Salmonella antibacterial Rhs polymorphic toxin inhibits translation through ADP-ribosylation of EF-Tu P-loop

Nucleic Acids Res. 2022 Dec 9;50(22):13114-13127. doi: 10.1093/nar/gkac1162.

Abstract

Rearrangement hot spot (Rhs) proteins are members of the broad family of polymorphic toxins. Polymorphic toxins are modular proteins composed of an N-terminal region that specifies their mode of secretion into the medium or into the target cell, a central delivery module, and a C-terminal domain that has toxic activity. Here, we structurally and functionally characterize the C-terminal toxic domain of the antibacterial Rhsmain protein, TreTu, which is delivered by the type VI secretion system of Salmonella enterica Typhimurium. We show that this domain adopts an ADP-ribosyltransferase fold and inhibits protein synthesis by transferring an ADP-ribose group from NAD+ to the elongation factor Tu (EF-Tu). This modification is specifically placed on the side chain of the conserved D21 residue located on the P-loop of the EF-Tu G-domain. Finally, we demonstrate that the TriTu immunity protein neutralizes TreTu activity by acting like a lid that closes the catalytic site and traps the NAD+.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AAA Domain*
  • ADP Ribose Transferases / chemistry
  • ADP Ribose Transferases / metabolism
  • ADP-Ribosylation
  • NAD / metabolism
  • Peptide Elongation Factor Tu* / chemistry
  • Peptide Elongation Factor Tu* / metabolism
  • Protein Folding
  • Salmonella

Substances

  • ADP Ribose Transferases
  • NAD
  • Peptide Elongation Factor Tu