metal ion homeostasis
descriptionOver
20 classes of metabolite-sensing regulatory RNAs (‘riboswitches’) have
been discovered for sensing of enzymatic cofactors, nucleobases, amino
acids, glucosamine-6-phosphate, and the second messenger molecule,
cyclic di-GMP. Certain riboswitch classes are exceptionally widespread
in their phylogenetic distribution, suggesting their presence prior to
the divergence of the major bacterial lineages. At least one class has
been discovered in algae, fungi and plants, and regulates splicing in
response to changing intracellular thiamine levels. Bioinformatics-aided
methods have also led to the identification of at least a dozen more
convincing categories of riboswitches, although the metabolites that
bind to them remain unidentified. These latter ‘orphan’ riboswitches are
likely to regulate expression of a wide variety of genes, including
numerous genes of unknown function. In the past several years our
research efforts have focused on the detailed analyses of riboswitch
mechanisms in general as well as investigation of several classes of
‘orphan’ riboswitches in particular. One orphan class, renamed as the
‘M-box’ element, is usually located upstream of putative magnesium
transport genes. Using a combination of genetic, biochemical and
biophysical approaches, our ongoing data reveals that the M-box RNA
structure functions as a direct sensor for divalent ions. Specifically,
association of divalent ions couples a global conformational change with
control of downstream gene expression. These data expand the riboswitch
ligand repertoire to include metals and suggest a simple biochemical
model for how an RNA-based metalloregulatory agent can be used to
regulate metal homeostasis. We are currently investigating several other
classes of riboswitches that regulate other metal ion transporters. We
are also exploring a variety of synthetic applications for
metalloregulatory RNAs.