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<p>Motility and colonization of motile bacteria largely depend on flagellar synthesis, ultimately modulating virulence and biofilm formation. In <i>Vibrio cholerae</i>, the two-component system (TCS) FlrB–FlrC, made of the sensor histidine kinase FlrB and σ<sup>54</sup>-dependent transcription activator FlrC, plays a pivotal role in transcription regulation of the flagellar genes encoding basal body, hook, and flagellin. As we observed before, heme binds to the architecturally unique PAS domain of FlrB as a sensory ligand. Heme binding triggers a conformational switch, assisting ATP binding to the catalytic (CA) domain. This facilitates autophosphorylation of the dimerization/phosphotransfer (DHp) domain of FlrB, followed by phosphotransfer to FlrC for downstream flagellar actions. In this study, we have shown a 40-fold higher affinity of DHp-CA towards ATP compared to the full-length FlrB, indicating that the PAS domain acts as a repressor. Conformational shift upon heme binding to PAS, therefore, weakens repression. Based on sequence and structural similarity searches, unbiased interatomic network analyses, and searches for ligands and their binding pockets, here we have identified 45 Gram-negative polar flagellated bacteria, including <i>V. cholerae</i>, that possess FlrB–FlrC or FleS–FleR-type TCSs. These TCSs contain all structural and functional requisites to execute the mechanisms of <i>V. cholerae</i> FlrB–FlrC. Phylogenetic analysis revealed similar evolutionary associations for the identified FlrB and FlrC proteins of 45 organisms. Interestingly, comparative genomic analyses revealed the presence of sensory histidine kinase genes, other flagellar apparatus, and TCS-associated genes in the accessory genome. The overall open pan-genome indicated that these bacterial members are evolutionarily operational.</p>

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Bioinformatic and genomic analyses on FlrB–FlrC-type TCS orthologs involved in flagellar synthesis of monotrichous Gram-negative bacteria

  • 期刊论文

  • 发表日期：

    2025年3月18日

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  • Peeali Mukherjee,
  • Wrick Chakraborty,
  • Subhayu Chowdhury,
  • Sayak Ganguli,
  • Jhimli Dasgupta

摘要

Motility and colonization of motile bacteria largely depend on flagellar synthesis, ultimately modulating virulence and biofilm formation. In Vibrio cholerae, the two-component system (TCS) FlrB–FlrC, made of the sensor histidine kinase FlrB and σ54-dependent transcription activator FlrC, plays a pivotal role in transcription regulation of the flagellar genes encoding basal body, hook, and flagellin. As we observed before, heme binds to the architecturally unique PAS domain of FlrB as a sensory ligand. Heme binding triggers a conformational switch, assisting ATP binding to the catalytic (CA) domain. This facilitates autophosphorylation of the dimerization/phosphotransfer (DHp) domain of FlrB, followed by phosphotransfer to FlrC for downstream flagellar actions. In this study, we have shown a 40-fold higher affinity of DHp-CA towards ATP compared to the full-length FlrB, indicating that the PAS domain acts as a repressor. Conformational shift upon heme binding to PAS, therefore, weakens repression. Based on sequence and structural similarity searches, unbiased interatomic network analyses, and searches for ligands and their binding pockets, here we have identified 45 Gram-negative polar flagellated bacteria, including V. cholerae, that possess FlrB–FlrC or FleS–FleR-type TCSs. These TCSs contain all structural and functional requisites to execute the mechanisms of V. cholerae FlrB–FlrC. Phylogenetic analysis revealed similar evolutionary associations for the identified FlrB and FlrC proteins of 45 organisms. Interestingly, comparative genomic analyses revealed the presence of sensory histidine kinase genes, other flagellar apparatus, and TCS-associated genes in the accessory genome. The overall open pan-genome indicated that these bacterial members are evolutionarily operational.