Defective lytic transglycosylase disrupts cell morphogenesis by hindering cell wall de-O-acetylation in N. meningitidis
- Institut Pasteur, France
- University of Wisconsin-Madison, United States
- Harvard Medical School, United States
Abstract
Lytic transglycosylases (LT) are enzymes involved in peptidoglycan (PG) remodeling. However, their contribution to cell wall-modifying complexes and their potential as antimicrobial drug targets remain unclear. Here, we determined a high-resolution structure of the LT, an outer membrane lipoprotein from Neisseria species with a disordered active site helix (alpha helix 30). We show that deletion of the conserved alpha-helix 30 interferes with the integrity of the cell wall, disrupts cell division, cell separation, and impairs the fitness of the human pathogen Neisseria meningitidis during infection. Additionally, deletion of alpha-helix 30 results in hyperacetylated PG, suggesting this LtgA variant affects the function of the PG de-O-acetylase (Ape 1). Our study revealed that Ape 1 requires LtgA for optimal function, demonstrating that LTs can modulate the activity of their protein-binding partner. We show that targeting specific domains in LTs can be lethal, which opens the possibility that LTs are useful drug-targets.
Data availability
Data Availability: Coordinates and structural data have been submitted to the Protein Data Bank under the accession code 6H5F.
Article and author information
Author details
Allison Hillary Williams
Funding
European Molecular Biology Organization (ALTF 732-2010)
- Allison Hillary Williams
European Research Council (PGN from SHAPE to VIR 202283)
- Ivo Gomperts Boneca
Fondation pour la Recherche Médicale (DBF20160635726)
- Ivo Gomperts Boneca
Institut Carnot-Pasteur (Maladies Infectious fellowship)
- Allison Hillary Williams
Institut Carnot Pasteur Microbes and Sante
- Ignacio Santecchia
Fondation pour la Recherche Médicale (FDT201805005258)
- Ignacio Santecchia
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Animal work in this study was carried out at the Institut Pasteur in strict accordance with the European Union Directive 2010/63/EU (and its revision 86/609/EEC) on the protection of animals used for scientific purposes. The laboratory at the Institut Pasteur has the administrative authorization for animal experimentation (Permit Number 75-1554) and the protocol was approved by the Institut Pasteur Review Board that is part of the Regional Committee of Ethics of Animal Experiments of Paris Region (Permit Number: 99-174). All the invasive procedures were performed under anesthesia and all possible efforts were made to minimize animal suffering.
Copyright
© 2020, Williams et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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