Abstract
Bacteria respond dynamically to the changes in zinc availability. Repression by the Bacillus subtilis transcription factor Zur requires Zn(II), which binds with negative cooperativity to two regulatory sites per dimer to form, sequentially, Zur2:Zn3 and Zur2:Zn4 forms of the repressor. Here we show that, as cells transition from zinc sufficiency to deficiency, operons regulated by Zur are derepressed in three distinct waves. The first includes the alternative RpmEB(L31*) and RpmGC(L33*) ribosomal proteins, which mobilize zinc from the ribosome, whereas the second includes the ZnuACB uptake system and the YciC metallochaperone. Finally, as zinc levels decrease further, the Zur2:Zn3 form loses Zn(II) leading to derepression of RpsNB(S14*) and FolE2, which allow continued ribosome assembly and folate synthesis, respectively. We infer that zinc mobilization from intracellular zinc stores takes priority over energy-dependent import, and our results link the biochemistry of zinc sensing by Zur to the molecular logic of the zinc deprivation response.
Highlights
Bacteria respond dynamically to the changes in zinc availability
Our results indicate that as cells transition from zinc sufficiency to zinc limitation operons regulated by zinc uptake regulator (Zur) are derepressed in three distinct waves
On the basis of these findings, we extended this analysis to include an additional Zur-regulated gene, rpmGC, which is a pseudogene in B. subtilis 168 due to a frameshift mutation
Summary
Bacteria respond dynamically to the changes in zinc availability. Repression by the Bacillus subtilis transcription factor Zur requires Zn(II), which binds with negative cooperativity to two regulatory sites per dimer to form, sequentially, Zur2:Zn3 and Zur2:Zn4 forms of the repressor. As might be anticipated for a stress response activated when an essential metal becomes limiting for growth, a key part of this adaptive response is the expression of a high-affinity ABC transporter uptake system encoded by the znuACB operon, which likely functions together with a Zn(II) scavenging lipoprotein, ZinT10–12, and a highly abundant member of the COG0523 family of metallochaperones (YciC) conserved in Bacteria, Eukarya and Archaea[13]. The expression of a third ribosomal protein paralogue (S14*, encoded by rpsNB) allows for de novo ribosome synthesis, which might otherwise become limited by the cell’s ability to synthesize the Zn-requiring S14 protein[7,18] Another process that becomes limiting when cells are zinc deficient is folate biosynthesis due to the Zn dependence of the FolE1 GTP cyclohydrolase. We conclude that the negative cooperativity in Zn(II) binding to Zur is responsible for the transition between the middle and late genes derepressed as part of the zinc limitation adaptive response
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