Cryo-EM analysis of S. aureus TarL, a polymerase in wall teichoic acid biogenesis central to virulence and antibiotic resistance

Sci Adv. 2024 Mar;10(9):eadj3864. doi: 10.1126/sciadv.adj3864. Epub 2024 Feb 28.

Abstract

Wall teichoic acid (WTA), a covalent adduct of Gram-positive bacterial cell wall peptidoglycan, contributes directly to virulence and antibiotic resistance in pathogenic species. Polymerization of the Staphylococcus aureus WTA ribitol-phosphate chain is catalyzed by TarL, a member of the largely uncharacterized TagF-like family of membrane-associated enzymes. We report the cryo-electron microscopy structure of TarL, showing a tetramer that forms an extensive membrane-binding platform of monotopic helices. TarL is composed of an amino-terminal immunoglobulin-like domain and a carboxyl-terminal glycosyltransferase-B domain for ribitol-phosphate polymerization. The active site of the latter is complexed to donor substrate cytidine diphosphate-ribitol, providing mechanistic insights into the catalyzed phosphotransfer reaction. Furthermore, the active site is surrounded by electropositive residues that serve to retain the lipid-linked acceptor for polymerization. Our data advance general insight into the architecture and membrane association of the still poorly characterized monotopic membrane protein class and present molecular details of ribitol-phosphate polymerization that may aid in the design of new antimicrobials.

MeSH terms

  • Cryoelectron Microscopy
  • Drug Resistance, Microbial
  • Methicillin-Resistant Staphylococcus aureus* / metabolism
  • Phosphates / metabolism
  • Ribitol / metabolism
  • Staphylococcus aureus* / metabolism
  • Teichoic Acids / analysis
  • Teichoic Acids / chemistry
  • Teichoic Acids / metabolism
  • Virulence

Substances

  • Ribitol
  • Teichoic Acids
  • Phosphates