Comparative genomics of bacterial zinc regulons: enhanced ion transport, pathogenesis, and rearrangement of ribosomal proteins

Abstract

Zinc is an important component of many proteins, but in large concentrations it is poisonous to the cell. Thus its transport is regulated by zinc repressors ZUR of proteobacteria and Gram-positive bacteria from the Bacillus group and AdcR of bacteria from the Streptococcus group. Comparative computational analysis allowed us to identify binding signals of ZUR repressors GAAATGTTATANTATAACATTTC for gamma-proteobacteria, GTAATGTAATAACATTAC for the Agrobacterium group, GATATGTTATAACATATC for the Rhododoccus group, TAAATCGTAATNATTACGATTTA for Gram-positive bacteria, and TTAACYRGTTAA of the streptococcal AdcR repressor. In addition to known transporters and their paralogs, zinc regulons were predicted to contain a candidate component of the ATP binding cassette, zinT (b1995 in Escherichia coli and yrpE in Bacillus subtilis). Candidate AdcR-binding sites were identified upstream of genes encoding pneumococcal histidine triad (PHT) proteins from a number of pathogenic streptococci. Protein functional analysis of this family suggests that PHT proteins are involved in the invasion process. Finally, repression by zinc was predicted for genes encoding a variety of paralogs of ribosomal proteins. The original copies of all these proteins contain zinc-ribbon motifs and thus likely bind zinc, whereas these motifs are destroyed in zinc-regulated paralogs. We suggest that the induction of these paralogs in conditions of zinc starvation leads to their incorporation in a fraction of ribosomes instead of the original ribosomal proteins; the latter are then degraded with subsequent release of some zinc for the utilization by other proteins. Thus we predict a mechanism for maintaining zinc availability for essential enzymes.

Fig. 1.

Phylogenetic tree of ZUR repressors from proteobacteria and consensuses of binding sites. Underlines, center of symmetry of inverted palindromes; boldfaced type, positions coinciding among the three signals.

Fig. 2.

ZinT domains and regulation of zinT genes. Circles, candidate zinc repressor-binding sites; striped arrows, adcA/znuA; hatched arrows, zinT; black rectangles, transmembrane segment; gray rectangles, histidine/aspartate/glutamate-rich segment.

Fig. 3.

The predicted regulation of ribosomal proteins by zinc. (Upper) Zn-rich conditions. The ribosomes contain the protein with functional Zn ribbon (black circles), and transcription of the gene encoding the paralog (gray arrow) is inhibited by the zinc repressor (ZUR or AcdR, black rectangle) bound to the upstream recognition site (double arrow). (Lower) Zn-depleted conditions. The paralog gene is expressed (broken arrow), and the protein is incorporated into a fraction of ribosomes (gray circles), thus releasing zinc (dotted arrow) for incorporation into Zn-dependent enzymes (triangles).