Bacterial cell-wall hydrolases must be tightly regulated during cell division. Insight into the molecular mechanism of this process is key to provide the structural basis for the rational design of novel antibiotics
The bacterial cell wall provides shape and physical integrity against environmental stress. A cross-linked polymer, the peptidoglycan (PG), serves as the structural template for the cell wall. The PG is formed by glycan strands of varying lengths, comprising repeating disaccharide N-acetylglucosamine (NAG)-N-acetylmuramic acid (NAM). The NAM unit has a short peptide stem, where the cross-linking occurs between two neighboring glycan strands. The PG and its biosynthesis pathway are targets of antibiotics, because of their critical role in bacterial survival. Two types of PG synthases, the “shape, elongation, division, and sporulation” (SEDS) proteins and the “penicillin-binding proteins” (PBPs), are central to these processes. Another series of enzymes, including PG hydrolases, are also involved in PG maturation and homeostasis. However, the full scope of these processes, and notably, the regulation of hydrolases, remains largely unknown.
In a collaborative effort led by the groups of Christophe Grangeasse (University of Lyon) and Juan A. Hermoso (IQF-CSIC), we disclose the molecular dialogue between the cell-wall hydrolase LytB, wall teichoic acids, and the eukaryotic-like protein kinase StkP in Streptococcus pneumoniae. After characterizing the peptidoglycan recognition mode by the catalytic domain of LytB, we further demonstrate that LytB possesses a modular organization allowing the specific binding to wall teichoic acids and to the protein kinase StkP. Structural and cellular studies notably reveal that the temporal and spatial localization of LytB is governed by the interaction between specific modules of LytB and the final PASTA domain of StkP. Our data collectively provide a comprehensive understanding of how LytB performs the final separation of daughter cells and highlights the regulatory role of eukaryotic-like kinases on bacterial lytic machineries.
The work has been published in Cell Reports (https://doi.org/10.1016/j.celrep.2023.112756)
