Functional definition of the two effector binding sites, the oligomerization and DNA binding domains of the <i>Bacillus subtilis</i> LysR‐type transcriptional regulator AlsR

Härtig, Elisabeth; Frädrich, Claudia; Behringer, Maren; Hartmann, Anja; Neumann‐Schaal, Meina; Jahn, Dieter

doi:10.1111/mmi.14089

Cited by 8 publications

(6 citation statements)

References 43 publications

(99 reference statements)

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“…These findings indicated that S100A11 regulates TKT at the transcriptional level. Previous reports demonstrated that the S100A family can act as transcription factors to modulate gene expression [ 18 , 19 ]. S100A11 was found to be strongly expressed in the nucleus in PDAC tissues (Fig.…”

Section: Resultsmentioning

confidence: 99%

S100A11 activates the pentose phosphate pathway to induce malignant biological behaviour of pancreatic ductal adenocarcinoma

et al. 2022

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most refractory malignancies and has a poor prognosis. In recent years, increasing evidence has shown that an imbalance of metabolism may contribute to unrestricted pancreatic tumour progression and that the pentose phosphate pathway (PPP) plays a pivotal role in cellular metabolism. S100A11 has been shown to regulate multiple biological functions related to the progression and metastasis of various cancer types. However, the exact mechanisms and prognostic value of S100A11 in PDAC remain unclear. Here, we found that S100A11 expression was increased in PDAC and significantly associated with worse prognosis and disease progression. Mechanistically, S100A11 knockdown suppressed the PPP by impairing nascent mRNA synthesis of TKT (transketolase). The current study also demonstrated that H3K4me3 at the −268/+77 region of the TKT promoter was required for its transcriptional activation and S100A11 promoted H3K4me3 loading to the TKT promoter by interacting with SMYD3 protein. Taking these findings together, this study provided new insights into the potential value of S100A11 for treating pancreatic cancer, suggesting that it could be a therapeutic target for PDAC patients.

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Section: Resultsmentioning

confidence: 99%

S100A11 activates the pentose phosphate pathway to induce malignant biological behaviour of pancreatic ductal adenocarcinoma

et al. 2022

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“…In these cases, additional binding sites are defined in the promoter region, and effector binding to the regulator provokes a conformational change that results in a shift of the DNA binding site, especially from a proximal SBS subsite to a distal SBS subsite, contributing to the relaxation of the DNA bending angle (29)(30)(31). In some other regulators, few changes in promoter binding are observed upon activation, and a mechanism differing from the sliding dimer is proposed (32). An increasing number of LTTR-regulated systems deviating from these architectures and activation mechanisms are being uncovered, so that no common activation mechanism can be proposed (33)(34)(35)(36)(37).…”

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confidence: 99%

“…Binding of DbdR to P dbhL (A), P orf18 (B) and P orf20 (C) promoter DNA. EMSAs of32 P-labeled promoter DNA fragments with purified extracts containing DbdR protein were performed as described in Materials and Methods with either no protein added (lane 1) or increasing amounts of DbdR-enriched extract (purified extract): (A) 0.8, 1, 1.2, 1.6, 1.8, and 2 g/l; (B) 0.1, 0.2, 0.3, 0.4, and 0.8 g/l (lanes 2 to 6); (C) 0.5, 0.8, 1, 1.2, 1.6, 1.8, and 2 g/l (lanes 2 to 8). An excess of specific unlabeled promoter DNA fragment (lane 8 in panel A, lane 7 in panel B, and lane 9 in panel C) was added to a reaction mixture that also contained the maximum amount of crude extract.…”

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confidence: 99%

DbdR, a New Member of the LysR Family of Transcriptional Regulators, Coordinately Controls Four Promoters in the Thauera aromatica AR-1 3,5-Dihydroxybenzoate Anaerobic Degradation Pathway

Pacheco-Sánchez

Molina-Fuentes

Marín

et al. 2019

Appl Environ Microbiol

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The facultative anaerobe Thauera aromatica strain AR-1 uses 3,5-dihydroxybenzoate (3,5-DHB) as a sole carbon and energy source under anoxic conditions using an unusual oxidative strategy to overcome aromatic ring stability. A 25-kb gene cluster organized in four main operons encodes the anaerobic degradation pathway for this aromatic. The dbdR gene coding for a LysR-type transcriptional regulator (LTTR), which is present at the foremost end of the cluster, is required for anaerobic growth on 3,5-DHB and for the expression of the main pathway operons. A model structure of DbdR showed conserved key residues for effector binding with its closest relative TsaR for p-toluenesulfonate degradation. We found that DbdR controlled expression of three promoters upstream from the operons coding for the three main steps of the pathway. While one of them (Porf20) was only active in the presence of 3,5-DHB, the other two (PdbhL and Porf18) showed moderate basal levels that were further induced in the presence of the pathway substrate, which needed be converted to hydroxyhydroquinone to activate transcription. Both basal and induced activities were strictly dependent on DbdR, which was also required for transcription from its own promoter. DbdR basal expression was moderately high and, unlike most LTTR, increased 2-fold in response to the presence of the effector. DbdR was found to be a tetramer in solution, producing a single retardation complex in binding assays with the three enzymatic promoters, consistent with its tetrameric structure. The three promoters had a conserved organization with a clear putative primary (regulatory) binding site and a putative secondary (activating) binding site positioned at the expected distances from the transcription start site. In contrast, two protein-DNA complexes were observed for the PdbdR promoter, which also showed significant sequence divergence from those of the three other promoters. Taken together, our results show that a single LTTR coordinately controls expression of the entire 3,5-DHB anaerobic degradation pathway in Thauera aromatica AR-1, allowing a fast and optimized response to the presence of the aromatic. IMPORTANCE Thauera aromatica AR-1 is a facultative anaerobe that is able to use 3,5-dihydroxybenzoat (3,5-DHB) as the sole carbon and energy source in a process that is dependent on nitrate respiration. We have shown that a single LysR-type regulator with unusual properties, DbdR, controls the expression of the pathway in response to the presence of the substrate; unlike other regulators of the family, DbdR does not repress but activates its own synthesis and is able to bind and activate three promoters directing the synthesis of the pathway enzymes. The promoter architecture is conserved among the three promoters but deviates from that of typical LTTR-dependent promoters. The substrate must be metabolized to an intermediate compound to activate transcription, which requires basal enzyme levels to always be present. The regulatory network present in this strain is designed to allow basal expression of the enzymatic machinery, which would rapidly metabolize the substrate when exposed to it, thus rendering the effector molecule. Once activated, the regulator induces the synthesis of the entire pathway through a positive feedback, increasing expression from all the target promoters to allow maximum growth.

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“…To efficiently activate the transcription of corresponding target genes and hence influence cellular processes in bacterial, the binding activity of LTTRs to its target gene is generally influenced by one or more effectors. For example, acetate is the effector of AlsR and activates the transcription of the alsSD operon for acetoin formation in Bacillus subtilis ( 26 , 38 ), glutarate is the effector of GcdR and controls glutarate catabolism in Pseudomonas putida KT2440 ( 29 ), hydroxyhydroquinone or possibly 2,3,5-trihydroxybenzoate is the effector of DbdR and influences expression of the entire 3,5-DHB anaerobic degradation pathway in Thauera aromatica ( 48 ), benzoate and cis,cis-muconate are the effectors of BenM and control aromatic compound degradation in Acinetobacter sp. ADP1 ( 45 ), 1-Naphthol is the effector of McbG to activate mcbBCDEF cluster transcription and involved in the upstream pathway of carbaryl degradation in Pseudomonas sp.…”

Section: Discussionmentioning

confidence: 99%

PsrA is a novel regulator contributes to antibiotic synthesis, bacterial virulence, cell motility and extracellular polysaccharides production in Serratia marcescens

Pan

You

Osire

et al. 2021

Nucleic Acids Research

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Serratia marcescens is a Gram-negative bacterium of the Enterobacteriaceae family that can produce numbers of biologically active secondary metabolites. However, our understanding of the regulatory mechanisms behind secondary metabolites biosynthesis in S. marcescens remains limited. In this study, we identified an uncharacterized LysR family transcriptional regulator, encoding gene BVG90_12635, here we named psrA, that positively controlled prodigiosin synthesis in S. marcescens. This phenotype corresponded to PsrA positive control of transcriptional of the prodigiosin-associated pig operon by directly binding to a regulatory binding site (RBS) and an activating binding site (ABS) in the promoter region of the pig operon. We demonstrated that L-proline is an effector for the PsrA, which enhances the binding affinity of PsrA to its target promoters. Using transcriptomics and further experiments, we show that PsrA indirectly regulates pleiotropic phenotypes, including serrawettin W1 biosynthesis, extracellular polysaccharide production, biofilm formation, swarming motility and T6SS-mediated antibacterial activity in S. marcescens. Collectively, this study proposes that PsrA is a novel regulator that contributes to antibiotic synthesis, bacterial virulence, cell motility and extracellular polysaccharides production in S. marcescens and provides important clues for future studies exploring the function of the PsrA and PsrA-like proteins which are widely present in many other bacteria.

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Functional definition of the two effector binding sites, the oligomerization and DNA binding domains of the Bacillus subtilis LysR‐type transcriptional regulator AlsR

Cited by 8 publications

References 43 publications

S100A11 activates the pentose phosphate pathway to induce malignant biological behaviour of pancreatic ductal adenocarcinoma

S100A11 activates the pentose phosphate pathway to induce malignant biological behaviour of pancreatic ductal adenocarcinoma

DbdR, a New Member of the LysR Family of Transcriptional Regulators, Coordinately Controls Four Promoters in the Thauera aromatica AR-1 3,5-Dihydroxybenzoate Anaerobic Degradation Pathway

PsrA is a novel regulator contributes to antibiotic synthesis, bacterial virulence, cell motility and extracellular polysaccharides production in Serratia marcescens

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