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Structural basis of lipopolysaccharide maturation by the WaaL O-antigen ligase

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Ashraf, Khuram U., Nygaard, Rie, Vickery, Owen N., Erramilli, Satchal K., Herrera, Carmen M., McConville, Thomas H., Petrou, Vasileios I., Giacometti, Sabrina I., Belcher Dufrisne, Meagan, Nosol, Kamil et al.
(2022) Structural basis of lipopolysaccharide maturation by the WaaL O-antigen ligase. Nature, 604 . pp. 371-376. doi:10.1038/s41586-022-04555-x ISSN 0028-0836.

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Official URL: https://doi.org/10.1038/s41586-022-04555-x

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Abstract

The outer membrane of Gram-negative bacteria has an external leaflet that is largely composed of lipopolysaccharide, which provides a selective permeation barrier, particularly against antimicrobials1. The final and crucial step in the biosynthesis of lipopolysaccharide is the addition of a species-dependent O-antigen to the lipid A core oligosaccharide, which is catalysed by the O-antigen ligase WaaL2. Here we present structures of WaaL from Cupriavidus metallidurans, both in the apo state and in complex with its lipid carrier undecaprenyl pyrophosphate, determined by single-particle cryo-electron microscopy. The structures reveal that WaaL comprises 12 transmembrane helices and a predominantly α-helical periplasmic region, which we show contains many of the conserved residues that are required for catalysis. We observe a conserved fold within the GT-C family of glycosyltransferases and hypothesize that they have a common mechanism for shuttling the undecaprenyl-based carrier to and from the active site. The structures, combined with genetic, biochemical, bioinformatics and molecular dynamics simulation experiments, offer molecular details on how the ligands come in apposition, and allows us to propose a mechanistic model for catalysis. Together, our work provides a structural basis for lipopolysaccharide maturation in a member of the GT-C superfamily of glycosyltransferases.

Item Type: Journal Article
Subjects: Q Science > QH Natural history > QH301 Biology
Q Science > QP Physiology
Divisions: Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- )
Library of Congress Subject Headings (LCSH): Endotoxins, Electron microscopy -- Technique, Electron microscopy -- Methodology, Glycosyltransferases, Molecular biology, OAntigen
Journal or Publication Title: Nature
Publisher: Nature Publishing
ISSN: 0028-0836
Official Date: 14 April 2022
Dates:
DateEvent
14 April 2022Published
6 April 2022Available
16 February 2022Accepted
Volume: 604
Page Range: pp. 371-376
DOI: 10.1038/s41586-022-04555-x
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Restricted or Subscription Access
Date of first compliant deposit: 21 February 2022
RIOXX Funder/Project Grant:
Project/Grant IDRIOXX Funder NameFunder ID
GM132120National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
AI150098National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
AI138576National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
AI129940National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
GM117372National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
GM116799 National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
U54 DK104309National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
T32 AI100852National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
K08 AI146284National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
208361/Z/17/ZWellcome Trusthttp://dx.doi.org/10.13039/100010269
MR/S009213/1[MRC] Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
BB/P01948X/1[BBSRC] Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
BB/R002517/1 [BBSRC] Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
BB/S003339/1[BBSRC] Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
EP/R029407/1[EPSRC] Engineering and Physical Sciences Research Councilhttp://dx.doi.org/10.13039/501100000266
EP/P020232/1 [EPSRC] Engineering and Physical Sciences Research Councilhttp://dx.doi.org/10.13039/501100000266
EP/T022108/1[EPSRC] Engineering and Physical Sciences Research Councilhttp://dx.doi.org/10.13039/501100000266
BB/M01116X/1 [BBSRC] Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
UNSPECIFIEDColumbia Universityhttp://dx.doi.org/10.13039/100006474
MR/N002679/1[MRC] Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
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