Metal ion sensory mechanisms are critical for cellularresponses to essential and toxic metals alike. Emergingfrom studies of microbial metalloregulatory systems are general models that serve as starting points forunderstanding the cell biology of metals in humans. The MerR and Fur families of metalloregulatory proteinscontrol the expression of an array of genes that protect the eubacterial cell from physical and chemical stressesincluding antibiotictreatments. In a variety of virulent microbes, Fur or a closely related iron-sensor proteincontrols toxin expression. A general but controversial mechanism for iron-responsive derepression has beenproposed but is as of yet unresolved. Mechanistic studies of these mercury and iron sensor proteins are now beginningto provide insightsinto zincand copper-responsive metalloregulation. The E. coli ZntR protein, a recently discovered member of the MerRfamily, is a zinc-specific metalloregulatory protein that controls expression of zinc export machinery. Itscounterpart, the Zur protein, is a member of the Fur family that exerts zinc-responsive control over the expressionof zinc uptake machinery. Together these genes govern zinc uptake and export, ensuring that cells experienceneither zinc starvation nor toxicity. In both cases the mechanisms of transcriptional control or the molecular basisof metal recognition are not yet established. This proposal focuses on energetic and structural aspects of metal recognition and metal-inducedconformation changes in the allosteric switching mechanism. MerR controls transcription in an unprecedentedmanner: metal-protein interactionsinduce distortions in DNA structure that make the DNA a better templatefor thetranscription machinery. By comparing the positive control mechanism for other family members such as ZntR, acomprehensive test of this DNA distortion mechanism is possible. Positive control mechanisms are poorlyunderstood and yet are of fundamental importance in understanding the molecular basis of genetic regulation. The molecular basis of heavy metal recognition in the ZntR, Zur, and Fur systems will be probed at thebiopolymer and coordination chemistry levels. The structure, function, and energetic insightsof these new stress-responsive transcription factors will provide a deeper understanding of molecular mechanisms and transition metalcell biology.
|Effective start/end date||9/15/09 → 2/29/12|
- National Institute of General Medical Sciences (3R37GM038784-22S1)