TY - JOUR TI - Mechanisms of substrate recognition by a typhoid toxin secretion-associated muramidase AU - Geiger, Tobias AU - Lara-Tejero, Maria AU - Xiong, Yong AU - Galán, Jorge E A2 - Laub, Michael T A2 - Storz, Gisela A2 - Hughes, Kelly VL - 9 PY - 2020 DA - 2020/01/20 SP - e53473 C1 - eLife 2020;9:e53473 DO - 10.7554/eLife.53473 UR - https://doi.org/10.7554/eLife.53473 AB - 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. KW - protein secretion KW - muramidase KW - peptidoglycan remodeling KW - bacterial envelope KW - L-D transpeptidase JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -