Crosstalk and the evolution of specificity in two-component signaling

Rowland, Michael; Deeds, Eric J.

doi:10.1073/pnas.1317178111

Cited by 98 publications

(89 citation statements)

References 45 publications

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“…Although the ␣3 helices of Actinobacteria, Firmicutes, and chloroflexi display substantial sequence similarity, the highly divergent ␣3 helix sequences of the Xanthomonadaceae/Pseudomonadaceae, the Cyanobacteria, and the Gallionellales cluster target a structurally similar motif that has been shown be bound by several noncognate LexA proteins (50,51). Recent work on the PhoQ-PhoP two-component signal transduction system has shown that there is a remarkable degree of sequence plasticity in the PhoQ-PhoP interface and that evolution has explored only a small fraction of the space of the PhoP-specific PhoQ motifs, due to both physiological and biochemical constraints on available mutational pathways (70)(71)(72). The results presented here suggest that the same is true for the LexA protein-DNA interface, which displays a varied palette of ␣3 helix and LexA-binding motif pairs.…”

Section: Resultsmentioning

confidence: 99%

“…The results presented here suggest that the same is true for the LexA protein-DNA interface, which displays a varied palette of ␣3 helix and LexA-binding motif pairs. Importantly, however, the available data indicate that the coevolution of the LexA recognition domain and its binding motif may face more restrictions than those displayed by two-component systems (70,71,73). In particular, the abundance of highly divergent ␣3 helix sequences targeting a similar, B. subtilis-type LexA-binding motif yields two nonexclusive scenarios.…”

Section: Resultsmentioning

confidence: 99%

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An SOS Regulon under Control of a Noncanonical LexA-Binding Motif in the Betaproteobacteria

et al. 2015

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The SOS response is a transcriptional regulatory network governed by the LexA repressor that activates in response to DNA damage. In the Betaproteobacteria, LexA is known to target a palindromic sequence with the consensus sequence CTGT-N 8 -ACAG. We report the characterization of a LexA regulon in the iron-oxidizing betaproteobacterium Sideroxydans lithotrophicus. In silico and in vitro analyses show that LexA targets six genes by recognizing a binding motif with the consensus sequence GAACGaaCGTTC, which is strongly reminiscent of the Bacillus subtilis LexA-binding motif. We confirm that the closely related Gallionella capsiferriformans shares the same LexA-binding motif, and in silico analyses indicate that this motif is also conserved in the Nitrosomonadales and the Methylophilales. Phylogenetic analysis of LexA and the alpha subunit of DNA polymerase III (DnaE) reveal that the organisms harboring this noncanonical LexA form a compact taxonomic cluster within the Betaproteobacteria. However, their lexA gene is unrelated to the standard Betaproteobacteria lexA, and there is evidence of its spread through lateral gene transfer. In contrast to other reported cases of noncanonical LexA-binding motifs, the regulon of S. lithotrophicus is comparable in size and function to that of many other Betaproteobacteria, suggesting that a convergent SOS regulon has reevolved under the control of a new LexA protein. Analysis of the DNA-binding domain of S. lithotrophicus LexA reveals little sequence similarity with that of other LexA proteins targeting similar binding motifs, suggesting that network structure may limit site evolution or that structural constrains make the B. subtilis-type motif an optimal interface for multiple LexA sequences. IMPORTANCEUnderstanding the evolution of transcriptional systems enables us to address important questions in microbiology, such as the emergence and transfer potential of different regulatory systems to regulate virulence or mediate responses to stress. The results reported here constitute the first characterization of a noncanonical LexA protein regulating a standard SOS regulon. This is significant because it illustrates how a complex transcriptional program can be put under the control of a novel transcriptional regulator. Our results also reveal a substantial degree of plasticity in the LexA recognition domain, raising intriguing questions about the space of protein-DNA interfaces and the specific evolutionary constrains faced by these elements.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

An SOS Regulon under Control of a Noncanonical LexA-Binding Motif in the Betaproteobacteria

et al. 2015

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“…The phosphoryl group is subsequently transferred to an aspartate residue in the RR, which induces a conformational change enabling the RR to function as a DNA binding transcriptional regulator. Although most bacterial TCSs are highly specific, cross talk between similar is observed in rare instances systems (19)(20)(21)(22). The bacterial response to the environmental signal is itself tightly regulated.…”

mentioning

confidence: 99%

The ChrSA and HrrSA Two-Component Systems Are Required for Transcriptional Regulation of the hemA Promoter in Corynebacterium diphtheriae

Burgos

Schmitt

2016

J Bacteriol

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Corynebacterium diphtheriae utilizes heme and hemoglobin (Hb) as iron sources for growth in low-iron environments. In C. diphtheriae, the two-component signal transduction systems (TCSs) ChrSA and HrrSA are responsive to Hb levels and regulate the transcription of promoters for hmuO, hrtAB, and hemA. ChrSA and HrrSA activate transcription at the hmuO promoter and repress transcription at hemA in an Hb-dependent manner. In this study, we show that HrrSA is the predominant repressor at hemA and that its activity results in transcriptional repression in the presence and absence of Hb, whereas repression of hemA by ChrSA is primarily responsive to Hb. DNA binding studies showed that both ChrA and HrrA bind to the hemA promoter region at virtually identical sequences. ChrA binding was enhanced by phosphorylation, while binding to DNA by HrrA was independent of its phosphorylation state. ChrA and HrrA are phosphorylated in vitro by the sensor kinase ChrS, whereas no kinase activity was observed with HrrS in vitro. Phosphorylated ChrA was not observed in vivo, even in the presence of Hb, which is likely due to the instability of the phosphate moiety on ChrA. However, phosphorylation of HrrA was observed in vivo regardless of the presence of the Hb inducer, and genetic analysis indicates that ChrS is responsible for most of the phosphorylation of HrrA in vivo. Phosphorylation studies strongly suggest that HrrS functions primarily as a phosphatase and has only minimal kinase activity. These findings collectively show a complex mechanism of regulation at the hemA promoter, where both two-component systems act in concert to optimize expression of heme biosynthetic enzymes. IMPORTANCEUnderstanding the mechanism by which two-component signal transduction systems function to respond to environmental stimuli is critical to the study of bacterial pathogenesis. The current study expands on the previous analyses of the ChrSA and HrrSA TCSs in the human pathogen C. diphtheriae. The findings here underscore the complex interactions between the ChrSA and HrrSA systems in the regulation of the hemA promoter and demonstrate how the two systems complement one another to refine and control transcription in the presence and absence of Hb.C orynebacterium diphtheriae, a strict human pathogen, is the etiologic agent of diphtheria (1-3). After colonizing the upper respiratory tract, actively dividing cells secrete the potent diphtheria toxin (DT), which disseminates throughout the host and elicits the major clinical symptoms of the disease (1-3). Expression of DT is negatively regulated at the transcriptional level by iron and the diphtheria toxin repressor protein DtxR (3, 4). Although essential for bacterial physiology, iron is not readily available for invading pathogens since much of it is sequestered by host proteins such as transferrin, lactoferrin, and hemoglobin (Hb) (5-7).To thrive in such a stringent environment, bacteria utilize a variety of tightly regulated iron-and heme-scavenging systems (7,8). C. diphtheriae, in part...

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“…Indeed, changes in regulatory networks are necessarily canalized by various internal and external factors. Internal factors include biophysical and structural constraints which have a number of effects, e.g., binding site programmability [50,53], buffering of noise in gene expression [92,93], regulatory crosstalk [94][95][96][97]85], gene susceptibility for accumulating mutations [98,99], evolvability [100], sensitivity to loss of interactions [101], genome architecture and chromosomal dynamics [102][103][104], etc. External factors include environmental conditions, thereby relating to various phenomena such as phenotypic plasticity [105][106][107], strength of selection [108,109], genetic drift [110], etc.…”

Section: Shared Edge Usage Even Amongst Highly Divergent Organismsmentioning

confidence: 99%

Drivers of structural features in gene regulatory networks: From biophysical constraints to biological function

Martin¹,

Krzywicki²,

Zagórski³

2016

Physics of Life Reviews

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Crosstalk and the evolution of specificity in two-component signaling

Cited by 98 publications

References 45 publications

An SOS Regulon under Control of a Noncanonical LexA-Binding Motif in the Betaproteobacteria

An SOS Regulon under Control of a Noncanonical LexA-Binding Motif in the Betaproteobacteria

The ChrSA and HrrSA Two-Component Systems Are Required for Transcriptional Regulation of the hemA Promoter in Corynebacterium diphtheriae

Drivers of structural features in gene regulatory networks: From biophysical constraints to biological function

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