Abstract
Typhoid toxin is a virulence factor for the bacterial pathogen Salmonella Typhi, which causes typhoid fever in humans. After its synthesis by intracellular bacteria, typhoid toxin is secreted into the lumen of the Salmonella-containing vacuole by a secretion mechanism strictly dependent on TtsA, a specific muramidase that facilitates toxin transport through the peptidoglycan layer. Here we show that substrate recognition by TtsA depends on a discrete domain within its carboxy terminus, which targets the enzyme to the bacterial poles to recognize YcbB-edited peptidoglycan. Comparison of the atomic structures of TtsA bound to its substrate and that of a close homolog with different specificity identified specific determinants involved in substrate recognition. Combined with structure-guided mutagenesis and in vitro and in vivo crosslinking experiments, this study provides an unprecedented view of the mechanisms by which a muramidase recognizes its peptidoglycan substrate to facilitate protein secretion.
Highlights
Most virulence factors must be secreted from bacterial cells so that they can interact with host determinants and aid bacterial replication within the host
Typhoid toxin secretion from the bacterial cell is mediated by a unique transport mechanism that requires the activity of TtsA, a specialized muramidase that facilitates the translocation of typhoid toxin from the cis to the trans side of the peptidoglycan (PG) layer of the bacterial envelope (Hodak and Galan, 2013; Geiger et al, 2018)
In previous studies we have shown that TtsA is unique in that it exerts its function at the bacterial poles, and it requires the activity of YcbB, a bacterial transpeptidase that is responsible for introducing L-D crosslinks to the peptides that link the glycan strands of the peptidoglycan layer (Geiger et al, 2018)
Summary
Most virulence factors must be secreted from bacterial cells so that they can interact with host determinants and aid bacterial replication within the host. In previous studies we have shown that TtsA is unique in that it exerts its function at the bacterial poles, and it requires the activity of YcbB, a bacterial transpeptidase that is responsible for introducing L-D crosslinks to the peptides that link the glycan strands of the peptidoglycan layer (Geiger et al, 2018). As the L-D-cross-links are most likely limited to specific subdomains of the PG layer, the substrate specificity exhibited by TtsA is thought to topologically restrict its activity Consistent with this hypothesis, TtsA-mediated PG remodeling and typhoid toxin secretion occurs exclusively at the bacterial poles (Geiger et al, 2018). These studies provide an unprecedented view of the mechanisms by which a bacterial muramidase involved in protein secretion engages its substrate
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