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In bacteria, the process of transcription is tightly regulated by diverse mechanisms; for a bacterial pathogen colonizing the infected host, this allows swift adaptation to host insults by “sensing” changes in a specific molecule or metal ion inside the cell. We are particularly interested in “one-component” sensors that detect an expanded range of inorganic stressors, from transition metals to reactive sulfur species (RSS), the latter of which accumulate in cells when hydrogen sulfide (H2S) concentrations rise. H2S/RSS homeostasis, like transition metal homeostasis, is an emerging feature of bacterial survival in the vertebrate host. Metallosensors make coordination complexes with specific transition metal ions, while per- and polysulfide sensors perform thiol chemistry with RSS; each allosterically inhibits DNA binding, leading to the upregulation of genes encoding enzymes that direct the adaptive response. These regulatory proteins thus function as inorganic allosteric switches. Comparative studies of diverse inorganic sensors from the same structural class provide an opportunity to identify not only general regulatory features but also insights into the evolution of distinct biological outputs (functional diversity) on an unchanging molecular scaffold. The results of NMR-based investigations into conformational dynamics, crystallographic and chemical specificity experiments on pairs of functionally distinct sensors from the dimeric arsenic repressor (ArsR) and tetrameric copper-sensitive operon repressor (CsoR) family of proteins will be discussed. Dynamical models of allostery appear to figure prominently in these repressor systems.
Publié le juillet 4, 2022