Copper is an essential metal ion that is toxic when accumulated to high intracellular concentrations. The yeast Mac1 protein is a copper-sensing transcription factor that is essential for both the activation and inactivation of genes required for high affinity copper ion transport. Here we demonstrate that in response to low copper ion concentrations Mac1 protein is rendered inactive for copper transporter gene transcription. Under high copper ion concentrations Mac1 is degraded in a rapid, copper-specific manner. This degradation is critical to prevent copper toxicity that would otherwise result from sustained expression of the copper transport genes. These results demonstrate that nutritional and toxic copper concentrations elicit distinct fates for the Mac1 copper-sensing transcription factor and establish a new mechanism by which trace metals regulate gene expression.
