Dataset Information

Roles of the Crp/Fnr Family Regulator ArcR in the Hemolysis and Biofilm of Staphylococcus aureus.

ABSTRACT: Staphylococcus aureus is an opportunistic human pathogen that is often involved in severe infections such as pneumonia and sepsis in which bacterial virulence factors play a key role. Infections caused by S. aureus are often difficult to eradicate, particularly when they are associated with biofilm. The physiological roles of the Crp/Fnr family regulator ArcR are elusive in S. aureus. In this study, it was found that the deletion of arcR increased the hemolytic ability and biofilm formation in S. aureus. Differential gene expression analysis by RNA-seq and real-time quantitative reverse transcription PCR showed that genes associated with hemolytic ability (hla and hlb) and biofilm formation (icaA, icaB, icaC and icaD) were significantly upregulated compared with those in the wild-type strain. The results revealed that ArcR regulated the expression of the hla and ica operon by binding to their promoter regions, respectively. This study provided new insights into the functional importance of ArcR in regulating the virulence and biofilm of S. aureus.

SUBMITTER: Fu T

PROVIDER: S-EPMC10384999 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Roles of the Crp/Fnr Family Regulator ArcR in the Hemolysis and Biofilm of Staphylococcus aureus.

Fu Tongtong T Fan Zheng Z Li Yujie Y Li Zhoufei Z Zhao Hanqing H Feng Yanling Y Xue Guanhua G Cui Jinghua J Yan Chao C Gan Lin L Feng Junxia J Yuan Jing J You Fuping F

Microorganisms 20230625 7

Staphylococcus aureus is an opportunistic human pathogen that is often involved in severe infections such as pneumonia and sepsis in which bacterial virulence factors play a key role. Infections caused by S. aureus are often difficult to eradicate, particularly when they are associated with biofilm. The physiological roles of the Crp/Fnr family regulator ArcR are elusive in S. aureus. In this study, it was found that the deletion of arcR increased the hemolytic abilit ...[more]

PMID: 37512829

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Project description:Phylogenetic and sequence similarity network analyses of the CRP (cyclic AMP receptor protein)/FNR (fumarate and nitrate reductase regulatory protein) family of transcription factors indicate the presence of numerous subgroups, many of which have not been analyzed. Five homologs of the CRP/FNR family are present in the Rhodobacter capsulatus genome. One is a member of a broadly disseminated, previously uncharacterized CRP/FNR family subgroup encoded by the gene rcc01561. In this study, we utilize mutational disruption, transcriptome sequencing (RNA-seq), and chromatin immunoprecipitation sequencing (ChIP-seq) to determine the role of RCC01561 in regulating R. capsulatus physiology. This analysis shows that a mutant strain disrupted for rcc01561 exhibits altered expression of 451 genes anaerobically. A detailed analysis of the affected loci shows that RCC01561 represses photosynthesis and favors catabolism over anabolism and the use of the Entner-Doudoroff shunt and glycolysis over that of the tricarboxylic acid (TCA) cycle to limit NADH and ATP formation. This newly characterized CRP/FNR family member with a predominant role in reducing the production of reducing potential and ATP is given the nomenclature RedB as it functions as an energy and redox brake. Beyond limiting energy production, RedB also represses the expression of numerous genes involved in protein synthesis, including those involved in translation initiation, tRNA synthesis and charging, and amino acid biosynthesis. IMPORTANCE CRP and FNR are well-characterized members of the CRP/FNR family of regulatory proteins that function to maximize cellular energy production. In this study, we identify several new subgroups of the CRP/FNR family, many of which have not yet been characterized. Using Rhodobacter capsulatus as a model, we have mutationally disrupted the gene rcc01561, which codes for a transcription factor that is a member of a unique subgroup of the CRP/FNR family. Transcriptomic analysis shows that the disruption of rcc01561 leads to the altered expression of 451 genes anaerobically. Analysis of these regulated genes indicates that RCC01561 has a novel role in limiting cellular energy production. To our knowledge, this is first example of a member of the CRP/FNR family that functions as a brake on cellular energy production.

Project description:Allostery is a fundamental process by which ligand binding to a protein alters its activity at a distinct site. There is growing evidence that allosteric cooperativity can be communicated by modulation of protein dynamics without conformational change. The mechanisms, however, for communicating dynamic fluctuations between sites are debated. We provide a foundational theory for how allostery can occur as a function of low-frequency dynamics without a change in structure. We have generated coarse-grained models that describe the protein backbone motions of the CRP/FNR family transcription factors, CAP of Escherichia coli and GlxR of Corynebacterium glutamicum. The latter we demonstrate as a new exemplar for allostery without conformation change. We observe that binding the first molecule of cAMP ligand is correlated with modulation of the global normal modes and negative cooperativity for binding the second cAMP ligand without a change in mean structure. The theory makes key experimental predictions that are tested through an analysis of variant proteins by structural biology and isothermal calorimetry. Quantifying allostery as a free energy landscape revealed a protein "design space" that identified the inter- and intramolecular regulatory parameters that frame CRP/FNR family allostery. Furthermore, through analyzing CAP variants from diverse species, we demonstrate an evolutionary selection pressure to conserve residues crucial for allosteric control. This finding provides a link between the position of CRP/FNR transcription factors within the allosteric free energy landscapes and evolutionary selection pressures. Our study therefore reveals significant features of the mechanistic basis for allostery. Changes in low-frequency dynamics correlate with allosteric effects on ligand binding without the requirement for a defined spatial pathway. In addition to evolving suitable three-dimensional structures, CRP/FNR family transcription factors have been selected to occupy a dynamic space that fine-tunes biological activity and thus establishes the means to engineer allosteric mechanisms driven by low-frequency dynamics.

Dataset Information

Roles of the Crp/Fnr Family Regulator ArcR in the Hemolysis and Biofilm of Staphylococcus aureus.

Publications

Roles of the Crp/Fnr Family Regulator ArcR in the Hemolysis and Biofilm of <i>Staphylococcus aureus</i>.

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