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

Li, Franco K.; Worrall, Liam J.; Gale, Robert T.; Brown, Eric D.; Strynadka, Natalie J.

doi:10.1126/sciadv.adj3864

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

Journal Article · 28 February 2024 · Science Advances

DOI: https://doi.org/10.1126/sciadv.adj3864 · OSTI ID:2470048

^[1]; Worrall, Liam J. ^[1]; Gale, Robert T. ^[2];

^[2];

^[1]

The University of British Columbia, Vancouver, BC (Canada)
McMaster University, Hamilton, ON (Canada)

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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF); National Institutes of Health (NIH)

Grant/Contract Number:: AC02-06CH11357; AC02-05CH11231

OSTI ID:: 2470048

Journal Information:: Science Advances, Journal Name: Science Advances Journal Issue: 9 Vol. 10; ISSN 2375-2548

Publisher:: AAASCopyright Statement

Country of Publication:: United States

Language:: English

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