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EnglishAccording to the grounding work of Jacob and Monod, transcription factors (TFs) regulate gene expression by modulating their DNA binding affinity in response to a particular signal, or in the presence of a specific cofactor, much akin inducible or repressible on-off switches. Whilst the vast majority of TFs recognize distinct elements through the readout of conserved nucleotide motifs in the major groove of DNA, a few are able to bind specifically in the minor groove. Here we report the finding of a TF able to discriminatively exploit the binding to either the major or the minor DNA groove in order to mediate opposite read-out of the same regulatory signal. This mechanism accounts for the ability of the ferric uptake regulator Fur, a widespread prokaryotic transcriptional regulator involved in metal ion homeostasis and virulence in many bacteria, to repress the expression of both iron-inducible and iron-repressible genes in the human pathogen Helicobacter pylori. In particular, we demonstrate that Fur exploits the two grooves of DNA to function like a molecular commutator switch. In the apo-form, Fur binds with higher affinity to an iron-induced promoter as dimer, through the readout of thymine dimers in the major groove, contributing to its transcriptional repression under iron-deplete conditions. Conversely, on iron-repressed promoters, the metal ion acts as co-repressor, inducing protein conformational changes that prompt multimerization of the regulator and high affinity binding to the minor groove in occurrence of AT-rich inverted repeats. The latter mechanism appears to involve an Arg residue in helix H1 of the HTH-DNA-binding domain. In addition, molecular modelling and in silico docking indicate that binding to the minor groove involves conformation of the HTH-DNA binding domains of four Fur monomers into a tetrameric DNA clamp. These results provide evidence for a novel regulatory mechanism that may be exploited also in other bacteria.
| Titolo: | Discriminative Recognition of Major or Minor DNA Grooves Commutates Between Iron-inducible and Iron-repressible Fur Regulation in the Human Pathogen Helicobacter pylori |
| Autore/i: | F. Agriesti; RONCARATI, DAVIDE; MUSIANI, FRANCESCO; C. Del Campo; M. Iurlaro; SPARLA, FRANCESCA; CIURLI, STEFANO LUCIANO; DANIELLI, ALBERTO; SCARLATO, VINCENZO |
| Autore/i Unibo: | |
| Anno: | 2011 |
| Titolo del libro: | PROCEEDINGS |
| Pagina iniziale: | 87 |
| Pagina finale: | 87 |
| Abstract: | According to the grounding work of Jacob and Monod, transcription factors (TFs) regulate gene expression by modulating their DNA binding affinity in response to a particular signal, or in the presence of a specific cofactor, much akin inducible or repressible on-off switches. Whilst the vast majority of TFs recognize distinct elements through the readout of conserved nucleotide motifs in the major groove of DNA, a few are able to bind specifically in the minor groove. Here we report the finding of a TF able to discriminatively exploit the binding to either the major or the minor DNA groove in order to mediate opposite read-out of the same regulatory signal. This mechanism accounts for the ability of the ferric uptake regulator Fur, a widespread prokaryotic transcriptional regulator involved in metal ion homeostasis and virulence in many bacteria, to repress the expression of both iron-inducible and iron-repressible genes in the human pathogen Helicobacter pylori. In particular, we demonstrate that Fur exploits the two grooves of DNA to function like a molecular commutator switch. In the apo-form, Fur binds with higher affinity to an iron-induced promoter as dimer, through the readout of thymine dimers in the major groove, contributing to its transcriptional repression under iron-deplete conditions. Conversely, on iron-repressed promoters, the metal ion acts as co-repressor, inducing protein conformational changes that prompt multimerization of the regulator and high affinity binding to the minor groove in occurrence of AT-rich inverted repeats. The latter mechanism appears to involve an Arg residue in helix H1 of the HTH-DNA-binding domain. In addition, molecular modelling and in silico docking indicate that binding to the minor groove involves conformation of the HTH-DNA binding domains of four Fur monomers into a tetrameric DNA clamp. These results provide evidence for a novel regulatory mechanism that may be exploited also in other bacteria. |
| Data prodotto definitivo in UGOV: | 17-giu-2013 |
| Data stato definitivo: | 15-gen-2016 |
| Appare nelle tipologie: | 4.02 Riassunto (Abstract) |
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