Metal sensor proteins: nature's metalloregulated allosteric switches

Metalloregulatory proteins control the expression of genes that allow organisms to quickly adapt to chronic toxicity or deprivation of both biologically essential metal ions and heavy metal pollutants found in their microenvironment. Emerging evidence suggests that metal ion homeostasis and resistance defines an important tug-of-war in human host-bacterial pathogen interactions. This adaptive response originates with the formation of "metal receptor" complexes of exquisite selectivity. In this perspective, we summarize consensus structural features of metal sensing coordination complexes and the evolution of distinct metal selectivities within seven characterized metal sensor protein families. In addition, we place recent efforts to understand the structural basis of metal-induced allosteric switching of these metalloregulatory proteins in a thermodynamic framework, and review the degree to which coordination chemistry drives changes in protein structure and dynamics in selected metal sensor systems. New insights into how metal sensor proteins function in the complex intracellular milieu of the cytoplasm of cells will require a more sophisticated understanding of the "metallome" and will benefit greatly from ongoing collaborative efforts in bioinorganic, biophysical and analytical chemistry, structural biology and microbiology.