Udskriv Udskriv
Switch language
Region Hovedstaden - en del af Københavns Universitetshospital

A hyperpromiscuous antitoxin protein domain for the neutralization of diverse toxin domains

Publikation: Bidrag til tidsskriftTidsskriftartikelpeer review


  1. Ablation of lysophosphatidic acid receptor 1 attenuates hypertrophic cardiomyopathy in a mouse model

    Publikation: Bidrag til tidsskriftTidsskriftartikelpeer review

  2. A protein of capillary endothelial cells, GPIHBP1, is crucial for plasma triglyceride metabolism

    Publikation: Bidrag til tidsskriftTidsskriftartikelpeer review

  1. Structural basis for PoxtA-mediated resistance to phenicol and oxazolidinone antibiotics

    Publikation: Bidrag til tidsskriftTidsskriftartikelpeer review

  2. RelA-SpoT Homolog toxins pyrophosphorylate the CCA end of tRNA to inhibit protein synthesis

    Publikation: Bidrag til tidsskriftTidsskriftartikelpeer review

  • Tatsuaki Kurata
  • Chayan Kumar Saha
  • Jessica A Buttress
  • Toomas Mets
  • Tetiana Brodiazhenko
  • Kathryn J Turnbull
  • Ololade F Awoyomi
  • Sofia Raquel Alves Oliveira
  • Steffi Jimmy
  • Karin Ernits
  • Maxence Delannoy
  • Karina Persson
  • Tanel Tenson
  • Henrik Strahl
  • Vasili Hauryliuk
  • Gemma C Atkinson
Vis graf over relationer

Toxin-antitoxin (TA) gene pairs are ubiquitous in microbial chromosomal genomes and plasmids as well as temperate bacteriophages. They act as regulatory switches, with the toxin limiting the growth of bacteria and archaea by compromising diverse essential cellular targets and the antitoxin counteracting the toxic effect. To uncover previously uncharted TA diversity across microbes and bacteriophages, we analyzed the conservation of genomic neighborhoods using our computational tool FlaGs (for flanking genes), which allows high-throughput detection of TA-like operons. Focusing on the widespread but poorly experimentally characterized antitoxin domain DUF4065, our in silico analyses indicated that DUF4065-containing proteins serve as broadly distributed antitoxin components in putative TA-like operons with dozens of different toxic domains with multiple different folds. Given the versatility of DUF4065, we have named the domain Panacea (and proteins containing the domain, PanA) after the Greek goddess of universal remedy. We have experimentally validated nine PanA-neutralized TA pairs. While the majority of validated PanA-neutralized toxins act as translation inhibitors or membrane disruptors, a putative nucleotide cyclase toxin from a Burkholderia prophage compromises transcription and translation as well as inducing RelA-dependent accumulation of the nucleotide alarmone (p)ppGpp. We find that Panacea-containing antitoxins form a complex with their diverse cognate toxins, characteristic of the direct neutralization mechanisms employed by Type II TA systems. Finally, through directed evolution, we have selected PanA variants that can neutralize noncognate TA toxins, thus experimentally demonstrating the evolutionary plasticity of this hyperpromiscuous antitoxin domain.

TidsskriftProceedings of the National Academy of Sciences of the United States of America
Udgave nummer6
StatusUdgivet - 8 feb. 2022

Bibliografisk note

Copyright © 2022 the Author(s). Published by PNAS.

ID: 79811294