Characterization and function of metal ion clusters in metallothionein and metallothionein-like proteins

Metal ions can interact with specific biological molecules and activate or regulate the function of these molecules by causing a change in molecular structure. Metallothioneins (MTs) are small, cysteine rich proteins that bind metal ions tenaciously. Metal ions are chelated within polymetallic clusters and undergo facile metal exchange reactions. MTs appear to function in metal ion regulation and detoxification. Metallothionein-3 (MT-3) is a brain specific member of the metallothionein family of metal binding proteins, and its absence has been implicated in the development of Alzheimer's disease (AD). The growth inhibitory activity of MT-3 appears to result from a distinct amino acid sequence and not unusual metal-binding properties compared with MT-1 or MT-2. The transcription factor Macl from S. cerevisiae regulates the expression of the high affinity copper uptake system in a copper dependent manner. When cells are exposed to copper concentration above starvation levels expression of genes in this uptake system is inhibited. Macl contains two cysteine rich motifs in the C-terminus which resemble Cu(I) binding cysteinyl sequences found in MTs. Macl was found to directly bind Cu(I) ions and a copper dependent intramolecular interaction between the N-terminal DNA binding domain and the C-terminal copper binding activation domain was identified. This interaction may result in the masking of the DNA binding domain in a copper dependent manner abolishing expression of Macl regulated genes. In yeast, MT genes are transcriptionally induced by copper, but not by other metal ions. The primary copper buffering protein in S. cerevisiae is a MT