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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月24日

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  • 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,
  • Raffaele Ieva

摘要

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.