protect transition metal ions within the cell, delivering them safely to the appropriate protein receptors (3). One such metallochaperone is yCCS, a yeast protein encoded by the LYS7 gene. This copper chaperone and its homologs in mice and humans deliver copper to the antioxidant enzyme copper-zinc superoxide dismutase (SOD1) and colocalize with SOD1 in vivo (4–6). SOD1 is mutated in people with an inherited form of familial amyotrophic lateral sclerosis, a fatal neurological disorder also known as Lou Gehrig's disease, that may be caused by aberrant effects of copper facilitated by improperly folded forms of the enzyme (7). Colocalization of CCS and SOD1 in mammalian tissue of the central nervous system is particularly intriguing and may yield clues for developing therapeutic strategies to treat this disease (6). On page 805 of this issue, Rae et al. show that yCCS directly inserts copper into SOD1 and is active at very low copper concentrations (8). In the course of their investigation, the authors made the remarkable discovery that the upper limit of so-called “free” pools of copper was far less than a single atom per cell. It had been commonly believed that metal ions were in equilibrium with metalloproteins. The implications of this finding are profound, especially if applicable to other physiologically important transition metals.

A study of how SOD1 acquires copper in vivo resulted in the discovery of yCCS (4). Yeast is an excellent model system to investigate the trafficking of transition metal ions in eukaryotes. The Ctr family of membrane proteins facilitates the transport of copper ions across the yeast plasma membrane, and yCCS and two other copper metallochaperones assure its delivery to specialized compartments or enzymes in the cell (9)(see the figure).