Origins of metal ion selectivity in the DtxR/MntR family of metalloregulators

Corynebacterium diphtheriae DtxR is an iron-specific repressor of diphtheria toxin expression and iron homeostasis functions. A homologue, MntR, serves as a manganese-specific repressor of Mn(II) uptake in Bacillus subtilis . When expressed in B. subtilis, DtxR regulates gene expression in response to either iron or manganese with comparable sensitivity. Replacement of two amino acids in the metal-sensing site with the corresponding residues from MntR results in a DtxR mutant that is highly selective for Mn(II). However, iron responsiveness can be partially restored in a fur mutant in which iron uptake is derepressed and intracellular iron pools elevated. Conversely, if the putative metal-binding residues in MntR are altered to those in DtxR, the resulting protein responds to both iron and manganese. These results suggest that the composition and geometry of the metal-binding site plays a major role in defining the metal-selectivity in this protein family. However, the broadened selectivity of DtxR when expressed in B. subtilis, and the effects of a fur mutation, demonstrate that cellular milieu also influences metal responsiveness.