Structural basis of lipopolysaccharide assembly by the outer membrane translocon holo-complex

Haoxiang Chen, Axel Siroy, Violette Morales, Dominik Gurvič, Yves Quentin, Stephanie Balor, Yassin A. Abuta’a, Maurine Marteau, Carine Froment, Anne Caumont-Sarcos, Julien Marcoux, Phillip J. Stansfeld (), Rémi Fronzes () and Raffaele Ieva ()
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Haoxiang Chen: Université de Toulouse, CNRS, Laboratoire de Microbiologie et Génétique Moléculaires (LMGM), Centre de Biologie Intégrative (CBI)
Axel Siroy: Institut Européen de Chimie et Biologie, Université de Bordeaux, CNRS, Microbiologie Fondamentale et Pathogénicité (MFP)
Violette Morales: Université de Toulouse, CNRS, Laboratoire de Microbiologie et Génétique Moléculaires (LMGM), Centre de Biologie Intégrative (CBI)
Dominik Gurvič: University of Warwick, School of Life Sciences and Department of Chemistry, Gibbet Hill Campus
Yves Quentin: Université de Toulouse, CNRS, Laboratoire de Microbiologie et Génétique Moléculaires (LMGM), Centre de Biologie Intégrative (CBI)
Stephanie Balor: Université de Toulouse, CNRS, METi, Centre de Biologie Intégrative (CBI)
Yassin A. Abuta’a: Université de Toulouse, CNRS, Laboratoire de Microbiologie et Génétique Moléculaires (LMGM), Centre de Biologie Intégrative (CBI)
Maurine Marteau: Université de Toulouse, CNRS, Laboratoire de Microbiologie et Génétique Moléculaires (LMGM), Centre de Biologie Intégrative (CBI)
Carine Froment: Université de Toulouse, CNRS, Institut de Pharmacologie et de Biologie Structurale (IPBS)
Anne Caumont-Sarcos: Université de Toulouse, CNRS, Laboratoire de Microbiologie et Génétique Moléculaires (LMGM), Centre de Biologie Intégrative (CBI)
Julien Marcoux: Université de Toulouse, CNRS, Institut de Pharmacologie et de Biologie Structurale (IPBS)
Phillip J. Stansfeld: University of Warwick, School of Life Sciences and Department of Chemistry, Gibbet Hill Campus
Rémi Fronzes: Institut Européen de Chimie et Biologie, Université de Bordeaux, CNRS, Microbiologie Fondamentale et Pathogénicité (MFP)
Raffaele Ieva: Université de Toulouse, CNRS, Laboratoire de Microbiologie et Génétique Moléculaires (LMGM), Centre de Biologie Intégrative (CBI)

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Lipopolysaccharide (LPS) assembly at the surfaces-exposed leaflet of the bacterial outer membrane (OM) is mediated by the OM LPS translocon. An essential transmembrane β-barrel protein, LptD, and a cognate lipoprotein, LptE, translocate LPS selectively into the OM external leaflet via a poorly understood mechanism. Here, we characterize two additional translocon subunits, the lipoproteins LptM and LptY (formerly YedD). We use single-particle cryo-EM analysis, functional assays and molecular dynamics simulations to visualize the roles of LptM and LptY at the translocon holo-complex LptDEMY, uncovering their impact on LptD conformational dynamics. Whereas LptY binds and stabilizes the periplasmic LptD β-taco domain that functions as LPS receptor, LptM intercalates the lateral gate of the β-barrel domain, promoting its opening and access by LPS. Remarkably, we demonstrate a conformational switch of the LptD β-taco/β-barrel interface alternating between contracted and extended states. β-strand 1 of LptD, which defines the mobile side of the lateral gate, binds LPS and performs a stroke movement toward the external leaflet during the contracted-to-extended state transition. Our findings support a detailed mechanistic framework explaining the selective transport of LPS to the membrane external leaflet.

Date: 2025
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DOI: 10.1038/s41467-025-65370-2

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