Rapid growth inhibitory activity of a YafQ-family endonuclease toxin of the Helicobacter pylori tfs4 integrative and conjugative element

Prokaryotic and archaeal chromosomes encode a diversity of toxin–antitoxin (TA) systems that contribute to a variety of stress-induced cellular processes in addition to stability and maintenance of mobile elements. Here, we find DinJ-YafQ family TA systems to be broadly distributed amongst diverse phyla, consistent with other ParE/RelE superfamily TAs, but more unusually occurring as a multiplicity of species-specific subtypes. In the gastric pathogen Helicobacter pylori we identify six distinct subtypes, of which three are predominantly associated with the mobilome, including the disease-associated integrative and conjugative element (ICE), tfs4. Whereas, the ICE-encoded proteins have characteristic features of DinJ-YafQ family Type II TA systems in general, the toxin component is distinguished by a broad metal-ion-dependent endonuclease activity with specificity for both RNA and DNA. We show that the remarkably rapid growth inhibitory activity of the ICE toxin is a correlate of a C-terminal lysine doublet which likely augments catalytic activity by increasing the positive electrostatic potential in the vicinity of the conserved active site. Our collective results reveal a structural feature of an ICE TA toxin that influences substrate catalysis and toxin function which may be relevant to specific TA-mediated responses in diverse genera of bacteria.