Structural basis of lipopolysaccharide maturation by the O-antigen ligase

Khuram U. Ashraf, Rie Nygaard, Owen N. Vickery, Satchal K. Erramilli, Carmen M. Herrera, Thomas H. McConville, Vasileios I. Petrou, Sabrina I. Giacometti, Meagan Belcher Dufrisne, Kamil Nosol, Allen P. Zinkle, Chris L. B. Graham, Michael Loukeris, Brian Kloss, Karolina Skorupinska-Tudek, Ewa Swiezewska, David I. Roper, Oliver B. Clarke, Anne-Catrin Uhlemann, Anthony A. Kossiakoff, M. Stephen Trent (), Phillip J. Stansfeld () and Filippo Mancia ()
Additional contact information
Khuram U. Ashraf: Columbia University Irving Medical Center
Rie Nygaard: Columbia University Irving Medical Center
Owen N. Vickery: University of Warwick
Satchal K. Erramilli: University of Chicago
Carmen M. Herrera: University of Georgia
Thomas H. McConville: Columbia University Medical Center
Vasileios I. Petrou: New Jersey Medical School, Rutgers Biomedical Health Sciences
Sabrina I. Giacometti: Columbia University Irving Medical Center
Meagan Belcher Dufrisne: Columbia University Irving Medical Center
Kamil Nosol: University of Chicago
Allen P. Zinkle: Columbia University Irving Medical Center
Chris L. B. Graham: University of Warwick
Michael Loukeris: New York Structural Biology Center
Brian Kloss: New York Structural Biology Center
Karolina Skorupinska-Tudek: Polish Academy of Sciences
Ewa Swiezewska: Polish Academy of Sciences
David I. Roper: Columbia University Irving Medical Center
Oliver B. Clarke: Columbia University Irving Medical Center
Anne-Catrin Uhlemann: Columbia University Medical Center
Anthony A. Kossiakoff: University of Chicago
M. Stephen Trent: University of Georgia
Phillip J. Stansfeld: University of Warwick
Filippo Mancia: Columbia University Irving Medical Center

Nature, 2022, vol. 604, issue 7905, 371-376

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41586-022-04555-x

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