The two paralogous copies of the YoeB–YefM toxin–antitoxin module in Staphylococcus aureus differ in DNA binding and recognition patterns

Lu, Xue; Khan, Muhammad Hidayatullah; Yue, Jian; Zhu, Zhongliang; Niu, Liwen

doi:10.1016/j.jbc.2021.101457

Cited by 6 publications

(6 citation statements)

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“…Our previous study demonstrated that the establishment of protein–DNA interaction might be associated with the recognition of both core and flanking sequences in the promoter DNA fragments [ 21 , 22 ]. To assess whether flanking sequences are critical to Ino2p DBD /Ino4p DBD /DNA mutual interaction, nucleotides corresponding to the flanking promoter DNA sequence were mutated (see Figure 5 A).…”

Section: Resultsmentioning

confidence: 99%

“…Taken together, these results suggest that residues (Ino2p His12/Glu16/Arg20/Arg44 and Ino4p His12/Glu16/Arg20 ) are critical for the optimal DNA binding affinity of the Ino2p DBD -Ino4p DBD heterodimer complex. Our previous study demonstrated that the establishment of protein-DNA interaction might be associated with the recognition of both core and flanking sequences in the promoter DNA fragments [21,22]. To assess whether flanking sequences are critical to Ino2p DBD /Ino4p DBD /DNA mutual interaction, nucleotides corresponding to the flanking promoter DNA sequence were mutated (see Figure 5A).…”

Section: Structural Basis For the Recognition And Binding Of Promoter...mentioning

confidence: 99%

“…To assess whether flanking sequences are critical to Ino2p DBD /Ino4p DBD /DNA mutual interaction, nucleotides corresponding to the flanking promoter DNA sequence were mutated (see Figure 5A). The corresponding biochemical (EMSA and ITC) experiments demonstrated that the mutated flanking promoter fragment Our previous study demonstrated that the establishment of protein-DNA interaction might be associated with the recognition of both core and flanking sequences in the promoter DNA fragments [21,22]. To assess whether flanking sequences are critical to Ino2p DBD /Ino4p DBD /DNA mutual interaction, nucleotides corresponding to the flanking promoter DNA sequence were mutated (see Figure 5A).…”

Section: Structural Basis For the Recognition And Binding Of Promoter...mentioning

confidence: 99%

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Structural Analysis of Ino2p/Ino4p Mutual Interactions and Their Binding Interface with Promoter DNA

Khan

Yue

et al. 2022

IJMS

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Gene expression is mediated by a series of regulatory proteins, i.e., transcription factors. Under different growth conditions, the transcriptional regulation of structural genes is associated with the recognition of specific regulatory elements (REs) in promoter DNA. The manner by which transcription factors recognize distinctive REs is a key question in structural biology. Previous research has demonstrated that Ino2p/Ino4p heterodimer is associated with the transcriptional regulation of phospholipid biosynthetic genes. Mechanistically, Ino2p/Ino4p could specifically recognize the inositol/choline-responsive element (ICRE), followed by the transcription activation of the phospholipid biosynthetic gene. While the promoter DNA sequence for Ino2p has already been characterized, the structural basis for the mutual interaction between Ino2p/Ino4p and their binding interface with promoter DNA remain relatively unexplored. Here, we have determined the crystalline structure of the Ino2pDBD/Ino4pDBD/DNA ternary complex, which highlights some residues (Ino2pHis12/Glu16/Arg20/Arg44 and Ino4pHis12/Glu16/Arg19/Arg20) associated with the sequence-specific recognition of promoter DNA. Our biochemical analysis showed that mutating these residues could completely abolish protein–DNA interaction. Despite the requirement of Ino2p and Ino4p for interprotein–DNA interaction, both proteins can still interact—even in the absence of DNA. Combined with the structural analysis, our in vitro binding analysis demonstrated that residues (Arg35, Asn65, and Gln69 of Ino2pDBD and Leu59 of Ino4pDBD) are critical for interprotein interactions. Together, these results have led to the conclusion that these residues are critical to establishing interprotein–DNA and protein–DNA mutual interactions.

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Section: Resultsmentioning

confidence: 99%

Section: Structural Basis For the Recognition And Binding Of Promoter...mentioning

confidence: 99%

Section: Structural Basis For the Recognition And Binding Of Promoter...mentioning

confidence: 99%

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Structural Analysis of Ino2p/Ino4p Mutual Interactions and Their Binding Interface with Promoter DNA

Khan

Yue

et al. 2022

IJMS

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“…Toxin–antitoxin modules were initially identified as a plasmid stability factor in the conjugative plasmids in the 1980s ( Ogura and Hiraga, 1983 ; Jaffe et al, 1985 ; Gerdes et al, 1986 ; Cooper and Heinemann, 2000 ; Van Melderen, 2010 ; Ni et al, 2021 ). Later, they turned out to be widely distributed on the chromosomes and mobile genetic elements (MGEs) in bacteria, archaea, and bacteriophage, especially pathogenic bacteria ( Ogura and Hiraga, 1983 ; Hayes and Van Melderen, 2011 ; Fraikin et al, 2020 ; Leroux et al, 2020 ; Kamruzzaman et al, 2021 ; Ni et al, 2021 ; Xue et al, 2022 ). It is worth noting that MGE is closely related to the genetic stability and formation of persisters through horizontal transfer and vertical transmission ( Cooper and Heinemann, 2000 ; Costa et al, 2001 ; Schumacher et al, 2012 , 2015 ; Blair et al, 2015 ; Levin-Reisman et al, 2017 ; Ni et al, 2021 ; Xia et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…Followed by the degradation of the corresponding antitoxin partner, the active toxin component was, thus, released to interact with cellular pathways to activate potentially deleterious toxic activities ( Muthuramalingam et al, 2016 ; Leroux et al, 2020 ; Sarpong and Murphy, 2021 ; Xia et al, 2021 ). Furthermore, the type II TAS, which is studied the most and best, is the most abundant in bacterial MGEs among eight TAS types investigated to date ( Xie et al, 2018 ; Kamruzzaman et al, 2021 ; Sarpong and Murphy, 2021 ; Zhang et al, 2021 ; Xue et al, 2022 ). For instance, Ep RatAB and Ep YefM-YoeB TAS from Edwardsiella piscicida are thought to be the model organism for the study of intracellular infections and refer to antibiotic resistance and host infection ( Ma et al, 2021 ; Du et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Structural insights into the PrpTA toxin–antitoxin system in Pseudoalteromonas rubra

et al. 2022

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Bacteria could survive stresses by a poorly understood mechanism that contributes to the emergence of bacterial persisters exhibiting multidrug tolerance (MDT). Recently, Pseudoalteromonas rubra prpAT module was found to encode a toxin PrpT and corresponding cognate antidote PrpA. In this study, we first reported multiple individual and complex structures of PrpA and PrpT, which uncovered the high-resolution three-dimensional structure of the PrpT:PrpA2:PrpT heterotetramer with the aid of size exclusion chromatography-multi-angle light scattering experiments (SEC-MALS). PrpT:PrpA2:PrpT is composed of a PrpA homodimer and two PrpT monomers which are relatively isolated from each other and from ParE family. The superposition of antitoxin monomer structures from these structures highlighted the flexible C-terminal domain (CTD). A striking conformational change in the CTDs of PrpA homodimer depolymerized from homotetramer was provoked upon PrpT binding, which accounts for the unique PrpT-PrpARHH mutual interactions and further neutralizes the toxin PrpT. PrpA2–54-form I and II crystal structures both contain a doughnut-shaped hexadecamer formed by eight homodimers organized in a cogwheel-like form via inter-dimer interface dominated by salt bridges and hydrogen bonds. Moreover, PrpA tends to exist in solution as a homodimer other than a homotetramer (SEC-MALS) in the absence of flexible CTD. Multiple multi-dimers, tetramer and hexamer included, of PrpA2–54 mediated by the symmetric homodimer interface and the complicated inter-dimer interface could be observed in the solution. SEC-MALS assays highlighted that phosphate buffer (PB) and the increase in the concentration appear to be favorable for the PrpA2–54 oligomerization in the solution. Taken together with previous research, a model of PrpA2–54 homotetramer in complex with prpAT promoter and the improved mechanism underlying how PrpTA controls the plasmid replication were proposed here.

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Structural and Functional Insight Into YefM–YoeB Complex of Toxin–Antitoxin System From Streptococcus pneumoniae

Kim,

Lee,

Jin

et al. 2024

J of Cellular Biochemistry

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Streptococcus pneumonia is a Gram‐positive and facultative anaerobic bacterium that causes a number of diseases, including otitis media, community‐acquired pneumonia, sepsis, and meningitis. With the emergence of antibiotic‐resistant strains, there is an urgent need to develop antibiotics with a novel mechanism. The toxin–antitoxin (TA) system, which is primarily found in prokaryotes, consists of a toxin and its equivalent antitoxin genes. The YefM–YoeB module is a Type II TA system, where the YoeB toxin functions as a putative mRNA interferase upon activation, while the YefM antitoxin acts as a transcription repressor by binding to its promoter region along with YoeB. In this study, we determined the crystal structure of the YefM–YoeB complex from S. pneumoniae TIGR4 to comprehend the binding mechanism of the TA system. Furthermore, an in vitro ribonuclease activity assay was conducted to identify the ribonuclease activity of the YoeB toxin. Additionally, furthermore, the oligomeric state of the YefM–YoeB complex in solution was investigated, and a DNA‐binding mode was proposed. These structural and functional insights into the YefM–YoeB complex could provide valuable information for the development of novel antibiotics targeting S. pneumonia‐associated diseases.

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The two paralogous copies of the YoeB–YefM toxin–antitoxin module in Staphylococcus aureus differ in DNA binding and recognition patterns

Cited by 6 publications

References 48 publications

Structural Analysis of Ino2p/Ino4p Mutual Interactions and Their Binding Interface with Promoter DNA

Structural Analysis of Ino2p/Ino4p Mutual Interactions and Their Binding Interface with Promoter DNA

Structural insights into the PrpTA toxin–antitoxin system in Pseudoalteromonas rubra

Structural and Functional Insight Into YefM–YoeB Complex of Toxin–Antitoxin System From Streptococcus pneumoniae

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