The metallothionein structural motif in gene expression

Metalloregulation in eukaryotic organisms is poorly understood. Only a limited number of physiological processes are currently known to be regulated by metal ions. Copper salts stimulate transcription of MT and SOD genes in fungi and repress expression of cytochrome c6 in algae. The Cu-activation of gene expression in fungi is mediated by a Cu1+ specific sensor protein. The mechanism of Cu-activation of the sensor molecule, ACE1 (and probably AMT1), appears to be the formation of a CuS polymetallic cluster as the structural core of the proteins. Structural similarities between ACE1, AMT1 and metallothionein suggest that the MT motif is a good structural model to explain the metal-specific activation and specificity of the two signal transducing proteins. Metal ion specificity is achieved by the propensity of proteins with a MT motif to form multinuclear CuS centers. Coordination inorganic chemistry appears to be the driving force for Cu1+ metalloregulation in biology. The metalloregulation of transcriptional activation of mammalian MT genes will be intriguing as metal ion selectivity is not as apparent. The MT motif is not expected to be a highly redundant structural theme. The intriguing observation by Uchida et al. (154) that the growth inhibitory factor (MTIII) deficient in the brains of Alzheimer's patients is homologous to metallothioneins raises the likelihood that coordination chemistry will be critical in stabilizing the bioactive form of MTIII. The motif may be observed in yet to be identified metalloregulatory proteins that regulate other processes in a Cu- or Zn-specific manner. Formation of metal:thiolate polymetallic clusters allows a significant volume of the protein structure to be altered, so metal-induced structural dynamics are possible. CuS polynuclear clusters may be more general than the MT motif in biology. The only molecules currently known to form CuS polynuclear clusters include MT, ACE1 and the Cu(gamma EC)nG complexes, although AMT1 and MTIII are expected to be the next members in the list. Three other Cys-rich proteins, papilloma viral E7 and LIM motif-containing CRP and CRIP, isolated as Zn2+ proteins exhibit facile metal exchange in vitro with Cu1+. The resulting Cu1+ proteins show optical properties similar to CuMTs (202,203). Although CuS clusters may form in E7 and LIM-containing proteins, it is premature to ascribe any biological significance to the Cu1+ conformers.