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Structural Basis for Toxin Inhibition in the VapXD Toxin-Antitoxin System

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Bacterial type II toxin-antitoxin (TA) modules encode a toxic protein that downregulates metabolism and a specific antitoxin that binds and inhibits the toxin during normal growth. In non-typeable Haemophilus influenzae, a common cause of infections in humans, the vapXD locus was found to constitute a functional TA module and contribute to pathogenicity; however, the mode of action of VapD and the mechanism of inhibition by the VapX antitoxin remain unknown. Here, we report the structure of the intact H. influenzae VapXD complex, revealing an unusual 2:1 TA molecular stoichiometry where a Cas2-like homodimer of VapD binds a single VapX antitoxin. VapX consists of an oligonucleotide/oligosaccharide-binding domain that docks into an asymmetrical cavity on the toxin dimer. Structures of isolated VapD further reveal how a symmetrical toxin homodimer adapts to interacting with an asymmetrical antitoxin and suggest how a primordial TA system evolved to become part of CRISPR-Cas immunity systems.

Original languageEnglish
JournalStructure
Volume29
Issue2
Pages (from-to)139-150.e3
ISSN0969-2126
DOIs
Publication statusPublished - Feb 2021

Bibliographical note

Copyright © 2020 Elsevier Ltd. All rights reserved.

    Research areas

  • CRISPR-Cas, Cas2, Haemophilus influenzae, OB fold, RNase, VapD

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